Journal articles: 'HMGCS2'

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Wang, Yuan-Hsi, Fat-Moon Suk, and Yi-Jen Liao. "Loss of HMGCS2 Enhances Lipogenesis and Attenuates the Protective Effect of the Ketogenic Diet in Liver Cancer." Cancers 12, no. 7 (July 4, 2020): 1797. http://dx.doi.org/10.3390/cancers12071797.

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Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor with limited treatment. The ketogenic diet (KD) emerged as a metabolic therapy for cancer; however, the antitumor effect on HCC remains controversial. We previously reported that the ketogenesis rate-limiting enzyme, 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), was downregulated in most patients with HCC. The knockdown of HMGCS2 enhanced the proliferation and metastasis ability of HCC cells. However, the role of HMGCS2 in affecting KD-mediated metabolic effects remains unclear. Here, we report that KD feeding upregulates HMGCS2 expression and inhibits HCC tumor growth, while a reverse correlation between tumor size and HMGCS2 expression was observed. We found that HCC cells with HMGCS2 downregulation possess altered lipid metabolism that increases fatty acid, triglyceride, and cholesterol synthesis. Under KD feeding, a higher tumor growth rate was observed in HMGCS2 knockdown tumors, which had increased lipid synthesis-related marker expression and a positive correlation between lipid quantity and tumor weight. In conclusion, these results demonstrate that the downregulation of HMGCS2 attenuates the protective effect of the KD by shifting ketone production to enhance de novo lipogenesis in HCC. Our study elucidates a new molecular mechanism underlying the crosstalk between HMGCS2 expression and the KD in cancer treatment, which provides more information for precision medicine in developing personalized treatment strategies.

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Venable, Andrea H., Lauren E. Lee, Kyle Feola, John Santoyo, Tatyana Broomfield, and Sarah C. Huen. "Fasting-induced HMGCS2 expression in the kidney does not contribute to circulating ketones." American Journal of Physiology-Renal Physiology 322, no. 4 (April 1, 2022): F460—F467. http://dx.doi.org/10.1152/ajprenal.00447.2021.

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The mitochondrial enzyme hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) catalyzes the rate-limiting step of ketogenesis. Although the liver constitutively expresses HMGCS2 and is considered the main ketogenic organ, HMGCS2 is induced in the kidney during fasting, leading to the proposal that the kidney contributes to fasting ketosis. We showed kidney HMGCS2 does not contribute to circulating ketones during fasting and cannot compensate for hepatic ketogenic insufficiency.

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Zou, Kejian, Yan Hu, Musheng Li, Hongli Wang, Yuhua Zhang, Ling Huang, Yuanwen Xie, et al. "Potential Role of HMGCS2 in Tumor Angiogenesis in Colorectal Cancer and Its Potential Use as a Diagnostic Marker." Canadian Journal of Gastroenterology and Hepatology 2019 (July 1, 2019): 1–8. http://dx.doi.org/10.1155/2019/8348967.

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Objective. HMGCS2 is the rate-limiting enzyme of ketogenesis, which is vital for tumor initiation or metastasis. The aim of this study is to determine the relationship between HMGCS2 and tumor angiogenesis.Materials and Methods. The study consisted of 100 cases with colorectal cancer and healthy control, the expression of HMGCS2 and the microvessel density (MVD) (marker: CD31) were analyzed by immunohistochemistry and tube formation, and the centration ofβ-hydroxybutyrate in serum was assessed by biochemical analysis.Results. The results showed that HMGCS2 expression is significantly reduced in colorectal cancer compared with healthy control, which is inversely correlated with MVD in colorectal cancer by IHC analysis. What is more, knockdown HMGCS2 expression in HT-29 cells significantly contributed endothelial cell tube formation.Conclusion. These findings implying HMGCS2 may have a negative regulation of tumor angiogenesis and provide an approach to inhibit tumor angiogenesis.

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Kim, Ji Tae, Chang Li, Heidi L. Weiss, Yuning Zhou, Chunming Liu, Qingding Wang, and B. Mark Evers. "Regulation of Ketogenic Enzyme HMGCS2 by Wnt/β-catenin/PPARγ Pathway in Intestinal Cells." Cells 8, no. 9 (September 19, 2019): 1106. http://dx.doi.org/10.3390/cells8091106.

