Статті в журналах: "ABCE1 biogenesis"

1

Yu, Qian, Xu Han, and Da-Li Tian. "Deficiency of Functional Iron-Sulfur Domains in ABCE1 Inhibits the Proliferation and Migration of Lung Adenocarcinomas By Regulating the Biogenesis of Beta-Actin In Vitro." Cellular Physiology and Biochemistry 44, no. 2 (2017): 554–66. http://dx.doi.org/10.1159/000485090.

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Background/Aims: ATP-binding cassette transporter E1 (ABCE1), a unique ABC superfamily member that bears two Fe-S clusters, is essential for metastatic progression in lung cancer. Fe-S clusters within ABCE1 are crucial for ribosome dissociation and translation reinitiation; however, whether these clusters promote tumor proliferation and migration is unclear. Methods: The interaction between ABCE1 and β-actin was confirmed using GST pull-down. The lung adenocarcinoma (LUAD) cell line A549 was transduced with lentiviral packaging vectors overexpressing either wild-type ABCE1 or ABCE1 with Fe-S cluster deletions (ΔABCE1). The role of Fe-S clusters in the viability and migration of cancer cells was evaluated using clonogenic, MTT, Transwell and wound healing assays. Cytoskeletal rearrangement was determined using immunofluorescent techniques. Results: Fe-S clusters were the key domains in ABCE1 involved in binding to β-actin. The proliferative and migratory capacity increased in cells overexpressing ABCE1. However, the absence of Fe-S clusters reversed these effects. A549 cells overexpressing ABCE1 exhibited irregular morphology and increased levels of cytoskeletal polymerization as indicated by the immunofluorescence images. In contrast, cells expressing the Fe-S cluster deletion mutant presented opposing effects. Conclusion: These results demonstrate the indispensable role of Fe-S clusters when ABCE1 participates in the proliferation and migration of LUADs by interacting with β-actin. The Fe-S clusters of ABCE1 may be potential targets for the prevention of lung cancer metastasis.

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Key, Jana, Nesli Ece Sen, Aleksandar Arsović, Stella Krämer, Robert Hülse, Natasha Nadeem Khan, David Meierhofer, Suzana Gispert, Gabriele Koepf, and Georg Auburger. "Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence." Cells 9, no. 10 (October 2, 2020): 2229. http://dx.doi.org/10.3390/cells9102229.

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Iron deprivation activates mitophagy and extends lifespan in nematodes. In patients suffering from Parkinson’s disease (PD), PINK1-PRKN mutations via deficient mitophagy trigger iron accumulation and reduce lifespan. To evaluate molecular effects of iron chelator drugs as a potential PD therapy, we assessed fibroblasts by global proteome profiles and targeted transcript analyses. In mouse cells, iron shortage decreased protein abundance for iron-binding nucleotide metabolism enzymes (prominently XDH and ferritin homolog RRM2). It also decreased the expression of factors with a role for nucleotide surveillance, which associate with iron-sulfur-clusters (ISC), and are important for growth and survival. This widespread effect included prominently Nthl1-Ppat-Bdh2, but also mitochondrial Glrx5-Nfu1-Bola1, cytosolic Aco1-Abce1-Tyw5, and nuclear Dna2-Elp3-Pold1-Prim2. Incidentally, upregulated Pink1-Prkn levels explained mitophagy induction, the downregulated expression of Slc25a28 suggested it to function in iron export. The impact of PINK1 mutations in mouse and patient cells was pronounced only after iron overload, causing hyperreactive expression of ribosomal surveillance factor Abce1 and of ferritin, despite ferritin translation being repressed by IRP1. This misregulation might be explained by the deficiency of the ISC-biogenesis factor GLRX5. Our systematic survey suggests mitochondrial ISC-biogenesis and post-transcriptional iron regulation to be important in the decision, whether organisms undergo PD pathogenesis or healthy aging.

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Nürenberg-Goloub, Elina, and Robert Tampé. "Ribosome recycling in mRNA translation, quality control, and homeostasis." Biological Chemistry 401, no. 1 (December 18, 2019): 47–61. http://dx.doi.org/10.1515/hsz-2019-0279.

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Abstract Protein biosynthesis is a conserved process, essential for life. Ongoing research for four decades has revealed the structural basis and mechanistic details of most protein biosynthesis steps. Numerous pathways and their regulation have recently been added to the translation system describing protein quality control and messenger ribonucleic acid (mRNA) surveillance, ribosome-associated protein folding and post-translational modification as well as human disorders associated with mRNA and ribosome homeostasis. Thus, translation constitutes a key regulatory process placing the ribosome as a central hub at the crossover of numerous cellular pathways. Here, we describe the role of ribosome recycling by ATP-binding cassette sub-family E member 1 (ABCE1) as a crucial regulatory step controlling the biogenesis of functional proteins and the degradation of aberrant nascent chains in quality control processes.

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Yokoyama, Shinji. "ABCA1 and Biogenesis of HDL." Journal of Atherosclerosis and Thrombosis 13, no. 1 (2006): 1–15. http://dx.doi.org/10.5551/jat.13.1.

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5

Wang, Shuhui, and Jonathan D. Smith. "ABCA1 and nascent HDL biogenesis." BioFactors 40, no. 6 (October 30, 2014): 547–54. http://dx.doi.org/10.1002/biof.1187.

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Yokoyama, Shinji, Reijiro Arakawa, Cheng-ai Wu, Noriyuki Iwamoto, Rui Lu, Maki Tsujita, and Sumiko Abe-Dohmae. "Calpain-mediated ABCA1 degradation: Post-translational regulation of ABCA1 for HDL biogenesis." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1821, no. 3 (March 2012): 547–51. http://dx.doi.org/10.1016/j.bbalip.2011.07.017.

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Wang, Jing, Qianqian Xiao, Luyun Wang, Yan Wang, Daowen Wang, and Hu Ding. "Role of ABCA1 in Cardiovascular Disease." Journal of Personalized Medicine 12, no. 6 (June 20, 2022): 1010. http://dx.doi.org/10.3390/jpm12061010.

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Cholesterol homeostasis plays a significant role in cardiovascular disease. Previous studies have indicated that ATP-binding cassette transporter A1 (ABCA1) is one of the most important proteins that maintains cholesterol homeostasis. ABCA1 mediates nascent high-density lipoprotein biogenesis. Upon binding with apolipoprotein A-I, ABCA1 facilitates the efflux of excess intracellular cholesterol and phospholipids and controls the rate-limiting step of reverse cholesterol transport. In addition, ABCA1 interacts with the apolipoprotein receptor and suppresses inflammation through a series of signaling pathways. Thus, ABCA1 may prevent cardiovascular disease by inhibiting inflammation and maintaining lipid homeostasis. Several studies have indicated that post-transcriptional modifications play a critical role in the regulation of ABCA1 transportation and plasma membrane localization, which affects its biological function. Meanwhile, carriers of the loss-of-function ABCA1 gene are often accompanied by decreased expression of ABCA1 and an increased risk of cardiovascular diseases. We summarized the ABCA1 transcription regulation mechanism, mutations, post-translational modifications, and their roles in the development of dyslipidemia, atherosclerosis, ischemia/reperfusion, myocardial infarction, and coronary heart disease.

