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1
Scherler, Laeticia, Sofia N. Verouti, Daniel Ackermann, Bruno Vogt, and Geneviève Escher. "Adenine-Induced Nephropathy Reduces Atherosclerosis in ApoE Knockout Mice." Biomolecules 12, no. 8 (August 19, 2022): 1147. http://dx.doi.org/10.3390/biom12081147.
Повний текст джерелаАнотація:
Background: Cardiovascular events are the main cause of death in patients with chronic kidney disease. We hypothesize that the protective effects of renal cholesterol and vitamin D3 metabolism are lost under this condition. Nephropathy was induced by adenine in Apolipoprotein E knockout mice. The atherosclerotic phenotype was compared to mice with normal renal function. Methods: Mice were fed a western diet ±0.15% adenine. Urine and feces were collected to assess renal function and fecal output. Atherosclerosis, serum lipoprotein composition and functionality, hepatic lipids, and expression of genes involved in lipid metabolism, vitamin D3 and Na+ homeostasis, were assessed. Bones were analyzed by microCT. Results: Mice fed with adenine showed enhanced urinary Na+, Ca2+, and Pi excretion, reduced urinary pH, UreaUrine/UreaSerum, and CreatinineUrine/CreatinineSerum ratios. They developed less atherosclerosis. Lipoproteins in serum and hepatic lipids remained unchanged. Cholesterol efflux increased. Fecal output of cholesteryl ester and triglycerides increased. In the liver, mRNA levels of Cyp27a1, Cyp7a1, and Scarb1 increased; in the kidneys, Slc9a3, Slc12a3, Vdr, and Cyp24a1 decreased. Adenine increased cholesterol efflux in vitro. Tibias were shorter. Conclusion: Adenine induced tubular damage and was athero-protective because of enhanced cholesterol efflux and lipids elimination in feces. Bone growth was also affected.
2
Yasuda, Kaori, Miyu Nishikawa, Kairi Okamoto, Kyohei Horibe, Hiroki Mano, Mana Yamaguchi, Risa Okon, et al. "Elucidation of metabolic pathways of 25-hydroxyvitamin D3 mediated by CYP24A1 and CYP3A using Cyp24a1 knockout rats generated by CRISPR/Cas9 system." Journal of Biological Chemistry 296 (January 2021): 100668. http://dx.doi.org/10.1016/j.jbc.2021.100668.
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3
Christakos, Sylvia, Puneet Dhawan, Annemieke Verstuyf, Lieve Verlinden, and Geert Carmeliet. "Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects." Physiological Reviews 96, no. 1 (January 2016): 365–408. http://dx.doi.org/10.1152/physrev.00014.2015.
Повний текст джерелаАнотація:
1,25-Dihydroxvitamin D3 [1,25(OH)2D3] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH)2D3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH)2D3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.
4
Girgis, Christian M., Nancy Mokbel, Kuan Minn Cha, Peter J. Houweling, Myriam Abboud, David R. Fraser, Rebecca S. Mason, Roderick J. Clifton-Bligh, and Jenny E. Gunton. "The Vitamin D Receptor (VDR) Is Expressed in Skeletal Muscle of Male Mice and Modulates 25-Hydroxyvitamin D (25OHD) Uptake in Myofibers." Endocrinology 155, no. 9 (September 1, 2014): 3227–37. http://dx.doi.org/10.1210/en.2014-1016.
Повний текст джерелаАнотація:
Abstract Vitamin D deficiency is associated with a range of muscle disorders, including myalgia, muscle weakness, and falls. In humans, polymorphisms of the vitamin D receptor (VDR) gene are associated with variations in muscle strength, and in mice, genetic ablation of VDR results in muscle fiber atrophy and motor deficits. However, mechanisms by which VDR regulates muscle function and morphology remain unclear. A crucial question is whether VDR is expressed in skeletal muscle and directly alters muscle physiology. Using PCR, Western blotting, and immunohistochemistry (VDR-D6 antibody), we detected VDR in murine quadriceps muscle. Detection by Western blotting was dependent on the use of hyperosmolar lysis buffer. Levels of VDR in muscle were low compared with duodenum and dropped progressively with age. Two in vitro models, C2C12 and primary myotubes, displayed dose- and time-dependent increases in expression of both VDR and its target gene CYP24A1 after 1,25(OH)2D (1,25 dihydroxyvitamin D) treatment. Primary myotubes also expressed functional CYP27B1 as demonstrated by luciferase reporter studies, supporting an autoregulatory vitamin D-endocrine system in muscle. Myofibers isolated from mice retained tritiated 25-hydroxyvitamin D3, and this increased after 3 hours of pretreatment with 1,25(OH)2D (0.1nM). No such response was seen in myofibers from VDR knockout mice. In summary, VDR is expressed in skeletal muscle, and vitamin D regulates gene expression and modulates ligand-dependent uptake of 25-hydroxyvitamin D3 in primary myofibers.
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Kurihara, Noriyoshi, Yukiko Kitagawa, Yuji Inagaki, Jolene J. Windle, John M. Chirgwin, and G. David Roodman. "TAF12 Enhances the Biological Reponses of Myeloma Cells to Low Concentrations of 1,25-(OH)2dvitamin D3." Blood 124, no. 21 (December 6, 2014): 2066. http://dx.doi.org/10.1182/blood.v124.21.2066.2066.
Повний текст джерелаАнотація:
Abstract Multiple myeloma (MM) is currently incurable, and its associated bone destruction is a major source of morbidity that significantly contributes to patient mortality. Development of novel treatments for MM is imperative, since myeloma patients continue to relapse and suffer the consequences of the bone disease, even when they are in remission. Thus new targets for treating and preventing MM induced bone destruction are needed. We found that TAF12 is highly expressed in CD138+ primary MM cells and bone marrow stromal cells (BMSC) from MM patients compared to their normal counterparts. TAF12 acts as a co-activator of VDR, that permits very low concentrations of 1,25-(OH)2D3 or analogs that bind VDR to enhance MM cell growth and bone destruction. The molecular responses of myeloma cells to vitamin D are unknown, as are its effects on the marrow microenvironment and myeloma bone disease. To assess the role of TAF12 in MM, we co-cultured JJN3 myeloma cell line with the human BMSC cell line (SAKA-T). The experiments showed that MM cells directly upregulates TAF12 in SAKA-T cells; this increase in TAF12 was mediated by IL-6 secreted by MM cells. Co-culture of MM cells with BMSC from TAF12 heterozygous knockout mice (TAF12+/-) blocked VCAM1 induction and the enhanced MM cell growth and osteoclast (OCL) formation in response to physiologic levels 1,25-(OH)2D3 (10-10 M) induced by BMSC. Thus, TAF12 plays an important role in increased cytokine production and adhesive interactions of MM cells/ BMSC induced by 1,25-(OH)2D3. We determined the role of TAF12 in the sensitivity of several MM cell lines to physiological concentrations of 1,25-(OH)2D3. TAF12 expression was tested in MM cell lines (MM1.S, JJN3, ANBL6, RPMI8226, U266 and OPM2). Five of 6 cell lines (except RPMI8226) expressed high levels of TAF12. In 3 of these five, 1,25-(OH)2D3 increasedRANKL. Interestingly, both MM1.S and JJN3 cells produced RANKL at very low concentrations of 1,25-(OH)2D3 (10-12-10-10 M), which also induced VEGF, DKK-1 and α4 integrin. To further investigate the mechanisms responsible the effects of low concentrations of 1,25-(OH)2D3 mediated by TAF12 in MM, we stably knocked-down (k/d) TAF12 in JJN3 myeloma cells using a TAF12 shRNA lentivirus (TAF12k/d-JJN3). The TAF12k/d-JJN3 cells demonstrated about 80% reduction in TAF12 protein. JJN3-Wt cells treated with 10-8M 1,25-(OH)2D3 increased CYP24A1 mRNA levels 60 fold compared to untreated cells. In contrast, CYP24A1 mRNA in TAF12k/d-JJN3 cells was not significantly induced even when treated with 10-8 M of 1,25-(OH)2D3. ChIP analysis using an anti-VDR or TAF12 antibody and primers flanking the two VDREs in the CYP24A1 promoter showed that 1,25-(OH)2D3 induced VDR and TAF12 binding to the CYP24A1 promoter in JJN3-Wt cells. In contrast, basal and induced levels of VDR binding were much lower in TAF12k/d-JJN3 cells. Further, VDR content in TAF12k/d-JJN3 cells treated with 1,25-(OH)2D3 (10-10-10-8M) was markedly decreased compared to JJN3-Wt cells. VDR content was quantified by Western blot. In addition, RANKL, VEGF, DKK1 and α4 integrin production by TAF12k/d-JJN3 cells treated with10-10 M of 1,25-(OH)2D3 were decreased 60% compared to JJN3-Wt cells. These results demonstrate that increased TAF12 in MM cells enhances transcriptional responses of a subset of VDR target genes, leading to hyper-responsivity to 1,25-(OH)2D3 in MM cells - suggesting that TAF12 is a potential therapeutic target for MM and MM bone disease. Disclosures Roodman: Eli Lilly and Co.: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.
6
Kono, Hiroshi, Blair U. Bradford, Ming Yin, Kathleen K. Sulik, Dennis R. Koop, Jeffrey M. Peters, Frank J. Gonzalez, et al. "CYP2E1 is not involved in early alcohol-induced liver injury." American Journal of Physiology-Gastrointestinal and Liver Physiology 277, no. 6 (December 1, 1999): G1259—G1267. http://dx.doi.org/10.1152/ajpgi.1999.277.6.g1259.
Повний текст джерелаАнотація:
The continuous intragastric enteral feeding protocol in the rat was a major development in alcohol-induced liver injury (ALI) research. Much of what has been learned to date involves inhibitors or nutritional manipulations that may not be specific. Knockout technology avoids these potential problems. Therefore, we used long-term intragastric cannulation in mice to study early ALI. Reactive oxygen species are involved in mechanisms of early ALI; however, their key source remains unclear. Cytochrome P-450 (CYP)2E1 is induced predominantly in hepatocytes by ethanol and could be one source of reactive oxygen species leading to liver injury. We aimed to determine if CYP2E1 was involved in ALI by adapting the enteral alcohol (EA) feeding model to CYP2E1 knockout (−/−) mice. Female CYP2E1 wild-type (+/+) or −/− mice were given a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin as control continuously for 4 wk. All mice gained weight steadily over 4 wk, and there were no significant differences between groups. There were also no differences in ethanol elimination rates between CYP2E1 +/+ and −/− mice after acute ethanol administration to naive mice or mice receiving EA for 4 wk. However, EA stimulated rates 1.4-fold in both groups. EA elevated serum aspartate aminotransferase levels threefold to similar levels over control in both CYP2E1 +/+ and −/− mice. Liver histology was normal in control groups. In contrast, mice given ethanol developed mild steatosis, slight inflammation, and necrosis; however, there were no differences between the CYP2E1 +/+ and −/− groups. Chronic EA induced other CYP families (CYP3A, CYP2A12, CYP1A, and CYP2B) to the same extent in CYP2E1 +/+ and −/− mice. Furthermore, POBN radical adducts were also similar in both groups. Data presented here are consistent with the hypothesis that oxidants from CYP2E1 play only a small role in mechanisms of early ALI in mice. Moreover, this new mouse model illustrates the utility of knockout technology in ALI research.