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The Wnt/β-catenin pathway plays a crucial role in development and renewal of the intestinal epithelium. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting ketogenic enzyme in the synthesis of ketone body β-hydroxybutyrate (βHB), contributes to the regulation of intestinal cell differentiation. Here, we have shown that HMGCS2 is a novel target of Wnt/β-catenin/PPARγ signaling in intestinal epithelial cancer cell lines and normal intestinal organoids. Inhibition of the Wnt/β-catenin pathway resulted in increased protein and mRNA expression of HMGCS2 and βHB production in human colon cancer cell lines LS174T and Caco2. In addition, Wnt inhibition increased expression of PPARγ and its target genes, FABP2 and PLIN2, in these cells. Conversely, activation of Wnt/β-catenin signaling decreased protein and mRNA levels of HMGCS2, βHB production, and expression of PPARγ and its target genes in LS174T and Caco2 cells and mouse intestinal organoids. Moreover, inhibition of PPARγ reduced HMGCS2 expression and βHB production, while activation of PPARγ increased HMGCS2 expression and βHB synthesis. Furthermore, PPARγ bound the promoter of HMGCS2 and this binding was enhanced by β-catenin knockdown. Finally, we showed that HMGCS2 inhibited, while Wnt/β-catenin stimulated, glycolysis, which contributed to regulation of intestinal cell differentiation. Our results identified HMGCS2 as a downstream target of Wnt/β-catenin/PPARγ signaling in intestinal epithelial cells. Moreover, our findings suggest that Wnt/β-catenin/PPARγ signaling regulates intestinal cell differentiation, at least in part, through regulation of ketogenesis.

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Wang, Yuan-Hsi, Chao-Lien Liu, Wan-Chun Chiu, Yuh-Ching Twu, and Yi-Jen Liao. "HMGCS2 Mediates Ketone Production and Regulates the Proliferation and Metastasis of Hepatocellular Carcinoma." Cancers 11, no. 12 (November 26, 2019): 1876. http://dx.doi.org/10.3390/cancers11121876.

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Hepatocellular carcinoma (HCC) is the most common primary malignant tumor worldwide; however, the traditional therapeutic approaches and survival rates are still limited. To improve current therapies, it is necessary to investigate the molecular mechanisms underlying liver cancer and to identify potential therapeutic targets. The aims of this study were to verify the mechanisms and therapeutic potential of the ketogenesis rate-limiting enzyme 3-Hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in HCC. Immunohistochemical staining of human liver disease tissue arrays showed that HMGCS2 is abundantly expressed in normal liver tissues but is downregulated in cirrhosis and HCC tissues. In HCC patients, lower HMGCS2 expression was correlated with higher pathological grades and clinical stages. In our investigation of the molecular mechanisms of HMGCS2 in HCC, we showed that knockdown of HMGCS2 decreased ketone production, which promoted cell proliferation, cell migration, and xenograft tumorigenesis by enhancing c-Myc/cyclinD1 and EMT signaling and by suppressing the caspase-dependent apoptosis pathway. Ketone body treatment reduced the proliferation- and migration-promoting effects of HMGCS2 knockdown in cells. In contrast, HMGCS2 overexpression increased the intracellular ketone level and inhibited cell proliferation, cell migration, and xenograft tumorigenesis. Finally, ketogenic diet administration significantly inhibited liver cancer cell growth in mice. Our studies highlight the potential therapeutic strategy of targeting HMGCS2-mediated ketogenesis in liver cancer.

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Suk, Fat-Moon, Chien-Ying Wu, Wan-Chun Chiu, Chia-Ying Chien, Tzu-Lang Chen, and Yi-Jen Liao. "HMGCS2 Mediation of Ketone Levels Affects Sorafenib Treatment Efficacy in Liver Cancer Cells." Molecules 27, no. 22 (November 18, 2022): 8015. http://dx.doi.org/10.3390/molecules27228015.