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8

Brunham, L. R. "Intestinal ABCA1 directly contributes to HDL biogenesis in vivo." Journal of Clinical Investigation 116, no. 4 (March 23, 2006): 1052–62. http://dx.doi.org/10.1172/jci27352.

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9

Gao, Jie, Yanni Xu, Yuan Yang, Yi Yang, Zhihui Zheng, Wei Jiang, Bin Hong, Xuguang Yan, and Shuyi Si. "Identification of Upregulators of Human ATP-Binding Cassette Transporter A1 via High-Throughput Screening of a Synthetic and Natural Compound Library." Journal of Biomolecular Screening 13, no. 7 (July 1, 2008): 648–56. http://dx.doi.org/10.1177/1087057108320545.

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The ATP-binding cassette transporter A1 (ABCA1) is a membrane transporter that directly contributes to high-density lipoprotein (HDL) biogenesis by mediating the cellular efflux of cholesterol and phospholipids to lipid-poor apolipoprotein A-I. Therefore, identification of a novel upregulator of ABCA1 would be beneficial for atherosclerosis prevention and/or therapy because of its pivotal role in cholesterol homeostasis and HDL metabolism. In this study, a high-throughput assay method for ABCA1 upregulators was developed and used for screening a synthetic and natural compound library. The cell-based high-throughput screen is conducted in a 96-well format using the human hepatoma HepG2 cells stably transfected with ABCA1 promoter-luciferase construct and calibrated with reference ABCA1 upregulators (oxysterols, 9-cis-retinoic acid, thiazolidinediones, cyclic adenosine monophosphate, verapamil, fenofibrate, and oncostatin M). Among 2600 compounds, 4 microbial compounds (pyrromycin, aclarubicin, daidzein, and pratensein) were picked up as hits by the high-throughput screening assay, and those compounds were further identified as upregulators of ABCA1 expression by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis. ( Journal of Biomolecular Screening 2008:648-656)

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10

Li, Li, Rongwen Li, Alex Zacharek, Fengjie Wang, Julie Landschoot-Ward, Michael Chopp, Jieli Chen, and Xu Cui. "ABCA1/ApoE/HDL Signaling Pathway Facilitates Myelination and Oligodendrogenesis after Stroke." International Journal of Molecular Sciences 21, no. 12 (June 19, 2020): 4369. http://dx.doi.org/10.3390/ijms21124369.

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ATP-binding cassette transporter A1 (ABCA1) plays an important role in the regulation of apolipoprotein E (ApoE) and the biogenesis of high-density lipoprotein (HDL) cholesterol in the mammalian brain. Cholesterol is a major source for myelination. Here, we investigate whether ABCA1/ApoE/HDL contribute to myelin repair and oligodendrogenesis in the ischemic brain after stroke. Specific brain ABCA1-deficient (ABCA1-B/-B) and ABCA1-floxed (ABCA1fl/fl) control mice were subjected to permanent distal middle-cerebral-artery occlusion (dMCAo) and were intracerebrally administered (1) artificial mouse cerebrospinal fluid (CSF) as vehicle control, (2) human plasma HDL3, and (3) recombined human ApoE2 starting 24 h after dMCAo for 14 days. All stroke mice were sacrificed 21 days after dMCAo. The ABCA1-B/-B–dMCAo mice exhibit significantly reduced myelination and oligodendrogenesis in the ischemic brain as well as decreased functional outcome 21 days after stroke compared with ABCA1fl/fl mice; administration of human ApoE2 or HDL3 in the ischemic brain significantly attenuates the deficits in myelination and oligodendrogenesis in ABCA1-B/-B–dMCAo mice ( p < 0.05, n = 9/group). In vitro, ABCA1-B/-B reduces ApoE expression and decreases primary oligodendrocyte progenitor cell (OPC) migration and oligodendrocyte maturation; HDL3 and ApoE2 treatment significantly reverses ABCA1-B/-B-induced reduction in OPC migration and oligodendrocyte maturation. Our data indicate that the ABCA1/ApoE/HDL signaling pathway contributes to myelination and oligodendrogenesis in the ischemic brain after stroke.

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Kypreos, Kyriakos E., and Vassilis I. Zannis. "Pathway of biogenesis of apolipoprotein E-containing HDL in vivo with the participation of ABCA1 and LCAT." Biochemical Journal 403, no. 2 (March 26, 2007): 359–67. http://dx.doi.org/10.1042/bj20061048.

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We have investigated the ability of apoE (apolipoprotein E) to participate in the biogenesis of HDL (high-density lipoprotein) particles in vivo using adenovirus-mediated gene transfer in apoA-I−/− (apolipoprotein A-I) or ABCA1−/− (ATP-binding cassette A1) mice. Infection of apoA-I−/− mice with 2×109 pfu (plaque-forming units) of an apoE4-expressing adenovirus increased both HDL and the triacylglycerol-rich VLDL (very-low-density lipoprotein)/IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein) fraction and generated discoidal HDL particles. ABCA1−/− mice treated similarly failed to form HDL particles, suggesting that ABCA1 is essential for the generation of apoE-containing HDL. Combined infection of apoA-I−/− mice with a mixture of adenoviruses expressing both apoE4 (2×109 pfu) and human LCAT (lecithin:cholesterol acyltransferase) (5×108 pfu) cleared the triacylglycerol-rich lipoproteins, increased HDL and converted the discoidal HDL into spherical HDL. Similarly, co-infection of apoE−/− mice with apoE4 and human LCAT corrected the hypercholesterolaemia and generated spherical particles, suggesting that LCAT is essential for the maturation of apoE-containing HDL. Overall, the findings indicate that apoE has a dual functionality. In addition to its documented functions in the clearance of triacylglycerol-rich lipoproteins, it participates in the biogenesis of HDL-sized apoE-containing particles. HDL particles generated by this pathway may account at least for some of the atheroprotective functions of apoE.

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12

Arakawa, Reijiro, Maki Tsujita, Noriyuki Iwamoto, Chisato Ito-Ohsumi, Rui Lu, Chen-Ai Wu, Kenji Shimizu, et al. "Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis." Journal of Lipid Research 50, no. 11 (May 20, 2009): 2299–305. http://dx.doi.org/10.1194/jlr.m900122-jlr200.

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13

Ghaznavi, Habib, Ehsan Aali, and Mohammad Soleiman Soltanpour. "Association Study of the ATP - Binding Cassette Transporter A1 (ABCA1) Rs2230806 Genetic Variation with Lipid Profile and Coronary Artery Disease Risk in an Iranian Population." Open Access Macedonian Journal of Medical Sciences 6, no. 2 (February 11, 2018): 274–79. http://dx.doi.org/10.3889/oamjms.2018.063.