7
Snyder, Jessica M., Guo Zhong, Cathryn Hogarth, Weize Huang, Traci Topping, Jeffrey LaFrance, Laura Palau, et al. "Knockout of Cyp26a1 and Cyp26b1 during postnatal life causes reduced lifespan, dermatitis, splenomegaly, and systemic inflammation in mice." FASEB Journal 34, no. 12 (October 26, 2020): 15788–804. http://dx.doi.org/10.1096/fj.202001734r.
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8
Zong, Haihong, Michal Armoni, Chava Harel, Eddy Karnieli, and Jeffrey E. Pessin. "Cytochrome P-450 CYP2E1 knockout mice are protected against high-fat diet-induced obesity and insulin resistance." American Journal of Physiology-Endocrinology and Metabolism 302, no. 5 (March 1, 2012): E532—E539. http://dx.doi.org/10.1152/ajpendo.00258.2011.
Повний текст джерелаАнотація:
Conventional (whole body) CYP2E1 knockout mice displayed protection against high-fat diet-induced weight gain, obesity, and hyperlipidemia with increased energy expenditure despite normal food intake and spontaneous locomotor activity. In addition, the CYP2E1 knockout mice displayed a marked improvement in glucose tolerance on both normal chow and high-fat diets. Euglycemic-hyperinsulinemic clamps demonstrated a marked protection against high-fat diet-induced insulin resistance in CYP2E1 knockout mice, with enhanced adipose tissue glucose uptake and insulin suppression of hepatic glucose output. In parallel, adipose tissue was protected against high-fat diet-induced proinflammatory cytokine production. Taken together, these data demonstrate that the CYP2E1 deletion protects mice against high-fat diet-induced insulin resistance with improved glucose homeostasis in vivo.
9
Escher, Geneviève, Isabelle Vögeli, Robert Escher, Robert C. Tuckey, Sandra Erickson, Zygmunt Krozowski, and Felix J. Frey. "Role of CYP27A1 in progesterone metabolism in vitro and in vivo." American Journal of Physiology-Endocrinology and Metabolism 297, no. 4 (October 2009): E949—E955. http://dx.doi.org/10.1152/ajpendo.00298.2009.
Повний текст джерелаАнотація:
In the kidney, progesterone is inactivated to 20α-dihydro-progesterone (20α-DH-progesterone) to protect the mineralocorticoid receptor from progesterone excess. In an attempt to clone the enzyme with 20α-hydroxysteroid activity using expression cloning in CHOP cells and a human kidney expression library, serendipitously cDNA encoding CYP27A1 was isolated. Overexpression of CYP27A1 in CHOP cells decreased progesterone conversion to 20α-DH-progesterone in a dose-dependent manner, an effect enhanced by cotransfection with adrenodoxin and adrenodoxin reductase. Incubation of CHOP cells with 27-hydroxycholesterol, a product of CYP27A1, increased the ratio of progesterone to 20α-DH-progesterone in a concentration-dependent manner, indicating that the effect of CYP27A1 overexpression was mediated by 27-hydroxycholesterol. To analyze whether these observations are relevant in vivo, progesterone and 20α-DH-progesterone were measured by gas chromatography-mass spectometry in 24-h urine of CYP27A1 gene knockout (ko) mice and their control wild-type and heterozygote littermates. In CYP27A1 ko mice, urinary progesterone concentrations were decreased, 20α-DH-progesterone increased, and the progesterone-to-20α-DH-progesterone ratio decreased threefold ( P < 0.001). Thus CYP27A1 modulates progesterone concentrations. The underlying mechanism is inhibition of 20α-hydroxysteroid dehydrogenase by 27-hydroxycholesterol.
10
Ding, Lili, Eryun Zhang, Qiaoling Yang, Lihua Jin, Kyle M. Sousa, Bingning Dong, Yangmeng Wang, et al. "Vertical sleeve gastrectomy confers metabolic improvements by reducing intestinal bile acids and lipid absorption in mice." Proceedings of the National Academy of Sciences 118, no. 6 (February 1, 2021): e2019388118. http://dx.doi.org/10.1073/pnas.2019388118.
Повний текст джерелаАнотація:
Vertical sleeve gastrectomy (VSG) is one of the most effective and durable therapies for morbid obesity and its related complications. Although bile acids (BAs) have been implicated as downstream mediators of VSG, the specific mechanisms through which BA changes contribute to the metabolic effects of VSG remain poorly understood. Here, we confirm that high fat diet-fed global farnesoid X receptor (Fxr) knockout mice are resistant to the beneficial metabolic effects of VSG. However, the beneficial effects of VSG were retained in high fat diet-fed intestine- or liver-specific Fxr knockouts, and VSG did not result in Fxr activation in the liver or intestine of control mice. Instead, VSG decreased expression of positive hepatic Fxr target genes, including the bile salt export pump (Bsep) that delivers BAs to the biliary pathway. This reduced small intestine BA levels in mice, leading to lower intestinal fat absorption. These findings were verified in sterol 27-hydroxylase (Cyp27a1) knockout mice, which exhibited low intestinal BAs and fat absorption and did not show metabolic improvements following VSG. In addition, restoring small intestinal BA levels by dietary supplementation with taurocholic acid (TCA) partially blocked the beneficial effects of VSG. Altogether, these findings suggest that reductions in intestinal BAs and lipid absorption contribute to the metabolic benefits of VSG.
11
Zurkinden, Line, Yosef T. Mansour, Beatrice Rohrbach, Bruno Vogt, Hiten D. Mistry, and Geneviève Escher. "Hepatic caveolin‐1 is enhanced in Cyp27a1/ApoE double knockout mice." FEBS Open Bio 6, no. 10 (September 26, 2016): 1025–35. http://dx.doi.org/10.1002/2211-5463.12123.
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Zurkinden, Line, Curzio Solca, Isabelle A. Vögeli, Bruno Vogt, Daniel Ackermann, Sandra K. Erickson, Felix J. Frey, Dmitri Sviridov, and Geneviève Escher. "Effect of Cyp27A1 gene dosage on atherosclerosis development in ApoE‐knockout mice." FASEB Journal 28, no. 3 (December 10, 2013): 1198–209. http://dx.doi.org/10.1096/fj.13-233791.
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MacLean, Glenn, Hui Li, Daniel Metzger, Pierre Chambon, and Martin Petkovich. "Apoptotic Extinction of Germ Cells in Testes of Cyp26b1 Knockout Mice." Endocrinology 148, no. 10 (October 1, 2007): 4560–67. http://dx.doi.org/10.1210/en.2007-0492.
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Reinke, Daniel C., Masakazu Kogawa, Kate R. Barratt, Howard A. Morris, Paul H. Anderson, and Gerald J. Atkins. "Evidence for altered osteoclastogenesis in splenocyte cultures from Cyp27b1 knockout mice." Journal of Steroid Biochemistry and Molecular Biology 164 (November 2016): 353–60. http://dx.doi.org/10.1016/j.jsbmb.2015.11.015.
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Correia, Maria Almira, and Doyoung Kwon. "Why Hepatic CYP2E1-Elevation by Itself Is Insufficient for Inciting NAFLD/NASH: Inferences from Two Genetic Knockout Mouse Models." Biology 9, no. 12 (November 26, 2020): 419. http://dx.doi.org/10.3390/biology9120419.
Повний текст джерелаАнотація:
Hepatic cytochrome P450 CYP2E1 is an enzyme engaged in the metabolic biotransformation of various xenobiotics and endobiotics, resulting in both detoxification and/or metabolic activation of its substrates to more therapeutic or toxic products. Elevated hepatic CYP2E1 content is implicated in various metabolic diseases including alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), diabetes and obesity. While hepatic CYP2E1 elevation is considered essential to the pathogenesis of these liver diseases, our findings in two mouse models of E3 ubiquitin ligase genetic ablation fed a regular lab chow diet, argue that it is not sufficient for triggering NAFLD/NASH. Thus, albeit comparable hepatic CYP2E1 elevation and functional stabilization in these two models upon E3 ubiquitin ligase genetic ablation and consequent disruption of its ubiquitin-dependent proteasomal degradation, NAFLD/NASH was only observed in the mouse livers that exhibited concurrent SREBP1c-transcriptional upregulation of hepatic lipogenesis. These findings reinforce the critical complicity of an associated prolipogenic scenario induced by either an inherently upregulated hepatic lipogenesis or a high fat/high carbohydrate diet in CYP2E1-mediated NAFLD/NASH.
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Alhasson, Firas, Diptadip Dattaroy, Suvarthi Das, Varun Chandrashekaran, Ratanesh Kumar Seth, Rick G. Schnellmann, and Saurabh Chatterjee. "NKT cell modulates NAFLD potentiation of metabolic oxidative stress-induced mesangial cell activation and proximal tubular toxicity." American Journal of Physiology-Renal Physiology 310, no. 1 (January 1, 2016): F85—F101. http://dx.doi.org/10.1152/ajprenal.00243.2015.
Повний текст джерелаАнотація:
Obesity and nonalcoholic fatty liver disease (NAFLD) are associated with the development and progression of chronic kidney disease. We recently showed that NAFLD induces liver-specific cytochrome P-450 (CYP)2E1-mediated metabolic oxidative stress after administration of the CYP2E1 substrate bromodichloromethane (BDCM) (Seth RK, Das S, Kumar A, Chanda A, Kadiiska MB, Michelotti G, Manautou J, Diehl AM, Chatterjee S. Toxicol Appl Pharmacol 274: 42–54, 2014; Seth RK, Kumar A, Das S, Kadiiska MB, Michelotti G, Diehl AM, Chatterjee S. Toxicol Sci 134:291–303, 2013). The present study examined the effects of CYP2E1-mediated oxidative stress in NAFLD leading to kidney toxicity. Mice were fed a high-fat diet for 12 wk to induce NAFLD. NAFLD mice were exposed to BDCM, a CYP2E1 substrate, for 4 wk. NAFLD + BDCM increased CYP2E1-mediated lipid peroxidation in proximal tubular cells compared with mice with NAFLD alone or BDCM-treated lean mice, thus ruling out the exclusive role of BDCM. Lipid peroxidation increased IL-1β, TNF-α, and interferon-γ. In parallel, mesangial cell activation was observed by increased α-smooth muscle actin and transforming growth factor-β, which was blocked by the CYP2E1 inhibitor diallyl sulphide both in vivo and in vitro. Mice lacking natural killer T cells (CD1d knockout mice) showed elevated (>4-fold) proinflammatory mediator release, increased Toll-like receptor (TLR)4 and PDGF2 mRNA, and mesangial cell activation in the kidney. Finally, NAFLD CD1D knockout mice treated with BDCM exhibited increased high mobility group box 1 and Fas ligand levels and TUNEL-positive nuclei, indicating that higher cell death was attenuated in TLR4 knockout mice. Tubular cells showed increased cell death and cytokine release when incubated with activated mesangial cells. In summary, an underlying condition of progressive NAFLD causes renal immunotoxicity and aberrant glomerular function possibly through high mobility group box 1-dependent TLR4 signaling and mesangial cell activation, which, in turn, is modulated by intrinsic CD1D-dependent natural killer T cells.