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Primary liver cancer is the fifth leading death of cancers in men, and hepatocellular carcinoma (HCC) accounts for approximately 90% of all primary liver cancer cases. Sorafenib is a first-line drug for advanced-stage HCC patients. Sorafenib is a multi-target kinase inhibitor that blocks tumor cell proliferation and angiogenesis. Despite sorafenib treatment extending survival, some patients experience side effects, and sorafenib resistance does occur. 3-Hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme for ketogenesis, which synthesizes the ketone bodies, β-hydroxybutyrate (β-HB) and acetoacetate (AcAc). β-HB is the most abundant ketone body which is present in a 4:1 ratio compared to AcAc. Recently, ketone body treatment was found to have therapeutic effects against many cancers by causing metabolic alternations and cancer cell apoptosis. Our previous publication showed that HMGCS2 downregulation-mediated ketone body reduction promoted HCC clinicopathological progression through regulating c-Myc/cyclin D1 and caspase-dependent signaling. However, whether HMGCS2-regulated ketone body production alters the sensitivity of human HCC to sorafenib treatment remains unclear. In this study, we showed that HMGCS2 downregulation enhanced the proliferative ability and attenuated the cytotoxic effects of sorafenib by activating expressions of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-P38, and p-AKT. In contrast, HMGCS2 overexpression decreased cell proliferation and enhanced the cytotoxic effects of sorafenib in HCC cells by inhibiting ERK activation. Furthermore, we showed that knockdown HMGCS2 exhibited the potential migratory ability, as well as decreasing zonula occludens protein (ZO)-1 and increasing c-Myc expression in both sorafenib-treated Huh7 and HepG2 cells. Although HMGCS2 overexpression did not alter the migratory effect, expressions of ZO-1, c-Myc, and N-cadherin decreased in sorafenib-treated HMGCS2-overexpressing HCC cells. Finally, we investigated whether ketone treatment influences sorafenib sensitivity. We showed that β-HB pretreatment decreased cell proliferation and enhanced antiproliferative effect of sorafenib in both Huh7 and HepG2 cells. In conclusion, this study defined the impacts of HMGCS2 expression and ketone body treatment on influencing the sorafenib sensitivity of liver cancer cells.

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Ding, Rongrong, Tianyou Chen, Yuan Zhang, Xiaorong Chen, Liping Zhuang, and Zongguo Yang. "HMGCS2 in metabolic pathways was associated with overall survival in hepatocellular carcinoma: A LASSO-derived study." Science Progress 104, no. 3 (July 2021): 003685042110317. http://dx.doi.org/10.1177/00368504211031749.

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This integrated bioinformatic study aimed to investigate potential prognostic candidates in hepatocellular carcinoma (HCC). In the GSE14520, GSE101685, and The Cancer Genome Atlas (TCGA) datasets, differentially expressed genes (DEGs) were identified and functional pathways of common DEGs were enriched. The least absolute shrinkage and selection operator (LASSO) model was used to screen the potential parameters associated with overall survival (OS) in HCC patients. Metabolic pathways were the most significantly enriched functional pathways of common DEGs in these three datasets. After LASSO model analysis, HMGCS2, UGP2, BCLC staging and TNM staging were screened as potential prognostic candidates for OS in HCC patients in GSE14520. HMGCS2 in the metabolic pathway was significantly downregulated in tumor tissues and peripheral blood mononuclear cells in HCC patients (all p < 0.05). Cox regression model indicated that HMGCS2 might be associate with OS in HCC patients in GSE14520 and in the TCGA ( p = 0.029 and p = 0.05, respectively). Kaplan–Meier analysis demonstrated that HMGCS2 downregulation in tumors contributed to an unfavorable OS in HCC patients, both in GSE14520 and in the TCGA ( p = 0.0001 and p = 0.0002, respectively). Additionally, HMGCS2 was significantly downregulated in HCC patients with high alpha-fetoprotein (AFP), main tumor size >5 cm, multinodular, advanced tumor staging including BCLC, TNM and CLIP (all p < 0.05). HMGCS2 was involved in metabolic pathways, and downregulated HMGCS2 in tumors was associated with unfavorable OS in HCC patients.