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BACKGROUND: ATP - binding cassette transporter A1 (ABCA1) plays essential roles in the biogenesis of high -density lipoprotein - cholesterol. Variations in the ABCA1 gene may influence the risk of coronary artery disease (CAD).AIM: Present study aimed to investigate the association of rs2230806 (R219K) polymorphism of ABCA1 gene with the development and severity of CAD in an Iranian population.MATERIALS AND METHODS: Our study population consisted of 100 patients with angiographically confirmed CAD and 100 controls. The genotyping of R219K mutation of ABCA1 gene was determined by PCR - RFLP method. Lipid profile was determined using routine colourimetric assays. Statistical analysis was done by SPSS - 16.RESULTS: The genotypic (P = 0.024) and allelic (P = 0.001) distribution of the ABCA1 R219K polymorphism were significantly different between the two groups. In a univariate analysis (with genotype RR as the reference), the RK genotype (OR = 0.46, 95%CI = 0.25-0.86, P = 0.020) and KK genotype (OR = 0.27, 95%CI = 0.11 – 0.66, P = 0.005) was significantly associated with a decreased risk of CAD. A multiple logistic regression analysis revealed that smoking (0.008), diabetes (P = 0.023), triglyceride (P = 0.001), HDL - cholesterol (P = 0.002) and ABCA1 KK genotype (P = 0.009) were significantly and independently associated with the risk of CAD. The association between different genotypes of R219K polymorphism with lipid profile was not significant in both groups (P > 0.05). The R219K polymorphism was significantly associated with severity of CAD (P < 0.05).CONCLUSION: The carriage of K allele of ABCA1 R219K polymorphism has a protective effect on CAD risk and correlates with a decreased severity of CAD. This protective effect seems to be mediated independently of plasma lipid levels.

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Chen, Yu-Sheng, Hsuan-Miao Liu, and Tzung-Yan Lee. "Ursodeoxycholic Acid Regulates Hepatic Energy Homeostasis and White Adipose Tissue Macrophages Polarization in Leptin-Deficiency Obese Mice." Cells 8, no. 3 (March 16, 2019): 253. http://dx.doi.org/10.3390/cells8030253.

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Obesity has been shown to play a role in the pathogenesis of several forms of metabolic syndrome, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. Ursodeoxycholic acid (UDCA) has been shown to possess antioxidant and anti-inflammatory properties and prevents mitochondrial dysfunction in the progression of obesity-associated diseases. The aim of the study was to evaluate the mechanisms of UDCA during obesity-linked hepatic mitochondrial dysfunction and obesity-associated adipose tissue macrophage-induced inflammation in obese mice. UDCA significantly decreased lipid droplets, reduced free fatty acids (FFA) and triglycerides (TG), improved mitochondrial function, and enhanced white adipose tissue browning in ob/ob mice. This is associated with increased hepatic energy expenditure, mitochondria biogenesis, and incorporation of bile acid metabolism (Abca1, Abcg1 mRNA and BSEP, FGFR4, and TGR5 protein). In addition, UDCA downregulated NF-κB and STAT3 phosphorylation by negative regulation of the expression of SOCS1 and SOCS3 signaling. These changes were accompanied by decreased angiogenesis, as shown by the downregulation of VEGF, VCAM, and TGF-βRII expression. Importantly, UDCA is equally effective in reducing whole body adiposity. This is associated with decreased adipose tissue expression of macrophage infiltration (CD11b, CD163, and CD206) and lipogenic capacity markers (lipofuscin, SREBP-1, and CD36). Furthermore, UDCA significantly upregulated adipose browning in association with upregulation of SIRT-1-PGC1-α signaling in epididymis adipose tissue (EWAT). These results suggest that multi-targeted therapies modulate glucose and lipid biosynthesis fluxes, inflammatory response, angiogenesis, and macrophage differentiation. Therefore, it may be suggested that UDCA treatment may be a novel therapeutic agent for obesity.

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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.

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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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Wagner, Brandee L., Annabel F. Valledor, Gang Shao, Chris L. Daige, Eric D. Bischoff, Mary Petrowski, Kristen Jepsen, et al. "Promoter-Specific Roles for Liver X Receptor/Corepressor Complexes in the Regulation of ABCA1 and SREBP1 Gene Expression." Molecular and Cellular Biology 23, no. 16 (August 15, 2003): 5780–89. http://dx.doi.org/10.1128/mcb.23.16.5780-5789.2003.

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ABSTRACT Liver X receptors (LXRs) regulate the expression of genes involved in cholesterol and fatty acid homeostasis, including the genes for ATP-binding cassette transporter A1 (ABCA1) and sterol response element binding protein 1 (SREBP1). Loss of LXR leads to derepression of the ABCA1 gene in macrophages and the intestine, while the SREBP1c gene remains transcriptionally silent. Here we report that high-density-lipoprotein (HDL) cholesterol levels are increased in LXR-deficient mice, suggesting that derepression of ABCA1 and possibly other LXR target genes in selected tissues is sufficient to result in enhanced HDL biogenesis at the whole-body level. We provide several independent lines of evidence indicating that the repressive actions of LXRs are dependent on interactions with the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT). While dissociation of NCoR and SMRT results in derepression of the ABCA1 gene in macrophages, it is not sufficient for derepression of the SREBP1c gene. These findings reveal differential requirements for corepressors in the regulation of genes involved in cholesterol and fatty acid homeostasis and raise the possibility that these interactions may be exploited to develop synthetic ligands that selectively modulate LXR actions in vivo.

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Lake, Nicole J., Rachael L. Taylor, Hugh Trahair, K. N. Harikrishnan, Joanne E. Curran, Marcio Almeida, Hemant Kulkarni, et al. "TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis." European Heart Journal 38, no. 48 (June 26, 2017): 3579–87. http://dx.doi.org/10.1093/eurheartj/ehx315.

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Francone, Omar L., Papasani V. Subbaiah, Arie van Tol, Lori Royer, and Mehrdad Haghpassand. "Abnormal Phospholipid Composition Impairs HDL Biogenesis and Maturation in Mice Lacking Abca1†." Biochemistry 42, no. 28 (July 2003): 8569–78. http://dx.doi.org/10.1021/bi034540v.

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Hossain, Mohammad Anwar, Maki Tsujita, Frank J. Gonzalez, and Shinji Yokoyama. "Effects of Fibrate Drugs on Expression of ABCA1 and HDL Biogenesis in Hepatocytes." Journal of Cardiovascular Pharmacology 51, no. 3 (March 2008): 258–66. http://dx.doi.org/10.1097/fjc.0b013e3181624b22.

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Priestley, Jessica R. C., Laura A. Adang, Sarah Drewes Williams, Uta Lichter-Konecki, Caitlin Menello, Nicole M. Engelhardt, James C. DiPerna, et al. "Newborn Screening for X-Linked Adrenoleukodystrophy: Review of Data and Outcomes in Pennsylvania." International Journal of Neonatal Screening 8, no. 2 (March 23, 2022): 24. http://dx.doi.org/10.3390/ijns8020024.