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Rowling, Matthew J., Christy Gliniak, JoEllen Welsh, and James C. Fleet. "High Dietary Vitamin D Prevents Hypocalcemia and Osteomalacia in CYP27B1 Knockout Mice." Journal of Nutrition 137, no. 12 (December 1, 2007): 2608–15. http://dx.doi.org/10.1093/jn/137.12.2608.
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Langton, Simne, and Lorraine J. Gudas. "CYP26A1 knockout embryonic stem cells exhibit reduced differentiation and growth arrest in response to retinoic acid." Developmental Biology 315, no. 2 (March 2008): 331–54. http://dx.doi.org/10.1016/j.ydbio.2007.12.021.
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Zurkinden, L., D. Sviridov, S. K. Erickson, B. Vogt, and G. Escher. "701 EFFECT OF HEPATIC CYP7A1 AND CYP3A11 MODULATION ON ATHEROSCLEROSIS IN cyp27A1/apoE DOUBLE KNOCKOUT MICE." Journal of Hepatology 58 (April 2013): S284. http://dx.doi.org/10.1016/s0168-8278(13)60703-5.
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Hirota, Yoshihisa, Kimie Nakagawa, Keigo Isomoto, Toshiyuki Sakaki, Noboru Kubodera, Maya Kamao, Naomi Osakabe, Yoshitomo Suhara, and Toshio Okano. "Eldecalcitol is more effective in promoting osteogenesis than alfacalcidol in Cyp27b1-knockout mice." PLOS ONE 13, no. 10 (October 3, 2018): e0199856. http://dx.doi.org/10.1371/journal.pone.0199856.
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Ye, Huanying, Danjuan Sui, Wei Liu, Yuannan Yuan, Zhen Ouyang, and Yuan Wei. "Effects of CYP2C11 gene knockout on the pharmacokinetics and pharmacodynamics of warfarin in rats." Xenobiotica 49, no. 12 (February 27, 2019): 1478–84. http://dx.doi.org/10.1080/00498254.2019.1579006.
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Wu, Di, Mingjuan Gu, Zhuying Wei, Chunling Bai, Guanghua Su, Xuefei Liu, Yuefang Zhao, Lei Yang, and Guangpeng Li. "Myostatin Knockout Regulates Bile Acid Metabolism by Promoting Bile Acid Synthesis in Cattle." Animals 12, no. 2 (January 15, 2022): 205. http://dx.doi.org/10.3390/ani12020205.
Повний текст джерелаАнотація:
Myostatin (MSTN) is a major negative regulator of skeletal muscle mass and causes a variety of metabolic changes. However, the effect of MSTN knockout on bile acid metabolism has rarely been reported. In this study, the physiological and biochemical alterations of serum in MSTN+/− and wild type (WT) cattle were investigated. There were no significant changes in liver and kidney biochemical indexes. However, compared with the WT cattle, lactate dehydrogenase, total bile acid (TBA), cholesterol, and high-density lipoprotein (HDL) in the MSTN+/− cattle were significantly increased, and glucose, low-density lipoprotein (LDL), and triglycerides (TG) were significantly decreased, indicating that MSTN knockout affected glucose and lipid metabolism and total bile acids content. Targeted metabolomic analysis of the bile acids and their derivatives was performed on serum samples and found that bile acids were significantly increased in the MSTN+/− cattle compared with the WT cattle. As the only bile acid synthesis organ in the body, we performed metabolomic analysis on the liver to study the effect of MSTN knockout on hepatic metabolism. Metabolic pathway enrichment analysis of differential metabolites showed significant enrichment of the primary bile acid biosynthesis and bile secretion pathway in the MSTN+/− cattle. Targeted metabolomics data further showed that MSTN knockout significantly increased bile acid content in the liver, which may have resulted from enhanced bile acid synthesis due to the expression of bile acid synthesis genes, cholesterol 7 alpha-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), and upregulation in the liver of the MSTN+/− cattle. These results indicate that MSTN knockout does not adversely affect bovine fitness but regulates bile acid metabolism via enhanced bile acid synthesis. This further suggests a role of MSTN in regulating metabolism.
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Kovacs, Werner J., Janis E. Shackelford, Khanichi N. Tape, Michael J. Richards, Phyllis L. Faust, Steven J. Fliesler, and Skaidrite K. Krisans. "Disturbed Cholesterol Homeostasis in a Peroxisome-Deficient PEX2 Knockout Mouse Model." Molecular and Cellular Biology 24, no. 1 (January 1, 2004): 1–13. http://dx.doi.org/10.1128/mcb.24.1.1-13.2004.
Повний текст джерелаАнотація:
ABSTRACT We evaluated the major pathways of cholesterol regulation in the peroxisome-deficient PEX2 −/− mouse, a model for Zellweger syndrome. Zellweger syndrome is a lethal inherited disorder characterized by severe defects in peroxisome biogenesis and peroxisomal protein import. Compared with wild-type mice, PEX2 −/− mice have decreased total and high-density lipoprotein cholesterol levels in plasma. Hepatic expression of the SREBP-2 gene is increased 2.5-fold in PEX2 −/− mice and is associated with increased activities and increased protein and expression levels of SREBP-2-regulated cholesterol biosynthetic enzymes. However, the upregulated cholesterogenic enzymes appear to function with altered efficiency, associated with the loss of peroxisomal compartmentalization. The rate of cholesterol biosynthesis in 7- to 9-day-old PEX2 −/− mice is markedly increased in most tissues, except in the brain and kidneys, where it is reduced. While the cholesterol content of most tissues is normal in PEX2 −/− mice, in the knockout mouse liver it is decreased by 40% relative to that in control mice. The classic pathway of bile acid biosynthesis is downregulated in PEX2 −/− mice. However, expression of CYP27A1, the rate-determining enzyme in the alternate pathway of bile acid synthesis, is upregulated threefold in the PEX2 −/− mouse liver. The expression of hepatic ATP-binding cassette (ABC) transporters (ABCA1 and ABCG1) involved in cholesterol efflux is not affected in PEX2 −/− mice. These data illustrate the diversity in cholesterol regulatory responses among different organs in postnatal peroxisome-deficient mice and demonstrate that peroxisomes are critical for maintaining cholesterol homeostasis in the neonatal mouse.
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Chen, Xue, Stephen C. Ward, Arthur I. Cederbaum, Huabao Xiong та Yongke Lu. "Alcoholic fatty liver is enhanced in CYP2A5 knockout mice: The role of the PPARα-FGF21 axis". Toxicology 379 (березень 2017): 12–21. http://dx.doi.org/10.1016/j.tox.2017.01.016.
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ALHASSON, FIRAS A., SUVARTHI DAS, Varun Chandrashekaran, Diptadip Dattaroy, Ratanesh Kumar Seth, Mitzi Nagarkatti, Prakash Nagarkatti, and Saurabh Chatterjee. "Adipokine Leptin mediated NOX-2 promotes kidney inflammation in nonalcoholic fatty liver disease via miR21-dependent mesangial cell immune activation." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 197.16. http://dx.doi.org/10.4049/jimmunol.198.supp.197.16.
Повний текст джерелаАнотація:
Abstract High insulin and leptin resistance followed by underlying inflammation is often ascribed to the ectopic manifestations in nonalcoholic fatty liver disease (NAFLD) but the exact molecular pathways remain unclear. We have shown previously that CYP2E1-mediated oxidative stress and circulating leptin in NAFLD is associated with renal disease severity. Extending the studies, we hypothesized that high circulatory leptin in NAFLD causes renal mesangial cell activation and tubular inflammation via a NOX2 dependent pathway that upregulates proinflammatorymiR21. High fat diet (60%kcal) was used to induce fatty liver phenotype with parallel insulin and leptin resistance in WT, Leptin knockout (ob/ob) and p47 phox knockout mice. Kidneys were collected after pathology showed NASH-like phenotype and accelerated oxidative stress in the liver. The kidneys were probed for mesangial cell activation and tubular inflammation. Results showed that NAFLD kidneys had significant increases in α-SMA, a marker of mesangial cell activation, miR21 levels, tyrosine nitration and renal inflammation while they were significantly decreased in leptin and p47 phox knockout mice. Micro RNA21 knockout mice showed decreased tubular immunotoxicity and proinflammatory mediator release. Mechanistically, use of apocynin or phenyl boronic acid (FBA) or DMPO or miR21 antagomir inhibited leptin primed-miR21-mediated mesangial cell activation in vitro suggesting a direct role of leptin-mediated NOX-2 in miR21-mediated mesangial cell activation. Finally JAK-STAT inhibitor completely abrogated the mesangial cell activation in leptin-primed cells suggesting that leptin signaling in the mesangial cells depended on the JAK-STAT pathway.
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Nishikawa, Miyu, Kaori Yasuda, Masashi Takamatsu, Keisuke Abe, Kimie Nakagawa, Naoko Tsugawa, Yoshihisa Hirota, et al. "Generation of 1,25-dihydroxyvitamin D3 in Cyp27b1 knockout mice by treatment with 25-hydroxyvitamin D3 rescued their rachitic phenotypes." Journal of Steroid Biochemistry and Molecular Biology 185 (January 2019): 71–79. http://dx.doi.org/10.1016/j.jsbmb.2018.07.012.
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Farhan, Fahad, Mohammad Almarhoun, Aileen Wong, Amy S. Findlay, Chris Bartholomew, Mark T. S. Williams, Toby W. Hurd, and Xinhua Shu. "Deletion of TSPO Causes Dysregulation of Cholesterol Metabolism in Mouse Retina." Cells 10, no. 11 (November 7, 2021): 3066. http://dx.doi.org/10.3390/cells10113066.