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Helenius, Terhi O., Julia O. Misiorek, Joel H. Nyström, Lina E. Fortelius, Aida Habtezion, Jian Liao, M. Nadeem Asghar, et al. "Keratin 8 absence down-regulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism." Molecular Biology of the Cell 26, no. 12 (June 15, 2015): 2298–310. http://dx.doi.org/10.1091/mbc.e14-02-0736.

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Simple-type epithelial keratins are intermediate filament proteins important for mechanical stability and stress protection. Keratin mutations predispose to human liver disorders, whereas their roles in intestinal diseases are unclear. Absence of keratin 8 (K8) in mice leads to colitis, decreased Na/Cl uptake, protein mistargeting, and longer crypts, suggesting that keratins contribute to intestinal homeostasis. We describe the rate-limiting enzyme of the ketogenic energy metabolism pathway, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), as a major down-regulated protein in the K8-knockout (K8−/−) colon. K8 absence leads to decreased quantity and activity of HMGCS2, and the down-regulation is not dependent on the inflammatory state, since HMGCS2 is not decreased in dextran sulfate sodium-induced colitis. Peroxisome proliferator–activated receptor α, a transcriptional activator of HMGCS2, is similarly down-regulated. Ketogenic conditions—starvation or ketogenic diet—increase K8+/+ HMGCS2, whereas this response is blunted in the K8−/− colon. Microbiota-produced short-chain fatty acids (SCFAs), substrates in the colonic ketone body pathway, are increased in stool, which correlates with decreased levels of their main transporter, monocarboxylate transporter 1 (MCT1). Microbial populations, including the main SCFA-butyrate producers in the colon, were not altered in the K8−/−. In summary, the regulation of the SCFA-MCT1-HMGCS2 axis is disrupted in K8−/− colonocytes, suggesting a role for keratins in colonocyte energy metabolism and homeostasis.

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Yi, Weijie, Xiao Xie, Miying Du, Yongjun Bu, Nannan Wu, Hui Yang, Chong Tian, et al. "Green Tea Polyphenols Ameliorate the Early Renal Damage Induced by a High-Fat Diet via Ketogenesis/SIRT3 Pathway." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–14. http://dx.doi.org/10.1155/2017/9032792.

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Scope. Several reports in the literature have suggested the renoprotective effects of ketone bodies and green tea polyphenols (GTPs). Our previous study found that GTP consumption could elevate the renal expression of the ketogenic rate-limiting enzyme, which was decreased by a high-fat diet (HFD) in rats. Here, we investigated whether ketogenesis can mediate renoprotection by GTPs against an HFD. Methods and Results. Wistar rats were fed a standard or HFD with or without GTPs for 18 weeks. The renal oxidative stress level, kidney function, renal expression, and activity levels of mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase 2 (HMGCS2) and sirtuin 3(SIRT3) were detected. The increased renal oxidative stress and the loss of renal function induced by the HFD were ameliorated by GTPs. Renal ketogenesis and SIRT3 expression and activity levels, which were reduced by the HFD, were restored by GTPs. In vitro, HEK293 cells were transfected with the eukaryotic expression plasmid pcDNA HMGCS2. GTP treatment could upregulate HMGCS2 and SIRT3 expression. Although SIRT3 expression was not affected by HMGCS2 transfection, the 4-hydroxy-2-nonenal (4-HNE) level and the acetyl-MnSOD (K122)/MnSOD ratio were reduced in HMGCS2-transfected cells in the context of H2O2. Conclusion. The ketogenesis/SIRT3 pathway mediates the renoprotection of GTPs against the oxidative stress induced by an HFD.

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Geisler, Caroline E., Susma Ghimire, Randy L. Bogan, and Benjamin J. Renquist. "Role of ketone signaling in the hepatic response to fasting." American Journal of Physiology-Gastrointestinal and Liver Physiology 316, no. 5 (May 1, 2019): G623—G631. http://dx.doi.org/10.1152/ajpgi.00415.2017.