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X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. It results from pathogenic variants in ABCD1, which encodes the peroxisomal very-long-chain fatty acid transporter, causing a spectrum of neurodegenerative phenotypes. The childhood cerebral form of the disease is particularly devastating. Early diagnosis and intervention improve outcomes. Because newborn screening facilitates identification of at-risk individuals during their asymptomatic period, X-ALD was added to the Pennsylvania newborn screening program in 2017. We analyzed outcomes from the first four years of X-ALD newborn screening, which employed a two-tier approach and reflexive ABCD1 sequencing. There were 51 positive screens with elevated C26:0-lysophosphatidylcholine on second-tier screening. ABCD1 sequencing identified 21 hemizygous males and 24 heterozygous females, and clinical follow up identified four patients with peroxisomal biogenesis disorders. There were two false-positive cases and one false-negative case. Three unscreened individuals, two of whom were symptomatic, were diagnosed following their young siblings’ newborn screening results. Combined with experiences from six other states, this suggests a U.S. incidence of roughly 1 in 10,500, higher than had been previously reported. Many of these infants lack a known family history of X-ALD. Together, these data highlight both the achievements and challenges of newborn screening for X-ALD.

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Tsujita, Maki, Mohammad Anwar Hossain, Rui Lu, Tomoe Tsuboi, Kuniko Okumura-Noji, and Shinji Yokoyama. "Exposure to High Glucose Concentration Decreases Cell Surface ABCA1 and HDL Biogenesis in Hepatocytes." Journal of Atherosclerosis and Thrombosis 24, no. 11 (2017): 1132–49. http://dx.doi.org/10.5551/jat.39156.

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Yamauchi, Yoshio, Shinji Yokoyama, and Ta-Yuan Chang. "ABCA1-dependent sterol release: sterol molecule specificity and potential membrane domain for HDL biogenesis." Journal of Lipid Research 57, no. 1 (October 24, 2015): 77–88. http://dx.doi.org/10.1194/jlr.m063784.

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Hu, Wei, Sumiko Abe-Dohmae, Maki Tsujita, Noriyuki Iwamoto, Osamu Ogikubo, Takanobu Otsuka, Yositaka Kumon, and Shinji Yokoyama. "Biogenesis of HDL by SAA is dependent on ABCA1 in the liver in vivo." Journal of Lipid Research 49, no. 2 (November 21, 2007): 386–93. http://dx.doi.org/10.1194/jlr.m700402-jlr200.

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Hafiane, Anouar, and Jacques Genest. "ATP binding cassette A1 (ABCA1) mediates microparticle formation during high-density lipoprotein (HDL) biogenesis." Atherosclerosis 257 (February 2017): 90–99. http://dx.doi.org/10.1016/j.atherosclerosis.2017.01.013.

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Zannis, Vassilis I., Angeliki Chroni, and Monty Krieger. "Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL." Journal of Molecular Medicine 84, no. 4 (February 25, 2006): 276–94. http://dx.doi.org/10.1007/s00109-005-0030-4.

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Vassilis, I., Su Shi, and Fotakis Panagiotis. "Role of apolipoproteins, ABCA1 and LCAT in the biogenesis of normal and aberrant high density lipoproteins." Journal of Biomedical Research 31, no. 6 (2017): 471. http://dx.doi.org/10.7555/jbr.31.20160082.

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Liu, Minjing, Xiaohu Mei, Haya Herscovitz, and David Atkinson. "N-terminal mutation of apoA-I and interaction with ABCA1 reveal mechanisms of nascent HDL biogenesis." Journal of Lipid Research 60, no. 1 (September 24, 2018): 44–57. http://dx.doi.org/10.1194/jlr.m084376.

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Ji, Ailing, Xuebing Wang, Victoria P. Noffsinger, Drew Jennings, Maria C. de Beer, Frederick C. de Beer, Lisa R. Tannock, and Nancy R. Webb. "Serum amyloid A is not incorporated into HDL during HDL biogenesis." Journal of Lipid Research 61, no. 3 (January 8, 2020): 328–37. http://dx.doi.org/10.1194/jlr.ra119000329.

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Liver-derived serum amyloid A (SAA) is present in plasma where it is mainly associated with HDL and from which it is cleared more rapidly than are the other major HDL-associated apolipoproteins. Although evidence suggests that lipid-free and HDL-associated forms of SAA have different activities, the pathways by which SAA associates and disassociates with HDL are poorly understood. In this study, we investigated SAA lipidation by hepatocytes and how this lipidation relates to the formation of nascent HDL particles. We also examined hepatocyte-mediated clearance of lipid-free and HDL-associated SAA. We prepared hepatocytes from mice injected with lipopolysaccharide or an SAA-expressing adenoviral vector. Alternatively, we incubated primary hepatocytes from SAA-deficient mice with purified SAA. We analyzed conditioned media to determine the lipidation status of endogenously produced and exogenously added SAA. Examining the migration of lipidated species, we found that SAA is lipidated and forms nascent particles that are distinct from apoA-I-containing particles and that apoA-I lipidation is unaltered when SAA is overexpressed or added to the cells, indicating that SAA is not incorporated into apoA-I-containing HDL during HDL biogenesis. Like apoA-I formation, generation of SAA-containing particles was dependent on ABCA1, but not on scavenger receptor class B type I. Hepatocytes degraded significantly more SAA than apoA-I. Taken together, our results indicate that SAA’s lipidation and metabolism by the liver is independent of apoA-I and that SAA is not incorporated into HDL during HDL biogenesis.

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Han, Yong-Hyun, Emily J. Onufer, Li-Hao Huang, Robert W. Sprung, W. Sean Davidson, Rafael S. Czepielewski, Mary Wohltmann, Mary G. Sorci-Thomas, Brad W. Warner, and Gwendalyn J. Randolph. "Enterically derived high-density lipoprotein restrains liver injury through the portal vein." Science 373, no. 6553 (July 22, 2021): eabe6729. http://dx.doi.org/10.1126/science.abe6729.

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The biogenesis of high-density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most of the HDL in the blood, HDL synthesis also occurs in the small intestine. Here, we show that intestine-derived HDL traverses the portal vein in the HDL3 subspecies form, in complex with lipopolysaccharide (LPS)–binding protein (LBP). HDL3, but not HDL2 or low-density lipoprotein, prevented LPS binding to and inflammatory activation of liver macrophages and instead supported extracellular inactivation of LPS. In mouse models involving surgical, dietary, or alcoholic intestinal insult, loss of intestine-derived HDL worsened liver injury, whereas outcomes were improved by therapeutics that elevated and depended upon raising intestinal HDL. Thus, protection of the liver from injury in response to gut-derived LPS is a major function of intestinally synthesized HDL.

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Duka, Adelina, Panagiotis Fotakis, Dimitra Georgiadou, Andreas Kateifides, Kalliopi Tzavlaki, Leonard von Eckardstein, Efstratios Stratikos, Dimitris Kardassis, and Vassilis I. Zannis. "ApoA-IV promotes the biogenesis of apoA-IV-containing HDL particles with the participation of ABCA1 and LCAT." Journal of Lipid Research 54, no. 1 (November 6, 2012): 107–15. http://dx.doi.org/10.1194/jlr.m030114.

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Toma, Laura, Teodora Barbălată, Gabriela M. Sanda, Loredan S. Niculescu, Anca V. Sima, and Camelia S. Stancu. "CRISPR/dCas9 Transcriptional Activation of Endogenous Apolipoprotein AI and Paraoxonase 1 in Enterocytes Alleviates Endothelial Cell Dysfunction." Biomolecules 11, no. 12 (November 25, 2021): 1769. http://dx.doi.org/10.3390/biom11121769.