Повний текст джерелаАнотація:
Cholesterol dysregulation has been implicated in age-related macular degeneration (AMD), the most common cause of visual impairment in the elderly. The 18 KDa translocator protein (TSPO) is a mitochondrial outer membrane protein responsible for transporting cholesterol from the mitochondrial outer membrane to the inner membrane. TSPO is highly expressed in retinal pigment epithelial (RPE) cells, and TSPO ligands have shown therapeutic potential for the treatment of AMD. Here, we characterized retinal pathology of Tspo knockout (KO) mice using histological, immunohistochemical, biochemical and molecular biological approaches. We found that Tspo KO mice had normal retinal morphology (by light microscopy) but showed elevated levels of cholesterol, triglycerides and phospholipids with perturbed cholesterol efflux in the RPE cells of Tspo KO mice. Expression of cholesterol-associated genes (Nr1h3, Abca1, Abcg1, Cyp27a1 and Cyp46a1) was significantly downregulated, and production of pro-inflammatory cytokines was markedly increased in Tspo KO retinas. Furthermore, microglial activation was also observed in Tspo KO mouse retinas. These findings provide new insights into the function of TSPO in the retina and may aid in the design of new therapeutic strategies for the treatment of AMD.
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Hirota, Yoshihisa, Kimie Nakagawa, Shino Mimatsu, Natsumi Sawada, Toshiyuki Sakaki, Noboru Kubodera, Maya Kamao, Naoko Tsugawa, Yoshitomo Suhara та Toshio Okano. "Nongenomic effects of 1α,25-dihydroxyvitamin D 3 on cartilage formation deduced from comparisons between Cyp27b1 and Vdr knockout mice". Biochemical and Biophysical Research Communications 483, № 1 (січень 2017): 359–65. http://dx.doi.org/10.1016/j.bbrc.2016.12.139.
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Song, Yurong, and James C. Fleet. "Intestinal Resistance to 1,25 Dihydroxyvitamin D in Mice Heterozygous for the Vitamin D Receptor Knockout Allele." Endocrinology 148, no. 3 (March 1, 2007): 1396–402. http://dx.doi.org/10.1210/en.2006-1109.
Повний текст джерелаАнотація:
We tested the hypothesis that low vitamin D receptor (VDR) level causes intestinal vitamin D resistance and intestinal calcium (Ca) malabsorption. To do so, we examined vitamin D regulated duodenal Ca absorption and gene expression [transient receptor potential channel, vallinoid subfamily member 6 (TRPV6), 24-hydroxylase, calbindin D9k (CaBP) mRNA, and CaBP protein] in wild-type mice and mice with reduced tissue VDR levels [i.e. heterozygotes for the VDR gene knockout (HT)]. Induction of 24-hydroxylase mRNA levels by 1,25 dihydroxyvitamin D3 [1,25(OH)2 D3] injection was significantly reduced in the duodenum and kidney of HT mice in both time-course and dose-response experiments. TRPV6 and CaBP mRNA levels in duodenum were significantly induced after 1,25(OH)2 D3 injection, but there was no difference in response between wild-type and HT mice. Feeding a low-calcium diet for 1 wk increased plasma PTH, renal 1α-hydroxylase (CYP27B1) mRNA level, and plasma 1,25(OH)2 D3, and this response was greater in HT mice (by 88, 55, and 37% higher, respectively). In contrast, duodenal TRPV6 and CaBP mRNA were not higher in HT mice fed the low-calcium diet. However, the response of duodenal Ca absorption and CaBP protein to increasing 1,25(OH)2 D3 levels was blunted by 40% in HT mice. Our data show that low VDR levels lead to resistance of intestinal Ca absorption to 1,25(OH)2 D3, and this resistance may be due to a role for the VDR (and VDR level) in the translation of CaBP.
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Jia, Lin, Yinyan Ma, Jamie Haywood, Long Jiang, Bingzhong Xue, Hang Shi, Paul A. Dawson, and Liqing Yu. "NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice." Cells 10, no. 12 (December 9, 2021): 3468. http://dx.doi.org/10.3390/cells10123468.
Повний текст джерелаАнотація:
Niemann–Pick C1-like 1 (NPC1L1) mediates intestinal uptake of dietary and biliary cholesterol and is the target of ezetimibe, a cholesterol absorption inhibitor used to treat hypercholesterolemia. Genetic deletion of NPC1L1 or ezetimibe treatment protects mice from high-fat diet (HFD)-induced obesity; however, the molecular mechanisms responsible for this therapeutic benefit remain unknown. A major metabolic fate of cholesterol is its conversion to bile acids. We found that NPC1L1 knockout (L1-KO) mice fed an HFD had increased energy expenditure, bile acid pool size, and fecal bile acid excretion rates. The elevated bile acid pool in the HFD-fed L1-KO mice was enriched with tauro-β-muricholic acid. These changes in the L1-KO mice were associated with reduced ileal mRNA expression of fibroblast growth factor 15 (FGF15) and increased hepatic mRNA expression of cholesterol 7α-hydroxylase (Cyp7A1) and mitochondrial sterol 27-hydroxylase (Cyp27A1). In addition, mRNA expression of the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and type 2 iodothyronine deiodinase (Dio2) were elevated in brown adipose tissue of L1-KO mice, which is known to promote energy expenditure. Thus, altered bile acid homeostasis and signaling may play a role in protecting L1-KO mice against HFD-induced obesity.
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Chhetri, Goma, Yanyan Liang, Juntang Shao, Dan Han, Yi Yang, Chao Hou, Peng Wang, et al. "Role of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Alcohol-Induced Liver Injury." Oxidative Medicine and Cellular Longevity 2020 (July 7, 2020): 1–15. http://dx.doi.org/10.1155/2020/9034864.
Повний текст джерелаАнотація:
Consumption of alcohol in immoderate quantity induces endoplasmic reticulum (ER) stress response (alcohol-induced ER stress). Mesencephalic astrocyte-derived neurotrophic factor (MANF), an ER stress-inducible protein, works as an evolutionarily conserved regulator of systemic and liver metabolic homeostasis. In this study, the effects of MANF on alcohol-induced liver injury were explored by using hepatocyte-specific MANF-knockout mice (MANFΔHep) in a chronic-plus-binge alcohol feeding model. We found that alcohol feeding upregulated MANF expression and MANFΔHep mice exhibited more severe liver injury with extra activated ER stress after alcohol feeding. In addition, we found that MANF deficiency activated iNOS and p65 and increased the production of NO and anti-inflammatory cytokines, which was further enhanced after alcohol treatment. Meanwhile, MANF deletion upregulated the levels of CYP2E1, 4-HNE, and MDA and downregulated the levels of GSH and SOD. These results indicate that MANF has potential protection on alcohol-induced liver injury, and the underlying mechanisms may be associated with meliorating the overactivated ER stress triggered by inflammation and oxidative stress via inhibiting and reducing NO/NF-κB and CYP2E1/ROS, respectively. Therefore, MANF might be a negative regulator in alcohol-induced ER stress and participate in the crosstalk between the NF-κB pathway and oxidative stress in the liver. Conclusions. This study identifies a specific role of MANF in alcohol-induced liver injury, which may provide a new approach for the treatment of ALI.
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Lei, Xin Gen, Jian-Hong Zhu, James P. McClung, Manuel Aregullin, and Carol A. Roneker. "Mice deficient in Cu,Zn-superoxide dismutase are resistant to acetaminophen toxicity." Biochemical Journal 399, no. 3 (October 13, 2006): 455–61. http://dx.doi.org/10.1042/bj20060784.
Повний текст джерелаАнотація:
Although antioxidants are used to treat an overdose of the analgaesic/antipyretic drug APAP (acetaminophen), roles of antioxidant enzymes in APAP-induced hepatotoxicity remain controversial. Our objective was to determine impacts of knockout of SOD1 (superoxide dismutase; Cu,Zn-SOD) alone or in combination with selenium-dependent GPX1 (glutathione peroxidase-1) on APAP-induced hepatotoxicity. All SOD1-null (SOD1−/−) and SOD1- and GPX1-double-knockout mice survived an intraperitoneal injection of 600 mg of APAP per kg of body mass, whereas 75% of WT (wild-type) and GPX1-null mice died within 20 h. Survival time of SOD1−/− mice injected with 1200 mg of APAP per kg of body mass was longer than that of the WT mice (934 compared with 315 min, P<0.05). The APAP-treated SOD1−/− mice had less (P<0.05) plasma ALT (alanine aminotransferase) activity increase and attenuated (P<0.05) hepatic glutathione depletion than the WT mice. The protection conferred by SOD1 deletion was associated with a block of the APAP-mediated hepatic protein nitration and a 50% reduction (P<0.05) in activity of a key APAP metabolism enzyme CYP2E1 (cytochrome P450 2E1) in liver. The SOD1 deletion also caused moderate shifts in the APAP metabolism profiles. In conclusion, deletion of SOD1 alone or in combination with GPX1 greatly enhanced mouse resistance to APAP overdose. Our results suggest a possible pro-oxidant role for the physiological level of SOD1 activity in APAP-mediated hepatotoxicity.
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Kiourtzidis, Mikis, Julia Kühn, Corinna Brandsch, and Gabriele I. Stangl. "Vitamin D Status of Mice Deficient in Scavenger Receptor Class B Type 1, Cluster Determinant 36 and ATP-Binding Cassette Proteins G5/G8." Nutrients 12, no. 8 (July 22, 2020): 2169. http://dx.doi.org/10.3390/nu12082169.
Повний текст джерелаАнотація:
Classical lipid transporters are suggested to modulate cellular vitamin D uptake. This study investigated the vitamin D levels in serum and tissues of mice deficient in SR-B1 (Srb1-/-), CD36 (Cd36-/-) and ABC-G5/G8 (Abcg5/g8-/-) and compared them with corresponding wild-type (WT) mice. All mice received triple-deuterated vitamin D3 (vitamin D3-d3) for six weeks. All knockout mice vs. WT mice showed specific alterations in their vitamin D concentrations. Srb1-/- mice had higher levels of vitamin D3-d3 in the serum, adipose tissue, kidney and heart, whereas liver levels of vitamin D3-d3 remained unaffected. Additionally, Srb1-/- mice had lower levels of deuterated 25-hydroxyvitamin D3 (25(OH)D3-d3) in the serum, liver and kidney compared to WT mice. In contrast, Cd36-/- and WT mice did not differ in the serum and tissue levels of vitamin D3-d3, but Cd36-/- vs. WT mice were characterized by lower levels of 25(OH)D3-d3 in the serum, liver and kidney. Finally, Abcg5/g8-/- mice tended to have higher levels of vitamin D3-d3 in the serum and liver. Major alterations in Abcg5/g8-/- mice were notably higher levels of 25(OH)D3-d3 in the serum and kidney, accompanied by a higher hepatic mRNA abundance of Cyp27a1 hydroxylase. To conclude, the current data emphasize the significant role of lipid transporters in the uptake, tissue distribution and activation of vitamin D.