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Ketosis is a metabolic adaptation to fasting, nonalcoholic fatty liver disease (NAFLD), and prolonged exercise. β-OH butyrate acts as a transcriptional regulator and at G protein-coupled receptors to modulate cellular signaling pathways in a hormone-like manner. While physiological ketosis is often adaptive, chronic hyperketonemia may contribute to the metabolic dysfunction of NAFLD. To understand how β-OH butyrate signaling affects hepatic metabolism, we compared the hepatic fasting response in control and 3-hydroxy-3-methylglutaryl-CoA synthase II (HMGCS2) knockdown mice that are unable to elevate β-OH butyrate production. To establish that rescue of ketone metabolic/endocrine signaling would restore the normal hepatic fasting response, we gave intraperitoneal injections of β-OH butyrate (5.7 mmol/kg) to HMGCS2 knockdown and control mice every 2 h for the final 9 h of a 16-h fast. In hypoketonemic, HMGCS2 knockdown mice, fasting more robustly increased mRNA expression of uncoupling protein 2 (UCP2), a protein critical for supporting fatty acid oxidation and ketogenesis. In turn, exogenous β-OH butyrate administration to HMGCS2 knockdown mice decreased fasting UCP2 mRNA expression to that observed in control mice. Also supporting feedback at the transcriptional level, β-OH butyrate lowered the fasting-induced expression of HMGCS2 mRNA in control mice. β-OH butyrate also regulates the glycemic response to fasting. The fast-induced fall in serum glucose was absent in HMGCS2 knockdown mice but was restored by β-OH butyrate administration. These data propose that endogenous β-OH butyrate signaling transcriptionally regulates hepatic fatty acid oxidation and ketogenesis, while modulating glucose tolerance. NEW & NOTEWORTHY Ketogenesis regulates whole body glucose metabolism and β-OH butyrate produced by the liver feeds back to inhibit hepatic β-oxidation and ketogenesis during fasting.

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Fang, Chih-Yuan, Mien-Cheng Chen, Tzu-Hao Chang, Chia-Chen Wu, Jen-Ping Chang, Hsien-Da Huang, Wan-Chun Ho, et al. "Idi1 and Hmgcs2 Are Affected by Stretch in HL-1 Atrial Myocytes." International Journal of Molecular Sciences 19, no. 12 (December 18, 2018): 4094. http://dx.doi.org/10.3390/ijms19124094.

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Background: Lipid expression is increased in the atrial myocytes of mitral regurgitation (MR) patients. This study aimed to investigate key regulatory genes and mechanisms of atrial lipotoxic myopathy in MR. Methods: The HL-1 atrial myocytes were subjected to uniaxial cyclic stretching for eight hours. Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism were analyzed by PCR assay (168 genes). Results: The stretched myocytes had significantly larger cell size and higher lipid expression than non-stretched myocytes (all p < 0.001). Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism in the myocytes were analyzed by PCR assay (168 genes). In comparison with their counterparts in non-stretched myocytes, seven genes in stretched monocytes (Idi1, Olr1, Nr1h4, Fabp2, Prkag3, Slc27a5, Fabp6) revealed differential upregulation with an altered fold change >1.5. Nine genes in stretched monocytes (Apoa4, Hmgcs2, Apol8, Srebf1, Acsm4, Fabp1, Acox2, Acsl6, Gk) revealed differential downregulation with an altered fold change <0.67. Canonical pathway analysis, using Ingenuity Pathway Analysis software, revealed that the only genes in the “superpathway of cholesterol biosynthesis” were Idi1 (upregulated) and Hmgcs2 (downregulated). The fraction of stretched myocytes expressing Nile red was significantly decreased by RNA interference of Idi1 (p < 0.05) and was significantly decreased by plasmid transfection of Hmgcs2 (p = 0.004). Conclusions: The Idi1 and Hmgcs2 genes have regulatory roles in atrial lipotoxic myopathy associated with atrial enlargement.

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Zhang, Dongjuan, Hang Yang, Xiaomu Kong, Kang Wang, Xuan Mao, Xianzhong Yan, Yuan Wang, et al. "Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes." American Journal of Physiology-Endocrinology and Metabolism 300, no. 2 (February 2011): E287—E295. http://dx.doi.org/10.1152/ajpendo.00308.2010.