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Atherosclerosis is the main cause of cardiovascular diseases with high prevalence worldwide. A promising therapeutic strategy to reverse atherosclerotic process is to improve the athero-protective potential of high-density lipoproteins (HDL). Since the small intestine is a source of HDL, we aimed to activate transcription of the endogenous HDL major proteins, apolipoprotein AI (ApoAI) and paraoxonase 1 (PON1), in enterocytes, and to evaluate their potential to correct the pro-inflammatory status of endothelial cells (EC). Caco-2 enterocytes were transfected with CRISPR activation plasmids targeting ApoAI or PON1, and their gene and protein expression were measured in cells and conditioned medium (CM). ATP binding cassette A1 and G8 transporters (ABCA1, ABCG8), scavenger receptor BI (SR-BI), and transcription regulators peroxisome proliferator-activated receptor γ (PPARγ), liver X receptors (LXRs), and sirtuin-1 (SIRT1) were assessed. Anti-inflammatory effects of CM from transfected enterocytes were estimated through its ability to inhibit tumor necrosis factor α (TNFα) activation of EC. Transcriptional activation of ApoAI or PON1 in enterocytes induces: (i) increase of their gene and protein expression, and secretion in CM; (ii) stimulation of ABCA1/G8 and SR-BI; (iii) upregulation of PPARγ, LXRs, and SIRT1. CM from transfected enterocytes attenuated the TNFα-induced inflammatory and oxidative stress in EC, by decreasing TNF receptor 1, monocyte chemoattractant protein-1, and p22phox. In conclusion, transcriptional activation of endogenous ApoAI or PON1 in enterocytes by CRISPR/dCas9 system is a realistic approach to stimulate biogenesis and function of major HDL proteins which can regulate cholesterol efflux transporters and reduce the inflammatory stress in activated EC.

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Klemp, Henry Gerd, Matthias Kettwig, Frank Streit, Jutta Gärtner, Hendrik Rosewich, and Ralph Krätzner. "LC-MS Based Platform Simplifies Access to Metabolomics for Peroxisomal Disorders." Metabolites 11, no. 6 (May 29, 2021): 347. http://dx.doi.org/10.3390/metabo11060347.

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Peroxisomes are central hubs for cell metabolism and their dysfunction is linked to devastating human disorders, such as peroxisomal biogenesis disorders and single peroxisomal enzyme/protein deficiencies. For decades, biochemical diagnostics have been carried out using classical markers such as very long-chain fatty acids (VLCFA), which can be inconspicuous in milder and atypical cases. Holistic metabolomics studies revealed several potentially new biomarkers for peroxisomal disorders for advanced laboratory diagnostics including atypical cases. However, establishing these new markers is a major challenge in routine diagnostic laboratories. We therefore investigated whether the commercially available AbsoluteIDQ p180 kit (Biocrates Lifesciences), which utilizes flow injection and liquid chromatography mass spectrometry, may be used to reproduce some key results from previous global metabolomics studies. We applied it to serum samples from patients with mutations in peroxisomal target genes PEX1, ABCD1, and the HSD17B4 gene. Here we found various changes in sphingomyelins and lysophosphatidylcholines. In conclusion, this kit can be used to carry out extended diagnostics for peroxisomal disorders in routine laboratories, even without access to a metabolomics unit.

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Zamanian-Daryoush, Maryam, Valentin Gogonea, Anthony J. DiDonato, Jennifer A. Buffa, Ibrahim Choucair, Bruce S. Levison, Randall A. Hughes, et al. "Site-specific 5-hydroxytryptophan incorporation into apolipoprotein A-I impairs cholesterol efflux activity and high-density lipoprotein biogenesis." Journal of Biological Chemistry 295, no. 15 (February 25, 2020): 4836–48. http://dx.doi.org/10.1074/jbc.ra119.012092.

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Apolipoprotein A-I (apoA-I) is the major protein constituent of high-density lipoprotein (HDL) and a target of myeloperoxidase-dependent oxidation in the artery wall. In atherosclerotic lesions, apoA-I exhibits marked oxidative modifications at multiple sites, including Trp72. Site-specific mutagenesis studies have suggested, but have not conclusively shown, that oxidative modification of Trp72 of apoA-I impairs many atheroprotective properties of this lipoprotein. Herein, we used genetic code expansion technology with an engineered Saccharomyces cerevisiae tryptophanyl tRNA-synthetase (Trp-RS):suppressor tRNA pair to insert the noncanonical amino acid 5-hydroxytryptophan (5-OHTrp) at position 72 in recombinant human apoA-I and confirmed site-specific incorporation utilizing MS. In functional characterization studies, 5-OHTrp72 apoA-I (compared with WT apoA-I) exhibited reduced ABC subfamily A member 1 (ABCA1)-dependent cholesterol acceptor activity in vitro (41.73 ± 6.57% inhibition; p < 0.01). Additionally, 5-OHTrp72 apoA-I displayed increased activation and stabilization of paraoxonase 1 (PON1) activity (μmol/min/mg) when compared with WT apoA-I and comparable PON1 activation/stabilization compared with reconstituted HDL (WT apoA-I, 1.92 ± 0.04; 5-OHTrp72 apoA-I, 2.35 ± 0.0; and HDL, 2.33 ± 0.1; p < 0.001, p < 0.001, and p < 0.001, respectively). Following injection into apoA-I–deficient mice, 5-OHTrp72 apoA-I reached plasma levels comparable with those of native apoA-I yet exhibited significantly reduced (48%; p < 0.01) lipidation and evidence of HDL biogenesis. Collectively, these findings unequivocally reveal that site-specific oxidative modification of apoA-I via 5-OHTrp at Trp72 impairs cholesterol efflux and the rate-limiting step of HDL biogenesis both in vitro and in vivo.

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Yammine, Aline, Amira Zarrouk, Thomas Nury, Anne Vejux, Norbert Latruffe, Dominique Vervandier-Fasseur, Mohammad Samadi, et al. "Prevention by Dietary Polyphenols (Resveratrol, Quercetin, Apigenin) Against 7-Ketocholesterol-Induced Oxiapoptophagy in Neuronal N2a Cells: Potential Interest for the Treatment of Neurodegenerative and Age-Related Diseases." Cells 9, no. 11 (October 23, 2020): 2346. http://dx.doi.org/10.3390/cells9112346.