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Jeong, Jae-Wook, Kevin Y. Lee, Inseok Kwak, Lisa D. White, Susan G. Hilsenbeck, John P. Lydon, and Francesco J. DeMayo. "Identification of Murine Uterine Genes Regulated in a Ligand-Dependent Manner by the Progesterone Receptor." Endocrinology 146, no. 8 (August 1, 2005): 3490–505. http://dx.doi.org/10.1210/en.2005-0016.
Повний текст джерелаАнотація:
Abstract Progesterone (P4) acting through its cognate receptor, the progesterone receptor (PR), plays an important role in uterine physiology. The PR knockout (PRKO) mouse has demonstrated the importance of the P4-PR axis in the regulation of uterine function. To define the molecular pathways regulated by P4-PR in the mouse uterus, Affymetrix MG U74Av2 oligonucleotide arrays were used to identify alterations in gene expression after acute and chronic P4 treatments. PRKO and wild-type mice were ovariectomized and then treated with vehicle or 1 mg P4 every 12 h. Mice were killed either 4 h after the first injection (acute P4 treatment) or after the fourth injection of P4 (chronic P4 treatment). At the genomic level, the major change in gene expression after acute P4 treatment was an increase in the expression of 55 genes. Conversely, the major change in gene expression after chronic P4 treatment was an overall reduction in the expression of 102 genes. In the analysis, retinoic acid metabolic genes, cytochrome P 450 26a1 (Cyp26a1), alcohol dehydrogenase 5, and aldehyde dehydrogenase 1a1 (Aldh1a1); kallikrein genes, Klk5 and Klk6; and specific transcription factors, GATA-2 and Cited2 [cAMP-corticosterone-binding protein/p300-interacting transactivator with glutamic acid (E) and aspartic acid (D)-rich tail], were validated as regulated by the P4-PR axis. Identification and analysis of these responsive genes will help define the role of PR in regulating uterine biology.
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Narvaez, Carmen J., Donald Matthews, Emily Broun, Michelle Chan, and JoEllen Welsh. "Lean Phenotype and Resistance to Diet-Induced Obesity in Vitamin D Receptor Knockout Mice Correlates with Induction of Uncoupling Protein-1 in White Adipose Tissue." Endocrinology 150, no. 2 (February 1, 2009): 651–61. http://dx.doi.org/10.1210/en.2008-1118.
Повний текст джерелаАнотація:
Increased adiposity is a feature of aging in both mice and humans, but the molecular mechanisms underlying age-related changes in adipose tissue stores remain unclear. In previous studies, we noted that 18-month-old normocalcemic vitamin D receptor (VDR) knockout (VDRKO) mice exhibited atrophy of the mammary adipose compartment relative to wild-type (WT) littermates, suggesting a role for VDR in adiposity. Here we monitored body fat depots, food intake, metabolic factors, and gene expression in WT and VDRKO mice on the C57BL6 and CD1 genetic backgrounds. Regardless of genetic background, both sc and visceral white adipose tissue depots were smaller in VDRKO mice than WT mice. The lean phenotype of VDRKO mice was associated with reduced serum leptin and compensatory increased food intake. Similar effects on adipose tissue, leptin and food intake were observed in mice lacking Cyp27b1, the 1α-hydroxylase enzyme that generates 1,25-dihydroxyvitamin D3, the VDR ligand. Although VDR ablation did not reduce expression of peroxisome proliferator-activated receptor-γ or fatty acid synthase, PCR array screening identified several differentially expressed genes in white adipose tissue from WT and VDRKO mice. Uncoupling protein-1, which mediates dissociation of cellular respiration from energy production, was greater than 25-fold elevated in VDRKO white adipose tissue. Consistent with elevation in uncoupling protein-1, VDRKO mice were resistant to high-fat diet-induced weight gain. Collectively, these studies identify a novel role for 1,25-dihydroxyvitamin D3 and the VDR in the control of adipocyte metabolism and lipid storage in vivo. Mice lacking the vitamin D receptor or its ligand display reduced adiposity, resistance to diet-induced obesity, and induction of uncoupling protein-1 in white adipose tissue.
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Pinterić, Marija, Iva I. Podgorski, Marijana Popović Hadžija, Ivana Tartaro Bujak, Ana Dekanić, Robert Bagarić, Vladimir Farkaš, Sandra Sobočanec, and Tihomir Balog. "Role of Sirt3 in Differential Sex-Related Responses to a High-Fat Diet in Mice." Antioxidants 9, no. 2 (February 20, 2020): 174. http://dx.doi.org/10.3390/antiox9020174.
Повний текст джерелаАнотація:
Metabolic homeostasis is differently regulated in males and females. Little is known about the mitochondrial Sirtuin 3 (Sirt3) protein in the context of sex-related differences in the development of metabolic dysregulation. To test our hypothesis that the role of Sirt3 in response to a high-fat diet (HFD) is sex-related, we measured metabolic, antioxidative, and mitochondrial parameters in the liver of Sirt3 wild-type (WT) and knockout (KO) mice of both sexes fed with a standard or HFD for ten weeks. We found that the combined effect of Sirt3 and an HFD was evident in more parameters in males (lipid content, glucose uptake, pparγ, cyp2e1, cyp4a14, Nrf2, MnSOD activity) than in females (protein damage and mitochondrial respiration), pointing towards a higher reliance of males on the effect of Sirt3 against HFD-induced metabolic dysregulation. The male-specific effects of an HFD also include reduced Sirt3 expression in WT and alleviated lipid accumulation and reduced glucose uptake in KO mice. In females, with a generally higher expression of genes involved in lipid homeostasis, either the HFD or Sirt3 depletion compromised mitochondrial respiration and increased protein oxidative damage. This work presents new insights into sex-related differences in the various physiological parameters with respect to nutritive excess and Sirt3.
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Xu, Jin, Yi Peng, Yi Zeng, Yi-qiao Hua та Xiao-le Xu. "2, 3, 4′, 5-tetrahydroxystilbene-2-0-β-d Glycoside Attenuates Age- and Diet-Associated Non-Alcoholic Steatohepatitis and Atherosclerosis in LDL Receptor Knockout Mice and Its Possible Mechanisms". International Journal of Molecular Sciences 20, № 7 (1 квітня 2019): 1617. http://dx.doi.org/10.3390/ijms20071617.
Повний текст джерелаАнотація:
The compound, 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (TSG), a primary bioactive polyphenolic component of Polygonum multiflorum exerts numerous pharmacological activities. However, its protective effect against non-alcoholic steatohepatitis (NASH), in the context of metabolic syndrome, remains poorly understood. The aim of the present study is to evaluate the effects of TSG treatment on middle-aged (12-mo-old) male LDLr−/− mice, which were fed a high fat diet for 12 weeks to induce metabolic syndrome and NASH. At the end of the experiment, the blood samples of mice were collected for determination of metabolic parameters. Liver and aorta tissues were collected for analysis, such as histology, immunofluorescence, hepatic lipid content, real-time PCR, and western blot. Our data show that TSG treatment improved the different aspects of NASH (steatosis, inflammation, and fibrosis) and atherosclerosis, as well as some of the metabolic basal characteristics. These modulatory effects of TSG are mediated, at least in part, through regulating key regulators of lipid metabolism (SREBP1c, PPARα and their target genes, ABCG5 and CYP7A1), inflammation (CD68, TNF-α, IL-6 and ICAM), fibrosis (α-SMA and TNFβ) and oxidative stress (NADPH-oxidase 2/4, CYP2E1 and antioxidant enzymes). These results suggest that TSG may be a promising candidate for preventing and treating the progression of NASH.
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Arora, Juhi, Devanshi R. Patel, McKayla J. Nicol, Cassandra J. Field, Katherine H. Restori, Jinpeng Wang, Nicole E. Froelich, et al. "Vitamin D and the Ability to Produce 1,25(OH)2D Are Critical for Protection from Viral Infection of the Lungs." Nutrients 14, no. 15 (July 26, 2022): 3061. http://dx.doi.org/10.3390/nu14153061.
Повний текст джерелаАнотація:
Vitamin D supplementation is linked to improved outcomes from respiratory virus infection, and the COVID-19 pandemic renewed interest in understanding the potential role of vitamin D in protecting the lung from viral infections. Therefore, we evaluated the role of vitamin D using animal models of pandemic H1N1 influenza and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. In mice, dietary-induced vitamin D deficiency resulted in lung inflammation that was present prior to infection. Vitamin D sufficient (D+) and deficient (D−) wildtype (WT) and D+ and D− Cyp27B1 (Cyp) knockout (KO, cannot produce 1,25(OH)2D) mice were infected with pandemic H1N1. D− WT, D+ Cyp KO, and D− Cyp KO mice all exhibited significantly reduced survival compared to D+ WT mice. Importantly, survival was not the result of reduced viral replication, as influenza M gene expression in the lungs was similar for all animals. Based on these findings, additional experiments were performed using the mouse and hamster models of SARS-CoV-2 infection. In these studies, high dose vitamin D supplementation reduced lung inflammation in mice but not hamsters. A trend to faster weight recovery was observed in 1,25(OH)2D treated mice that survived SARS-CoV-2 infection. There was no effect of vitamin D on SARS-CoV-2 N gene expression in the lung of either mice or hamsters. Therefore, vitamin D deficiency enhanced disease severity, while vitamin D sufficiency/supplementation reduced inflammation following infections with H1N1 influenza and SARS-CoV-2.
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Zinser, Glendon M., and JoEllen Welsh. "Accelerated Mammary Gland Development during Pregnancy and Delayed Postlactational Involution in Vitamin D3 Receptor Null Mice." Molecular Endocrinology 18, no. 9 (September 1, 2004): 2208–23. http://dx.doi.org/10.1210/me.2003-0469.
Повний текст джерелаАнотація:
Abstract The vitamin D receptor (VDR) is present in mammary gland, and VDR ablation is associated with accelerated glandular development during puberty. VDR is a nuclear receptor whose ligand, 1,25-dihydroxyvitamin D [1,25-(OH)2D] is generated after metabolic activation of vitamin D by specific vitamin D hydroxylases. In these studies, we demonstrate that both the VDR and the vitamin D 1-α hydroxylase (CYP27B1), which produces 1,25-(OH)2D are present in mammary gland and dynamically regulated during pregnancy, lactation, and involution. Furthermore, we show that mice lacking VDR exhibit accelerated lobuloalveolar development and premature casein expression during pregnancy and delayed postlactational involution compared with mice with functional VDR. The delay in mammary gland regression after weaning of VDR knockout mice is associated with impaired apoptosis as demonstrated by reductions in terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling staining, caspase-3 activation and Bax induction. Under the conditions used in this study, VDR ablation was not associated with hypocalcemia, suggesting that altered mammary gland development in the absence of the VDR is not related to disturbances in calcium homeostasis. Furthermore, in the setting of normocalcemia, VDR ablation does not affect milk protein or calcium content. These studies suggest that the VDR contributes to mammary cell turnover during the reproductive cycle, and its effects may be mediated via both endocrine and autocrine signaling pathways. Unlike many mammary regulatory factors that exert transient, stage-specific effects, VDR signaling impacts on mammary gland biology during all phases of the reproductive cycle.