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Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. To date, the molecular mechanisms of DN remain largely unclear. The present study aimed to identify and characterize novel proteins involved in the development of DN by a proteomic approach. Proteomic analysis revealed that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase 2 (HMGCS2), the key enzyme in ketogenesis, was increased fourfold in the kidneys of type 2 diabetic db/db mice. Consistently, the activity of HMGCS2 in kidneys and 24-h urinary excretion of the ketone body β-hydroxybutyrate (β-HB) were significantly increased in db/db mice. Immunohistochemistry, immunofluorescence, and real-time PCR studies further demonstrated that HMGCS2 was highly expressed in renal glomeruli of db/db mice, with weak expression in the kidneys of control mice. Because filtered ketone bodies are mainly reabsorbed in the proximal tubules, we used RPTC cells, a rat proximal tubule cell line, to examine the effect of the increased level of ketone bodies. Treating cultured RPTC cells with 1 mM β-HB significantly induced transforming growth factor-β1 expression, with a marked increase in collagen I expression. β-HB treatment also resulted in a marked increase in vimentin protein expression and a significant reduction in E-cadherin protein levels, suggesting an enhanced epithelial-to-mesenchymal transition in RPTCs. Collectively, these findings demonstrate that diabetic kidneys exhibit excess ketogenic activity resulting from increased HMGCS2 expression. Enhanced ketone body production in the diabetic kidney may represent a novel mechanism involved in the pathogenesis of DN.

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Kostiuk, Morris A., Bernd O. Keller, and Luc G. Berthiaume. "Palmitoylation of ketogenic enzyme HMGCS2 enhances its interaction with PPARα and transcription at the Hmgcs2 PPRE." FASEB Journal 24, no. 6 (February 2, 2010): 1914–24. http://dx.doi.org/10.1096/fj.09-149765.

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NADAL, Alícia, Pedro F. MARRERO, and Diego HARO. "Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1." Biochemical Journal 366, no. 1 (August 15, 2002): 289–97. http://dx.doi.org/10.1042/bj20020598.

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Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. This allows the use of ketone bodies for energy, thereby preserving the limited glucose for use by the brain. This adaptative response is switched off by insulin rapidly inhibiting the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) gene, which is a key control site of ketogenesis. We decided to investigate the molecular mechanism of this inhibition. In the present study, we show that FKHRL1, a member of the forkhead in rhabdosarcoma (FKHR) subclass of the Fox family of transcription factors, stimulates transcription from transfected 3-hydroxy-3-methylglutaryl-CoA synthase promoter-luciferase reporter constructs, and that this stimulation is repressed by insulin. An FKHRL1-responsive sequence AAAAATA, located 211bp upstream of the HMGCS2 gene transcription start site, was identified by deletion analysis. It binds FKHRL1 in vivo and in vitro and confers FKHRL1 responsiveness on homologous and heterologous promoters. If it is mutated, it partially blocks the effect of insulin in HepG2 cells, both in the absence and presence of overexpressed FKHRL1. These results suggest that FKHRL1 contributes to the regulation of HMGCS2 gene expression by insulin.

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Jiang, Yujie, Dekai Wang, Kangjing Wu, Feifeng Wang, Qingwen Yang, Ruilian Han, Zongsuo Liang, and Qiaojun Jia. "Cloning and Characterization of the Gene Encoding HMGS Synthase in Polygonatum sibiricum." BioMed Research International 2022 (October 7, 2022): 1–10. http://dx.doi.org/10.1155/2022/7441296.

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The saponins of Polygonatum sibiricum had many pharmacological activities such as antitumor, antioxidation, and blood sugar lowering, which were synthesized by two pathways: mevalonate (MVA) and methylerythritol phosphate (MEP). 3-Hydroxy-3-methylglutaryl coenzyme A synthase (HMGS) was the key enzyme in the MVA synthesis pathway, and its expression level may affect the accumulation of saponins which were the main active ingredients of P. sibiricum. In this study, we successfully cloned HMGS1 and HMGS2 from P. sibiricum and their sequence similarity was 93.71% with 89 different sites. The multiple sequence alignment results indicated that the N-terminal sequences of HMGS were conserved. Phylogenetic analysis showed that P. sibiricum, A. officinalis, N. tazetta, D. nobile, and other relatives had a common evolutionary ancestor. The expression levels of both HMGSs and the total saponin content in different tissues revealed that HMGS expression in rhizomes was positively correlated with total saponin content. Further study of the abiotic stress effect of Methyl Jasmonate (MeJA) demonstrated that the expression of HMGS1 and HMGS2 genes was induced by MeJA, peaked at 24 h, and fell by 48 h. Our present findings would provide a blueprint for future studies of HMGS and its role in triterpenoid biosynthesis in P. sibiricum.