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The Mediterranean diet is associated with health benefits due to bioactive compounds such as polyphenols. The biological activities of three polyphenols (quercetin (QCT), resveratrol (RSV), apigenin (API)) were evaluated in mouse neuronal N2a cells in the presence of 7-ketocholesterol (7KC), a major cholesterol oxidation product increased in patients with age-related diseases, including neurodegenerative disorders. In N2a cells, 7KC (50 µM; 48 h) induces cytotoxic effects characterized by an induction of cell death. When associated with RSV, QCT and API (3.125; 6.25 µM), 7KC-induced toxicity was reduced. The ability of QCT, RSV and API to prevent 7KC-induced oxidative stress was characterized by a decrease in reactive oxygen species (ROS) production in whole cells and at the mitochondrial level; by an attenuation of the increase in the level and activity of catalase; by attenuating the decrease in the expression, level and activity of glutathione peroxidase 1 (GPx1); by normalizing the expression, level and activity of superoxide dismutases 1 and 2 (SOD1, SOD2); and by reducing the decrease in the expression of nuclear erythroid 2-like factor 2 (Nrf2) which regulates antioxidant genes. QCT, RSV and API also prevented mitochondrial dysfunction in 7KC-treated cells by counteracting the loss of mitochondrial membrane potential (ΨΔm) and attenuating the decreased gene expression and/or protein level of AMP-activated protein kinase α (AMPKα), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) implicated in mitochondrial biogenesis. At the peroxisomal level, QCT, RSV and API prevented the impact of 7KC by counteracting the decrease in ATP binding cassette subfamily D member (ABCD)3 (a peroxisomal mass marker) at the protein and mRNA levels, as well as the decreased expresssion of genes associated with peroxisomal biogenesis (Pex13, Pex14) and peroxisomal β-oxidation (Abcd1, Acox1, Mfp2, Thiolase A). The 7KC-induced decrease in ABCD1 and multifunctional enzyme type 2 (MFP2), two proteins involved in peroxisomal β-oxidation, was also attenuated by RSV, QCT and API. 7KC-induced cell death, which has characteristics of apoptosis (cells with fragmented and/or condensed nuclei; cleaved caspase-3; Poly(ADP-ribose) polymerase (PARP) fragmentation) and autophagy (cells with monodansyl cadaverine positive vacuoles; activation of microtubule associated protein 1 light chain 3–I (LC3-I) to LC3-II, was also strongly attenuated by RSV, QCT and API. Thus, in N2a cells, 7KC induces a mode of cell death by oxiapoptophagy, including criteria of OXIdative stress, APOPTOsis and autoPHAGY, associated with mitochondrial and peroxisomal dysfunction, which is counteracted by RSV, QCT, and API reinforcing the interest for these polyphenols in prevention of diseases associated with increased 7KC levels.

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Zhang, Lin-Hua, Vaijinath S. Kamanna, Shobha H. Ganji, Xi-Ming Xiong, and Moti L. Kashyap. "Niacin increases HDL biogenesis by enhancing DR4-dependent transcription of ABCA1 and lipidation of apolipoprotein A-I in HepG2 cells." Journal of Lipid Research 53, no. 5 (March 1, 2012): 941–50. http://dx.doi.org/10.1194/jlr.m020917.

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Corzo, Deyanira, William Gibson, Kisha Johnson, Grant Mitchell, Guy LePage, Gerald F. Cox, Robin Casey, et al. "Contiguous Deletion of the X-Linked Adrenoleukodystrophy Gene (ABCD1) and DXS1357E: A Novel Neonatal Phenotype Similar to Peroxisomal Biogenesis Disorders." American Journal of Human Genetics 70, no. 6 (June 2002): 1520–31. http://dx.doi.org/10.1086/340849.

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Lu, Rui, Tomoe Tsuboi, Kuniko Okumura-Noji, Noriyuki Iwamoto, and Shinji Yokoyama. "Caveolin-1 facilitates internalization and degradation of ABCA1 and probucol oxidative products interfere with this reaction to increase HDL biogenesis." Atherosclerosis 253 (October 2016): 54–60. http://dx.doi.org/10.1016/j.atherosclerosis.2016.08.025.

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38

Boyd, Joseph S., Telsa M. Mittelmeier, Mary Rose Lamb, and Carol L. Dieckmann. "Thioredoxin-family protein EYE2 and Ser/Thr kinase EYE3 play interdependent roles in eyespot assembly." Molecular Biology of the Cell 22, no. 9 (May 2011): 1421–29. http://dx.doi.org/10.1091/mbc.e10-11-0918.

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The eyespot of the biflagellate unicellular green alga Chlamydomonas reinhardtii is a complex organelle that facilitates directional responses of the cell to environmental light stimuli. The eyespot, which assembles de novo after every cell division and is associated with the daughter four-membered (D4) microtubule rootlet, comprises an elliptical patch of rhodopsin photoreceptors on the plasma membrane and stacks of carotenoid-rich pigment granule arrays in the chloroplast. Two loci, EYE2 and EYE3, define factors involved in the formation and organization of the eyespot pigment granule arrays. Whereas EYE3, a serine/threonine kinase of the ABC1 family, localizes to pigment granules, EYE2 localization corresponds to an area of the chloroplast envelope in the eyespot. EYE2 is positioned along, and adjacent to, the D4 rootlet in the absence of pigment granules. The eyespot pigment granule array is required for maintenance of the elliptical shape of both the overlying EYE2 and channelrhodopsin-1 photoreceptor patches. We propose a model of eyespot assembly wherein rootlet and photoreceptor direct EYE2 to an area of the chloroplast envelope, where it acts to facilitate assembly of pigment granule arrays, and EYE3 plays a role in the biogenesis of the pigment granules.

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Abumrad, Nada A., and Nicholas O. Davidson. "Role of the Gut in Lipid Homeostasis." Physiological Reviews 92, no. 3 (July 2012): 1061–85. http://dx.doi.org/10.1152/physrev.00019.2011.

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Intestinal lipid transport plays a central role in fat homeostasis. Here we review the pathways regulating intestinal absorption and delivery of dietary and biliary lipid substrates, principally long-chain fatty acid, cholesterol, and other sterols. We discuss the regulation and functions of CD36 in fatty acid absorption, NPC1L1 in cholesterol absorption, as well as other lipid transporters including FATP4 and SRB1. We discuss the pathways of intestinal sterol efflux via ABCG5/G8 and ABCA1 as well as the role of the small intestine in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. We review the pathways and genetic regulation of chylomicron assembly, the role of dominant restriction points such as microsomal triglyceride transfer protein and apolipoprotein B, and the role of CD36, l-FABP, and other proteins in formation of the prechylomicron complex. We will summarize current concepts of regulated lipoprotein secretion (including HDL and chylomicron pathways) and include lessons learned from families with genetic mutations in dominant pathways (i.e., abetalipoproteinemia, chylomicron retention disease, and familial hypobetalipoproteinemia). Finally, we will provide an integrative view of intestinal lipid homeostasis through recent findings on the role of lipid flux and fatty acid signaling via diverse receptor pathways in regulating absorption and production of satiety factors.

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Zannis, V. I., and K. E. Kypreos. "Mo-W15:8 Novel pathway of biogenesis of apoe-containing HDL with the participation of ABCA1 and LCAT: Implications for dyslipidemias and atherogenesis." Atherosclerosis Supplements 7, no. 3 (January 2006): 39. http://dx.doi.org/10.1016/s1567-5688(06)80124-8.

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Kypreos, Kyriakos E. "ABCA1 Promotes the de Novo Biogenesis of Apolipoprotein CIII-Containing HDL Particles in Vivo and Modulates the Severity of Apolipoprotein CIII-Induced Hypertriglyceridemia†." Biochemistry 47, no. 39 (September 30, 2008): 10491–502. http://dx.doi.org/10.1021/bi801249c.