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Teodorescu, Patric, Yuya Nagai, Guo Zhong, Vikram Mathews, Nina Isoherranen, and Gabriel Ghiaur. "Arsenic Trioxide Reprograms the Bone-Marrow Microenvironment to Sensitize Minimal Residual Disease in Acute Myeloid Leukemia." Blood 138, Supplement 1 (November 5, 2021): 1166. http://dx.doi.org/10.1182/blood-2021-153244.
Повний текст джерелаАнотація:
Abstract Eliminating minimal residual disease (MRD) in order to prevent relapse is an unmet need in acute myeloid leukemia (AML). One of the success stories is acute promyelocytic leukemia (APL), a unique subtype of AML. The use of arsenic trioxide (ATO) in combination with all-trans retinoic acid (ATRA) has essentially eliminated disease relapse (<1% ATRA+ATO vs. ~18% ATRA+ chemotherapy - NEJM (2013), 369(2), 111-121). This is even more impressive as neither agent alone results in significant cure of patients with APL. In fact, single agent ATRA induces remission without cure due to bone marrow stroma expression of CYP26 enzymes (PloS one (2015), 10(6), e0127790), which are induced by ATRA, inactivate retinoids and protect APL MRD (Leukemia (2020), 34(11), 3077-3081). While ATO may synergize with ATRA by restoring PML nuclear bodies (Nature medicine (2014), 20(2), 167-174) and rescuing RAR-α dependent transcription (Nature reviews. Cancer (2018), 18(2), 117-127) in the bulk of the APL tumor cells, it is unclear how these mechanisms contribute to elimination of MRD, particularly given the hypothesized lack of ATRA in the bone marrow niche. It was previously reported that combination of ATRA with ATO may be associated with high incidence of transaminitis and headaches (NEJM (2013), 369(2), 111-121). Since these may be clinical signs of ATRA toxicity, we investigated if addition of ATO changes the pharmacokinetics (PKs) of ATRA in patients with APL. We determined the area under the plasma concentration versus time curve (AUC) for ATRA in patients suspected of APL and treated with single agent ATRA ("preATO") and in the same patients after the diagnoses of APL was confirmed and the patients received ATO ("postATO"). Even though ATRA should have an expected drop in AUC during the first 3-4 days of therapy (JPET (2017), 361(2), 246-258), addition of ATO resulted in improved ATRA PKs (Figure A). Since ATRA levels are mainly controlled by clearance via hepatic CYP26s, we tested if treatment with ATO changes the levels of CYP26 or its induction by ATRA. We found that exposure to ATO decreases both baseline and ATRA-induced upregulation of CYP26B1 in HepG2 cells (Figure B). Similarly, ATO decreases CYP26B1 levels in human bone marrow derived mesenchymal stroma cells (MSCs) at baseline (21%±7% of NO ATO control, n=3, p<0.01) and after ATRA-induced upregulation (66%±14% of ATRA only control, n=3, p<0.01). These changes resulted in improved ATRA PKs in vitro in the presence of bone marrow MSCs (Figure C). Next, we used NB4-EvAsR cells (NB4R), ATO-resistant APL cells to test if ATO-induced improvement of MSC-dependent ATRA PKs may contribute to elimination of APL MRD. We found that ATO sensitizes NB4R to ATRA in the presence of BM MSCs but not in stroma free conditions (Figure D). ATO had no effect on ATRA-induced differentiation of NB4R in the presence of CYP26B1 knockout stroma (this stroma offers no protection from ATRA) or if stroma expresses CYP26B1 under the control of a viral promoter and thus, resistant to ATO downregulation. This data suggest that ATO-induced changes of BM MSC expression of CYP26 may contribute to elimination of MRD in APL. Stromal CYP26 protects not only APL but also non-APL AML cells from retinoids (Leukemia (2020), 34(11), 3077-3081). Retinoids are synergistic with FLT3 inhibitors to eliminate mutant FLT3 AML cells (Blood (2016), 127(23), 2867-2878) and stromal CYP26 breaks this synergism (Blood (2015) 126 (23): 790). We tested if ATO sensitizes mutant FLT3 AML cells, MV4;11 to gilteritinib in the presence of BM MSCs. For this, we derived MV4.11 cells resistant to ATO (MV4.11R) via long term exposure to increasing concentration of ATO. As seen with NB4R, ATO treatment synergizes with gilteritinib to decrease the IC50 of gilteritinib against the clonogenic activity of MV4.11R in the presence of stroma but not in stroma free conditions (Figure E). In an effort to fully explore the translational potential of these findings, we are currently investigating the mechanism by which ATO changes CYP26 levels. Taken together these findings support a model in which ATO changes the bone marrow niche and it's ability to metabolize retinoids and thus, sensitizes MRD in AML to targeted therapy. Figure 1 Figure 1. Disclosures Mathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor. Ghiaur: Syros Pharmaceuticals: Consultancy; Menarini Richerche: Research Funding.
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Alonso, Salvador, William Matsui, Richard J. Jones, and Gabriel Ghiaur. "Bone Marrow Niche - Multiple Myeloma Cross-Talk Generates Bortezomib Resistance." Blood 126, no. 23 (December 3, 2015): 914. http://dx.doi.org/10.1182/blood.v126.23.914.914.
Повний текст джерелаАнотація:
Abstract Bortezomib (BTZ), a proteasome inhibitor that induces accumulation of misfolded proteins and apoptosis in highly secretory cells, has improved survival in multiple myeloma (MM) but fails to achieve cure. It has been postulated that a population of MM cells, phenotypically similar to B-cells, are intrinsically resistant to BTZ, and contribute to minimal residual disease (MRD) and relapse (Matsui et al., 2008). Bone marrow (BM) stroma expresses CYP26 enzymes and creates a retinoic acid (RA)-low environment that prevents differentiation of normal and malignant cells (Meng et al., 2015). Since RA promotes plasma cell differentiation, Ig secretion (Ertesvag et al., 2007) and thus, ER-stress (Xu et al., 2007), we tested if the BM niche induces BTZ resistance by promoting a B-cell program in MM. Consistent with this, MM cells (H929 and MM1S) cultured under low RA conditions (co-cultured with BM stroma or treated with AGN194310, a pan-RA receptor inhibitor) up regulated B-cell markers (BCL6), and down regulated genes associated with plasma cell differentiation and BTZ sensitivity (XBP1s, Blimp, CHOP) (Fig 1A). In addition, inhibition of stromal CYP26 via R115866 reversed these gene expression changes in stroma co-culture conditions (Fig 1A). To verify whether a low-RA environment promotes BTZ resistance, we incubated MM cells with BM mesenchymal cells for 5 days. Then, MM cells were separated from stroma, and treated with BTZ. Incubation with BM stroma induced BTZ resistance of MM cells, which was completely overcome by CYP26 inhibition or by the CYP26 resistant retinoid IRX5183 (Fig 1B). Moreover, MM cells pretreated with AGN for 5 days were also resistant to BTZ (Fig 1B). Interestingly, this BTZ resistant phenotype was preserved for up to 48h upon removal of MM cells from stromal co-culture (Fig 1C). Recent studies suggest that malignant cells remodel their microenvironments to build a more protective niche (Schepers et al., 2013). Consistent with this, we found that stromal CYP26A1 was highly upregulated after co-culture with MM cells. Supernatant from MM cells had similar effects, implicating a soluble factor on this interaction. Since secretion of SHH was implicated in chemotherapy resistance in MM (Liu et al., 2014), we tested if MM-induced CYP26 up-regulation was dependent on SHH signaling. As hypothesized, treatment with the Smo antagonist cyclopamine, or the use of SMO knockout (KO) stromal cells, overcame CYP26A1 up regulation by MM cells (Fig 1D) To test if cell extrinsic SHH signaling in stromal niche contributes to BTZ resistance by modulating RA pathway in MM cells, we modeled MM-BM stroma interactions in a xenograft setting. Each mouse carried two subcutaneous tumors consisting of Luciferase expressing MM1S cells and SmoFl/Fl BM stroma cells, transduced with either a control vector (WT stroma) or Cre-recombinase (Smo KO stroma) (Fig E). Mice were treated with IRX5183, BTZ, or the combination. Consistent with our in vitro data, tumors with Smo KO stroma showed a significant response to BTZ, while those with WT stroma were refractory, as determined by exponential increase in bioluminescence. However, the combination of IRX+BTZ resulted in a dramatic and equivalent response regardless of the phenotype of the stromal compartment (Fig 2A, 2B). Moreover, tumors with Smo KO stroma, or treated with IRX, showed decrease expression of B-cell markers, and up-regulation of genes associated with plasma cell differentiation and BTZ sensitivity. In conclusion, we show that the BM niche promotes a B-cell program in MM, characterized by a low ER-stress and BTZ resistance. This niche-induced program is maintained even after displacement from the BM, which may have important implications for the use of mobilization-sensitization strategies. Finally, we propose the existence of a bi-directional crosstalk between MM cells and their respective niches. In our model, MM cells via secretion of SHH modify BM stroma to create RA-low environments, induce BTZ resistance and contribute to MRD. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
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Ueda, Hajime, Akira Honda, Teruo Miyazaki, Yukio Morishita, Takeshi Hirayama, Junichi Iwamoto, Nobuhiro Nakamoto, and Tadashi Ikegami. "Sex-, age-, and organ-dependent improvement of bile acid hydrophobicity by ursodeoxycholic acid treatment: A study using a mouse model with human-like bile acid composition." PLOS ONE 17, no. 7 (July 12, 2022): e0271308. http://dx.doi.org/10.1371/journal.pone.0271308.
Повний текст джерелаАнотація:
Cyp2a12-/-Cyp2c70-/- double knockout (DKO) mice have a human-like hydrophobic bile acid (BA) composition and show reduced fertility and liver injury. Ursodeoxycholic acid (UDCA) is a hydrophilic and cytoprotective BA used to treat various liver injuries in humans. This study investigated the effects of orally administered UDCA on fertility and liver injury in DKO mice. UDCA treatment prevented abnormal delivery (miscarriage and preterm birth) in pregnant DKO mice, presumably by increasing the hydrophilicity of serum BAs. UDCA also prevented liver damage in six-week-old DKO mice, however liver injury emerged in UDCA-treated 20-week-old female, but not male, DKO mice. In 20-week-old male UDCA-treated DKO mice, conjugated plus unconjugated UDCA proportions in serum, liver, and bile were 71, 64, and 71% of the total BAs, respectively. In contrast, conjugated plus unconjugated UDCA proportions in serum, liver, and bile of females were 56, 34, and 58% of the total BAs, respectively. The UDCA proportion was considerably low in female liver only and was compensated by highly hydrophobic lithocholic acid (LCA). Therefore, UDCA treatment markedly reduced the BA hydrophobicity index in the male liver but not in females. This appears to be why UDCA treatment causes liver injury in 20-week-old female mice. To explore the cause of LCA accumulation in the female liver, we evaluated the hepatic activity of CYP3A11 and SULT2A1, which metabolize LCAs to more hydrophilic BAs. However, there was no evidence to suggest that either enzyme activity was lower in females than in males. As female mice have a larger BA pool than males, excessive loading of LCAs on the hepatic bile salt export pump (BSEP) may be the reason for the hepatic accumulation of LCAs in female DKO mice with prolonged UDCA treatment. Our results suggest that the improvement of BA hydrophobicity in DKO mice by UDCA administration is sex-, age-, and organ-dependent.
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Arul, Glancis Luzeena Raja, Ezequiel Tolosa, Ryan M. Carr, and Martin E. Fernandez-Zapico. "Abstract B002: Modeling evolutionary therapy for GI malignancies." Cancer Research 82, no. 10_Supplement (May 15, 2022): B002. http://dx.doi.org/10.1158/1538-7445.evodyn22-b002.
Повний текст джерелаАнотація:
Abstract Despite development of personalized treatments GI cancer like pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) remain dismal outcomes. While some patients are potentially curable with surgery and chemotherapy, most unresectable cases are invariably lethal. To advance patient care, we rely on clinical trials to test new therapeutic approaches. Here, we assume that the highest dose of a drug that does not cause severe toxicities is optimal for cancer treatment. However, this treatment strategy, in many cases, may be more harmful for the patient. Adopting principles from the field of evolutionary biology and pest management could offer more effective strategies that can be used for patients with metastatic PDAC and CRC. Resistance mechanisms are assumed to come with an energy cost, making the organism/cell less fit than others in the population. When high doses of treatment are applied, it results in a significant selection gradient by eliminating sensitive populations, freeing resources and facilitating resistant population growth. Such evolutionary dynamics and interactions within the tumor microenvironment can be modeled and exploited, in the form of adaptive strategies, for treatment of CRC and PDAC. It is our central hypothesis that integration of evolutionary dynamics and into PDAC and CRC treatment will delay emergence of resistance, enhance quality of life, and improve clinical outcomes. Our preliminary observations in co-cultured drug sensitive and resistant cell containing spheroids show that a higher proportion of drug sensitive cells inhibits the proliferation of drug resistant cells over time, in the presence of chemotherapeutic agents 5-FU and Oxaliplatin. We also demonstrate a role for the MLL family of histone methyltransferases in the epigenetic regulation of genes involved in chemoresistance. RNA-seq data has shown differential gene expression in metabolic genes regulated by histone methyltransferase KMT2A, KM2TB and KMT2D knockout (KO) cells including Gstt1, CYP26B1 and PYGL. In addition to this, KMT2A, KM2TB and KMT2D KOs show differential sensitivity to chemotherapeutic agents Gemcitabine, SN-38, 5-FU and Oxaliplatin. Further, analysis of KMT2A, KM2TB and KMT2D KO cells will provide mechanistic insight of the epigenetic regulation of metabolic patterns in drug resistant cells. This strategy would provide an approach for reducing exposure to toxic drugs, improving patient quality of life and renewing hope for prolonged control of metastatic PDAC and CRC. This proposal represents a bedside-to-bench-to-bedside project; identifying a shortcoming in how we currently treat PDAC and CRC patients, developing solutions in the lab and ultimately translating such strategies to benefit patients. Citation Format: Glancis Luzeena Raja Arul, Ezequiel Tolosa, Ryan M. Carr, Martin E. Fernandez-Zapico. Modeling evolutionary therapy for GI malignancies [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B002.
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Sigurdsson, Valgardur, Hajime Takei, Svetlana Soboleva, Takashi Iida, Hiroshi Nittono, and Kenichi Miharada. "Taurine-Conjugated Bile Acids Protect Expanding Hematopoietic Stem/Progenitor Cells from Unfolded Protein Stress As Natural Chaperones." Blood 124, no. 21 (December 6, 2014): 4318. http://dx.doi.org/10.1182/blood.v124.21.4318.4318.
Повний текст джерелаАнотація:
Abstract Hematopoietic stem cells (HSCs) give rise to all lineages of hematopoietic cells in the body for entire life span and are thus protected from risk factors by multiple defense systems. We have recently discovered that HSCs are highly susceptible to stress caused by accumulation of mis-/un-folded proteins, so called endoplasmic reticulum (ER) stress upon enhanced growth conditions, and addition of a specific type of bile acid (BA), Tauroursodeoxycholic acid (TUDCA), known as a chemical chaperone can maintain functional murine HSCs for 2 weeks in vitro, by reducing ER stress (Miharada et al., Cell Rep. 2014). This work depicts the importance of proper protein quality control in HSC maintenance, particularly during the expansion. HSCs are kept in dormant state in the adult body, but actively expanding in the fetal liver. BAs are synthesized from cholesterol in the liver. Interestingly, bile acid synthesis is highly up-regulated in the fetal liver during embryogenesis and the composition of fetal BAs gradually reduces after birth. In addition, composition of bile acids in the fetus is different from adult liver, with the vast majority of fetal BAs are of Taurine-conjugated form that is more stable and non-toxic. Of note, hematopoietic cells and hepatocytes producing BAs are in close contact in the fetal liver and HSCs are therefore exposed to BAs, whereas the adult liver has anatomically isolated bile duct structures that separate blood flow and bile flow. However the role for these fetal BAs has been unknown. Here we report that bile acids support expansion of hematopoietic stem and progenitor cells (HSPCs) in the fetal liver and ex vivo. Since TUDCA is a rare component in human and mouse BAs, even in the fetal liver, we sought analogue(s) that similarly function as ER stress inhibitors. We identified that Taurocholic acid (TCA), one of the main components of fetal BA, and Tauro-alpha-muricholic acid (TαMCA) that is a rodent specific BA have a potential to reduce ER stress, similar to TUDCA. Mouse HSCs cultured with TCA or TαMCA in vitro for 2 weeks showed a robust increase in the reconstitution level compared to non-treated cells (14-fold, n=14, p<0.001 and 13-fold, n=9, p<0.05, respectively), which has comparable or even better potential to support HSC function than TUDCA. To study physiological roles of BA in ER stress reduction and HSC expansion in the fetal liver, an inhibitor of BA synthesis, GW4064 (an agonist of a nuclear receptor FxR that negatively regulates key enzymes in the BA biosynthesis, CYP7A1 and CYP8B1), was intraperitoneally injected into pregnant mice. E16.5 fetuses derived from GW4064-injected pregnant mice showed severe decrease in the number of HSPCs (0.40-fold, n=28-33, p<0.001) in the fetal liver, due to increased apoptosis triggered by elevated ER stress levels. Importantly, co-injection of TCA or Salubrinal (inhibitor of the ER stress-induced apoptosis signal) rescued the effects of GW4064 on cellularity of the fetal liver and levels of ER stress, confirming that the phenotype seen here is due to increased ER stress resulting from lowered levels of BA. Analyses of CYP27A1 knockout (KO) mice that have reduced BA synthesis observed decreased HSC number and increased ER stress in the fetal liver, whereas CYP8B1 KO mice that have increased Tα/βMCA synthesis instead of lack of TCA didn’t show any difference. These findings strongly suggest that fetal BA, particularly TCA and TαMCA, supports the expansion of HSPCs in the fetal liver and the ex vivo culture as chemical chaperones by lowering ER stress levels. Our findings propose a new role of bile acids in hematopoiesis as natural chaperones and provide a novel connection between hematopoiesis and fetal liver. Disclosures No relevant conflicts of interest to declare.
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Ilenwabor, Barnabas P., Heidi Schigt, Andreas Kompatscher, Caro Bos, Malou Zuidscherwoude, Bram C. J. van der Eerden, Joost G. J. Hoenderop, and Jeroen H. F. de Baaij. "FAM111A is dispensable for electrolyte homeostasis in mice." Scientific Reports 12, no. 1 (June 17, 2022). http://dx.doi.org/10.1038/s41598-022-14054-8.
Повний текст джерелаАнотація:
AbstractAutosomal dominant mutations in FAM111A are causative for Kenny-Caffey syndrome type 2. Patients with Kenny-Caffey syndrome suffer from severe growth retardation, skeletal dysplasia, hypoparathyroidism, hypocalcaemia, hyperphosphataemia and hypomagnesaemia. While recent studies have reported FAM111A to function in antiviral response and DNA replication, its role in regulating electrolyte homeostasis remains unknown. In this study, we assessed the role of FAM111A in the regulation of serum electrolyte balance using a Fam111a knockout (Fam111a−/−) C57BL/6 N mouse model. Fam111a−/− mice displayed normal weight and serum parathyroid hormone (PTH) concentration and exhibited unaltered magnesium, calcium and phosphate levels in serum and 24-hour urine. Expression of calciotropic (including Cabp28k, Trpv5, Klotho and Cyp24a1), magnesiotropic (including Trpm6, Trpm7, Cnnm2 and Cnnm4) and phosphotropic (Slc20a1, Slc20a2, Slc34a1 and Slc34a3) genes in the kidneys, duodenum and colon were not affected by Fam111a depletion. Only Slc34a2 expression was significantly upregulated in the duodenum, but not in the colon. Analysis of femurs showed unaffected bone morphology and density in Fam111a−/− mice. Kidney and parathyroid histology were also normal in Fam111a−/− mice. In conclusion, our study is the first to characterise the function of FAM111A in vivo and we report that mice lacking FAM111A exhibit normal electrolyte homeostasis on a standard diet.
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Nishikawa, Miyu, Kaori Yasuda, Hiroki Mano, Shinichi Ikushiro, and Toshiyuki Sakaki. "Generation of Genetically Modified Rats Using CRISPR/Cas9 Genome-Editing System to Reveal Novel Vitamin D Actions." Medical Research Archives 9, no. 9 (2021). http://dx.doi.org/10.18103/mra.v9i9.2558.