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Salerno, Alessandro G., Thiago Rentz, Gabriel G. Dorighello, Ana Carolina Marques, Estela Lorza-Gil, Amarylis C. B. A. Wanschel, Audrey de Moraes, Anibal E. Vercesi, and Helena C. F. Oliveira. "Lack of mitochondrial NADP(H)-transhydrogenase expression in macrophages exacerbates atherosclerosis in hypercholesterolemic mice." Biochemical Journal 476, no. 24 (December 20, 2019): 3769–89. http://dx.doi.org/10.1042/bcj20190543.

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The atherosclerosis prone LDL receptor knockout mice (Ldlr−/−, C57BL/6J background) carry a deletion of the NADP(H)-transhydrogenase gene (Nnt) encoding the mitochondrial enzyme that catalyzes NADPH synthesis. Here we hypothesize that both increased NADPH consumption (due to increased steroidogenesis) and decreased NADPH generation (due to Nnt deficiency) in Ldlr−/− mice contribute to establish a macrophage oxidative stress and increase atherosclerosis development. Thus, we compared peritoneal macrophages and liver mitochondria from three C57BL/6J mice lines: Ldlr and Nnt double mutant, single Nnt mutant and wild-type. We found increased oxidants production in both mitochondria and macrophages according to a gradient: double mutant > single mutant > wild-type. We also observed a parallel up-regulation of mitochondrial biogenesis (PGC1a, TFAM and respiratory complexes levels) and inflammatory (iNOS, IL6 and IL1b) markers in single and double mutant macrophages. When exposed to modified LDL, the single and double mutant cells exhibited significant increases in lipid accumulation leading to foam cell formation, the hallmark of atherosclerosis. Nnt deficiency cells showed up-regulation of CD36 and down-regulation of ABCA1 transporters what may explain lipid accumulation in macrophages. Finally, Nnt wild-type bone marrow transplantation into LDLr−/− mice resulted in reduced diet-induced atherosclerosis. Therefore, Nnt plays a critical role in the maintenance of macrophage redox, inflammatory and cholesterol homeostasis, which is relevant for delaying the atherogenesis process.

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Smirnova, Evgeniya V., Therese S. Collingwood, Catherine Bisbal, Oxana M. Tsygankova, Marina Bogush, Judy L. Meinkoth, Earl E. Henderson, Roland S. Annan, and Alexander Y. Tsygankov. "TULA proteins bind to ABCE-1, a host factor of HIV-1 assembly, and inhibit HIV-1 biogenesis in a UBA-dependent fashion." Virology 372, no. 1 (March 2008): 10–23. http://dx.doi.org/10.1016/j.virol.2007.10.012.

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Hall, Patricia L., Hong Li, Arthur F. Hagar, S. Caleb Jerris, Angela Wittenauer, and William Wilcox. "Newborn Screening for X-Linked Adrenoleukodystrophy in Georgia: Experiences from a Pilot Study Screening of 51,081 Newborns." International Journal of Neonatal Screening 6, no. 4 (October 23, 2020): 81. http://dx.doi.org/10.3390/ijns6040081.

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We screened 51,081 newborns for X-linked adrenoleukodystrophy (ALD) using a two-tiered strategy quantifying very long chain lysophosphatadylcholines (LPC). Our testing strategy used flow injection tandem mass spectrometry for the first-tier analysis of LPCs, and second-tier quantification of C26:0 LPC using liquid chromatography tandem mass spectrometry. There were 364 specimens considered abnormal using our first-tier algorithm that relied on the four LPC measurements and post-analytical tools. Second-tier test results were reported as normal or abnormal based on a cutoff for the single analyte, C26:0 LPC. Eleven cases were reported as abnormal based on second-tier test results. One male with ALD was identified, and two females with peroxisomal biogenesis disorders were also identified. A single female case remains unresolved, due to a loss to follow up after a negative molecular test result for ABCD1 gene sequencing. The positive predictive value for confirmed, clinically relevant disorders during this pilot study was 27.3%. Challenges identified during the study period were based around coverage for confirmatory testing, particularly if family members needed molecular testing, which is an ongoing issue with newborn screening in Georgia. We also encountered issues with the follow up for a patient who remained asymptomatic. Due to the different timelines involved with clinical findings in ALD, follow-up coordination may be more difficult, particularly if the child identified by newborn screening (NBS) is the only member of the family affected, or able to be tested.

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Hassan, Houssein Hajj, Maxime Denis, Dong-Young Donna Lee, Iulia Iatan, Dana Nyholt, Isabelle Ruel, Larbi Krimbou, and Jacques Genest. "Identification of an ABCA1-dependent phospholipid-rich plasma membrane apolipoprotein A-I binding site for nascent HDL formation: implications for current models of HDL biogenesis." Journal of Lipid Research 48, no. 11 (July 26, 2007): 2428–42. http://dx.doi.org/10.1194/jlr.m700206-jlr200.

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Hotta, Noriko, Sumiko Abe-Dohmae, Ryo Taguchi, and Shinji Yokoyama. "Preferential incorporation of shorter and less unsaturated acyl phospholipids into high density lipoprotein-like particles in the ABCA1- and ABCA7-mediated biogenesis with apoA-I." Chemistry and Physics of Lipids 187 (April 2015): 1–9. http://dx.doi.org/10.1016/j.chemphyslip.2015.01.005.

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Price, Nathan L., Xinbo Zhang, Pablo Fernández-Tussy, Abhishek K. Singh, Sean A. Burnap, Noemi Rotllan, Leigh Goedeke, et al. "Loss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis." Proceedings of the National Academy of Sciences 118, no. 5 (January 25, 2021): e2006478118. http://dx.doi.org/10.1073/pnas.2006478118.

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miR-33 is an intronic microRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve high-density lipoprotein (HDL) biogenesis in the liver and increase circulating HDL-C levels in both rodents and nonhuman primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole-body miR-33–knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function, and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardiometabolic diseases.

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Koukos, Georgios, Angeliki Chroni, Adelina Duka, Dimitris Kardassis, and Vassilis I. Zannis. "Naturally occurring and bioengineered apoA-I mutations that inhibit the conversion of discoidal to spherical HDL: the abnormal HDL phenotypes can be corrected by treatment with LCAT." Biochemical Journal 406, no. 1 (July 26, 2007): 167–74. http://dx.doi.org/10.1042/bj20070296.