Повний текст джерелаАнотація:
We previously revealed that the anti-proliferative activity of 25-hydroxyvitamin D3 (25(OH)D3) in human prostate PZ-HPV-7 cells depends on the direct action of 25(OH)D3 through the vitamin D receptor (VDR). We then attempted to confirm the direct action of 25(OH)D3 in vivo using Cyp27b1 knockout (KO) mice. Daily administration of 25(OH)D3 at 250 μg/kg bw/day rescued the rachitic conditions in Cyp27b1 KO mice. The plasma levels of calcium, phosphorus, and parathyroid hormonea as well as the bone mineral density and female sexual cycle were normalized via the administration of 25(OH)D3. These results strongly suggest the direct action of 25(OH)D3. However, to our surprise, normal levels of 1a,25(OH)2D3 were detected in the plasma of Cyp27b1 KO mice, probably due to Cyp27a1, which has a weak 1a-hydroxylation activity toward 25(OH)D3. Next, we generated a novel in vivo system using genetically modified (GM) rats deficient in the Cyp27b1 or Vdr gene to reveal the molecular mechanisms of vitamin D action. Human type II rickets model rats with mutant Vdr (R270L), which recognizes 1,25(OH)2D3 with an affinity equivalent to that of 25(OH)D3, were also generated. Cyp27b1-knockout (KO), Vdr-KO, and Vdr (R270L) rats showed symptoms of rickets, including growth retardation and abnormal bone formation. Among these model animals, Cyp27b1-KO rats had notably low levels of calcium in the blood and the most severe growth retardation, while Vdr-KO rats showed abnormal skin formation and alopecia. Administration of 25(OH)D3 restored rickets symptoms in Cyp27b1-KO and Vdr (R270L) rats. As shown in Cyp27b1-KO mice, 1,25(OH)2D3 was also synthesized in Cyp27b1-KO rats. In contrast, the effects of 25(OH)D3 on Vdr (R270L) rats strongly suggest that 25(OH)D3 exerts a direct action via VDR-genomic pathways. These results suggest that our novel in vivo system containing three different types of GM rats is useful for elucidating the molecular mechanism of vitamin D action.
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Ji, Wen-Heng, Dan-Dan Li, Dan-Ping Wei, Ai-Qin Gu, Ying Yang, and Jing-Pian Peng. "Cytochrome P450 26A1 Modulates the Polarization of Uterine Macrophages During the Peri-Implantation Period." Frontiers in Immunology 12 (October 12, 2021). http://dx.doi.org/10.3389/fimmu.2021.763067.
Повний текст джерелаАнотація:
Uterine M1/M2 macrophages activation states undergo dynamic changes throughout pregnancy, and inappropriate macrophages polarization can cause adverse pregnancy outcomes, especially during the peri-implantation period. Our previous studies have confirmed that Cytochrome P450 26A1 (CYP26A1) can affect embryo implantation by regulating uterine NK cells and DCs. The aim of this study was to investigate whether CYP26A1 regulates the polarization of uterine macrophages in early pregnancy. Here, we observed that Cyp26a1 was significantly upregulated in M1 as compared with M2 of uterine macrophages, Raw264.7 and iBMDM. Knockdown of CYP26A1 in mice uterine significantly decreased the number of embryo implantation sites and the proportion of CD45+F4/80+CD206− M1-like uterine macrophages. Primary uterine macrophages treated with anti-CYP26A1 antibody expressed significantly lower levels of M1 markers Nos2, Il1b, Il6 and Tnf-a. In CYP26A1 knockout Raw264.7 cells, the protein levels of M1 markers TNF-α, IL-6 and CD86 were significantly decreased as compared with the wild type cells. Moreover, CYP26A1 deficiency decreased the ability to produce nitric oxide and increased the phagocytosis capacity of Raw264.7 cells under M1 stimulation state. The re-introduction of CYP26A1 partially reversed the polarization levels of M1 in CYP26A1 knockout Raw264.7 cells. CYP26A1 may regulate the polarization of uterine macrophages to M1 through Stap1 and Slc7a2. In summary, these results indicate that CYP26A1 plays a significant role in macrophage polarization, and knockdown of CYP26A1 can cause insufficient M1 polarization during the peri-implantation period, which has adverse effects on blastocyst implantation.
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Paul, Bidisha, Leena H. Shewade, and Daniel R. Buchholz. "cyp21a2 knockout tadpoles survive metamorphosis despite low corticosterone." Endocrinology, October 27, 2022. http://dx.doi.org/10.1210/endocr/bqac182.
Повний текст джерелаАнотація:
Abstract Corticosteroids are vital for organ maturation such that reduced corticosteroid signaling during post-embryonic development causes death in terrestrial vertebrates. Indeed, death occurs at metamorphosis in frogs lacking proopiomelanocortin (pomc) or the glucocorticoid receptor (GR; nr3c1). Some residual corticosteroids exist in pomc mutants to activate the wild-type GR and mineralocorticoid receptor (MR), and the elevated corticosteroids in GR mutants may activate MR. Thus, we expected a more severe developmental phenotype in tadpoles with inactivation of 21-hydroxylase, which should eliminate all interrenal corticosteroid biosynthesis. Using CRISPR/Cas9 in Xenopus tropicalis we produced an 11-base pair deletion in cyp21a2, the gene encoding 21-hydroxylase. Growth and development were delayed in cyp21a2 mutant tadpoles, but unlike the other frog models, they survived metamorphosis. Consistent with an absence of 21-hydroxylase, mutant tadpoles had a 95% reduction of aldosterone in tail tissue, but they retained some corticosterone (∼40% of wild-type siblings), an amount, however, too low for survival in pomc mutants. Decreased corticosteroid signaling was evidenced by reduced expression of corticosteroid-response gene, klf9 and by impaired negative feedback in the hypothalamus-pituitary-interrenal axis with higher mRNA expression levels of crh, pomc, star, and cyp11b2 and a ∼30-fold increase in tail content of progesterone. In-vitro tail tip culture showed that progesterone can transactivate the frog GR. The inadequate activation of GR by CORT in cyp21a2 mutants was likely compensated for by sufficient corticosteroid signaling from other GR ligands to allow survival through the developmental transition from aquatic to terrestrial life.
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Zurkinden, Line, Dmitri Sviridov, Bruno Vogt, and Geneviève Escher. "Sterol 27-hydroxylase gene dosage and the antiatherosclerotic effect of Rifampicin in mice." Bioscience Reports 38, no. 1 (January 25, 2018). http://dx.doi.org/10.1042/bsr20171162.
Повний текст джерелаАнотація:
Sterol 27-hydroxylase (CYP27A1) catalyzes the hydroxylation of cholesterol to 27-hydroxycholesterol (27-OHC) and regulates cholesterol homeostasis. In Cyp27a1/ Apolipoprotein E (ApoE) double knockout (KO) mice fed with Western diet (WD), the atherosclerotic phenotype found in ApoE KO mice was reversed. As protective mechanism, up-regulation of Cyp3a11 and Cyp7a1 was proposed. Cyp27a1 heterozygote/ApoE KO (het) mice, with reduced Cyp27a1 expression and normal levels of Cyp7a1 and Cyp3a11, developed more severe lesions than ApoE KO mice. To analyze the contribution of Cyp3a11 to the protection of atherosclerosis development, Cyp3a11 was induced by Rifampicin (RIF) in ApoE KO and het mice. Males were fed with WD and treated daily with RIF (10 mg/kg ip) or vehicle for 4 weeks. Atherosclerosis was quantified in the aortic valve. Plasma lipids and 27-hydroxycholesterol (27-OHC), expression of cytochromes P450 and genes involved in cholesterol transport and bile acids (BAs) signaling in liver and intestine, and intestinal cholesterol absorption were analyzed. RIF increased expression of hepatic but not intestinal Cyp3a11 4-fold in both genotypes. In ApoE KO mice treated with RIF, we found a 2-fold decrease in plasma cholesterol, and a 2-fold increase in high-density lipoprotein/low-density lipoprotein ratio and CY27A1 activity. Intestinal cholesterol absorption remained unchanged and atherosclerotic lesions decreased approximately 3-fold. In het mice, RIF had no effect on plasma lipids composition, CYP27A1 activity, and atherosclerotic plaque development, despite a reduction in cholesterol absorption. In conclusion, the antiatherogenic effect of Cyp3a11 induction by RIF was also dependent on Cyp27a1 expression.
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Li, Se-Ruo, Zhu-Xia Tan, Yuan-Hua Chen, Biao Hu, Cheng Zhang, Hua Wang, Hui Zhao та De-Xiang Xu. "Vitamin D deficiency exacerbates bleomycin-induced pulmonary fibrosis partially through aggravating TGF-β/Smad2/3-mediated epithelial-mesenchymal transition". Respiratory Research 20, № 1 (27 листопада 2019). http://dx.doi.org/10.1186/s12931-019-1232-6.
Повний текст джерелаАнотація:
Abstract Background Our earlier report indicated that active vitamin D3 inhibited epithelial-mesenchymal transition (EMT) in bleomycin (BLM)-induced pulmonary fibrosis. The objective of this study was to further investigate whether vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis. Methods This study consists of two independent experiments. Experiment 1, male mice were fed with vitamin D deficient (VDD) fodder. Experiment 2, Cyp27b1+/+, Cyp27b1+/− and Cyp27b1−/− mice were fed with standard diet. For pulmonary fibrosis, mice were intratracheally instilled with a single dose of BLM (1.5 mg/kg). Serum 25(OH) D level was measured. Pulmonary collagen deposition was assessed by Sirius red staining. EMT was measured and transforming growth factor-beta (TGF-β)/Smad3 signaling was evaluated in the lungs of BLM-treated mice. Results The relative weight of lungs was elevated in BLM-treated mice. Col1α1 and Col1α2, two collagen protein genes, were upregulated, and collagen deposition, as determined by Sirius red staining, was observed in the lungs of BLM-treated mice. E-cadherin, an epithelial marker, was downregulated. By contrast, vimentin and α-SMA, two EMT markers, were upregulated in the lungs of BLM-treated mice. Pulmonary TGF-β/Smad3 signaling was activated in BLM-induced lung fibrosis. Further analysis showed that feeding VDD diet, leading to vitamin D deficiency, aggravated elevation of BLM-induced relative lung weight. Moreover, feeding VDD diet aggravated BLM-induced TGF-β/Smad3 activation and subsequent EMT in the lungs. In addition, feeding VDD diet exacerbated BLM-induced pulmonary fibrosis. Additional experiment showed that Cyp27b1 gene knockout, leading to active vitamin D3 deficiency, exacerbated BLM-induced pulmonary fibrosis. Moreover, Cyp27b1 gene knockout aggravated pulmonary TGF-β/Smad2/3 activation and subsequent EMT in BLM-induced lung fibrosis. Conclusion Vitamin D deficiency exacerbates BLM-induced pulmonary fibrosis partially through aggravating TGF-β/Smad2/3-mediated EMT in the lungs.