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In the present study we have used adenovirus-mediated gene transfer of apoA-I (apolipoprotein A-I) mutants in apoA-I−/− mice to investigate how structural mutations in apoA-I affect the biogenesis and the plasma levels of HDL (high-density lipoprotein). The natural mutants apoA-I(R151C)Paris, apoA-I(R160L)Oslo and the bioengineered mutant apoA-I(R149A) were secreted efficiently from cells in culture. Their capacity to activate LCAT (lecithin:cholesterol acyltransferase) in vitro was greatly reduced, and their ability to promote ABCA1 (ATP-binding cassette transporter A1)-mediated cholesterol efflux was similar to that of WT (wild-type) apoA-I. Gene transfer of the three mutants in apoA-I−/− mice generated aberrant HDL phenotypes. The total plasma cholesterol of mice expressing the apoA-I(R160L)Oslo, apoA-I(R149A) and apoA-I(R151C)Paris mutants was reduced by 78, 59 and 61% and the apoA-I levels were reduced by 68, 64 and 55% respectively, as compared with mice expressing the WT apoA-I. The CE (cholesteryl ester)/TC (total cholesterol) ratio of HDL was decreased and the apoA-I was distributed in the HDL3 region. apoA-I(R160L)Oslo and apoA-I(R149A) promoted the formation of preβ1 and α4-HDL subpopulations and gave a mixture of discoidal and spherical particles. apoA-I(R151C)Paris generated subpopulations of different sizes that migrate between preβ and α-HDL and formed mostly spherical and a few discoidal particles. Simultaneous treatment of mice with adenovirus expressing any of the three mutants and human LCAT normalized plasma apoA-I, HDL cholesterol levels and the CE/TC ratio. It also led to the formation of spherical HDL particles consisting mostly of α-HDL subpopulations of larger size. The correction of the aberrant HDL phenotypes by treatment with LCAT suggests a potential therapeutic intervention for HDL abnormalities that result from specific mutations in apoA-I.

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Besse, Andrej, Lenka Besse, Sara C. Stolze, Amin Sobh, Esther A. Zaal, Alwin J. van der Ham, Mario Ruiz, et al. "Nelfinavir Overcomes Proteasome Inhibitor Resistance in Multiple Myeloma By Modulating Membrane Lipid Bilayer Composition and Fluidity." Blood 136, Supplement 1 (November 5, 2020): 11. http://dx.doi.org/10.1182/blood-2020-136253.

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INTRODUCTION Nelfinavir is a highly lipophilic, first generation HIV-protease inhibitor (HIV-PI) approved for HIV treatment. It has largely been replaced by next-generation HIV-PI with increased specificity and efficacy for HIV therapy, partly reflecting the significant rate of the off-target activity of nelfinavir. Increasing preclinical and clinical evidence shows that nelfinavir has broad anti-cancer activity as a single agent and in combination, potentially related to its off-target activity in mammalian cells. Nelfinavir is particularly effective in the treatment of proteasome inhibitor-refractory multiple myeloma (MM), where the combination of nelfinavir+bortezomib+dexamethasone yielded an overall response rate (ORR, PR or better) > 65% in a Phase II clinical trial. The targets and molecular mechanism of action of nelfinavir in MM are unknown. This hampers both, a rational clinical repositioning and development of nelfinavir as antineoplastic drug, as well as the design, synthesis and testing of next generation nelfinavir-like compounds with optimized antineoplastic activity and improved specificity or pharmacologic properties. We therefore aimed to take an unbiased target-identification approach to identify molecular targets of nelfinavir in human malignant cells and link them to cell biological processes and mechanisms that mediate sensitivity or resistance to nelfinavir treatment. METHODS Proteome-wide affinity-purification of targets binding the nelfinavir active site was combined with genome-wide CRISPR/Cas9-based screening to identify protein partners interacting with nelfinavir and candidate genetic contributors affecting nelfinavir cytotoxicity. Multiple intracellular reporter systems including RUSH system, ATP/ADP constructs; FRAP microscopy, Seahorse measurements, flow cytometry, qPCR, metabolic labelling, lipidomics and viability assays were used to dissect functional alterations in pathways related to nelfinavir targets. RESULTS We identified a common set of proteins interacting specifically with the active site of nelfinavir. These proteins are embedded in intracellular, lipid-rich membranes of mitochondria (VDAC1,2,3, ANT2), endoplasmic reticulum (BCAP31, CANX, SRPRB) and nuclear envelope (PGRMC2) and are consistent across multiple cancer cell types. ADIPOR2, a key regulator gene of membrane lipid fluidity, was identified as a key nelfinavir resistance gene, while genes involved in fatty acids (FAs) and cholesterol metabolism, vesicular trafficking and mitochondria biogenesis are candidate sensitivity genes. We further show that via binding to proteins in lipid-rich membranes nelfinavir affects membrane composition and reduces membrane fluidity, leading to induction of FAs synthesis and the unfolded protein response (UPR). Via its structural interference with membrane fluidity, nelfinavir impairs the function and mobility of a diverse set of membrane-associated proteins and processes, such as glucose flux and processing, mitochondria respiration, energy supply, transmembrane vesicular transport and ABCB1-mediated drug efflux, as we show in different reporter systems in live MM cells. These functional effects are prevented by addition of metabolically inert lipids to be incorporated in membranes, supporting a direct structural activity of nelfinavir. The adaptive biology of proteasome inhibitor (PI)-resistant myeloma relies on metabolic reprogramming and changes in lipid composition, drug export and down-modulation of the UPR. Modulation of membrane fluidity and depletion of FAs/cholesterol is synergistic with proteasome inhibitors in PI-resistant MM. Thus, the mechanism of action of nelfinavir perfectly matches with the biology of PI-resistant MM, serving as a molecular rational for its significant clinical activity. CONCLUSION We here demonstrate in vitro that the activity of nelfinavir against MM cells is triggered through changes in lipid metabolism and the fluidity of lipid-rich membranes. Pharmacologic targeting of membrane fluidity is a novel, potent mechanism to achieve anti-cancer activity, in particular against PI-refractory MM. This mechanism explains the clinical activity of nelfinavir in MM treatment as well as the key side effects of nelfinavir during antiretroviral therapy. Disclosures No relevant conflicts of interest to declare.

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Navarro-Quiles, Carla, Eduardo Mateo-Bonmatí, Héctor Candela, Pedro Robles, Antonio Martínez-Laborda, Yolanda Fernández, Jan Šimura, et al. "The Arabidopsis ATP-Binding Cassette E protein ABCE2 is a conserved component of the translation machinery." Frontiers in Plant Science 13 (October 17, 2022). http://dx.doi.org/10.3389/fpls.2022.1009895.

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ATP-Binding Cassette E (ABCE) proteins dissociate cytoplasmic ribosomes after translation terminates, and contribute to ribosome recycling, thus linking translation termination to initiation. This function has been demonstrated to be essential in animals, fungi, and archaea, but remains unexplored in plants. In most species, ABCE is encoded by a single-copy gene; by contrast, Arabidopsis thaliana has two ABCE paralogs, of which ABCE2 seems to conserve the ancestral function. We isolated apiculata7-1 (api7-1), the first viable, hypomorphic allele of ABCE2, which has a pleiotropic morphological phenotype reminiscent of mutations affecting ribosome biogenesis factors and ribosomal proteins. We also studied api7-2, a null, recessive lethal allele of ABCE2. Co-immunoprecipitation experiments showed that ABCE2 physically interacts with components of the translation machinery. An RNA-seq study of the api7-1 mutant showed increased responses to iron and sulfur starvation. We also found increased transcript levels of genes related to auxin signaling and metabolism. Our results support for the first time a conserved role for ABCE proteins in translation in plants, as previously shown for the animal, fungal, and archaeal lineages. In Arabidopsis, the ABCE2 protein seems important for general growth and vascular development, likely due to an indirect effect through auxin metabolism.

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