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Casselbrant, Anna, Ville Wallenius, Erik Elebring, Hanns-Ulrich Marschall, Bengt R. Johansson, Herbert F. Helander, and Lars Fändriks. "Morphological Adaptation in the Jejunal Mucosa after Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers: Data from a Randomized Crossover Study." Nutrients 14, no. 19 (October 4, 2022): 4123. http://dx.doi.org/10.3390/nu14194123.

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Background and aims: The conditions for jejunal glucose absorption in healthy subjects have not been thoroughly studied. In this study we investigated differences in the jejunal villi enlargement factor, as well as ultrastructural aspects of the surface enterocytes and mitochondria, comparing 2 weeks of high-carbohydrate (HCD) versus high-fat diets (HFD). We also measured the ketogenesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) in relation to jejunal mitochondria. Methods: A single-centre, randomized, unblinded crossover study in 15 healthy volunteers ingesting strictly controlled equicaloric diets (either HCD or HFD), with 60% energy from the respective source. An enteroscopy was carried out after 2 weeks of each diet and jejunal mucosal biopsies were acquired. Conventional histology, immunofluorescent staining, transmission electron microscopy and confocal microscopy were used. Results: The villi did not demonstrate any change in the epithelial enlargement factor. Despite an increased mitosis, there were no changes in apoptotic indices. However, the ultrastructural analysis demonstrated a significant increase in the enlargement factor at the bases of the villi. The mitochondria demonstrated increased amounts of cristae after the HFD. The confocal microscopy revealed increased HMGCS2 per mitochondrial marker at the top of the villi after the HFD compared to the HCD. Conclusion: There is a morphometric adaption in the jejunal mucosa following the 2-week diets, not only on a histological level, but rather on the ultrastructural level. This study supports the notion that mitochondrial HMGCS2 is regulated by the fat content of the diet and is involved in the expression of monosaccharide transporters.

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Zhang, Huazhong, Jinsong Zhang, Jinquan Li, Zhengsheng Mao, Jian Qian, Cheng Zong, Hao Sun, and Beilei Yuan. "Multi-Omics Analyses Reveal the Mechanisms of Early Stage Kidney Toxicity by Diquat." Toxics 11, no. 2 (February 16, 2023): 184. http://dx.doi.org/10.3390/toxics11020184.

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Diquat (DQ), a widely used bipyridyl herbicide, is associated with significantly higher rates of kidney injuries compared to other pesticides. However, the underlying molecular mechanisms are largely unknown. In this study, we identified the molecular changes in the early stage of DQ-induced kidney damage in a mouse model through transcriptomic, proteomic and metabolomic analyses. We identified 869 genes, 351 proteins and 96 metabolites that were differentially expressed in the DQ-treated mice relative to the control mice (p < 0.05), and showed significant enrichment in the PPAR signaling pathway and fatty acid metabolism. Hmgcs2, Cyp4a10, Cyp4a14 and Lpl were identified as the major proteins/genes associated with DQ-induced kidney damage. In addition, eicosapentaenoic acid, linoleic acid, palmitic acid and (R)-3-hydroxybutyric acid were the major metabolites related to DQ-induced kidney injury. Overall, the multi-omics analysis showed that DQ-induced kidney damage is associated with dysregulation of the PPAR signaling pathway, and an aberrant increase in Hmgcs2 expression and 3-hydroxybutyric acid levels. Our findings provide new insights into the molecular basis of DQ-induced early kidney damage.

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Sikder, Kunal, Sanket Kumar Shukla, Neel Patel, Harpreet Singh, and Khadija Rafiq. "High Fat Diet Upregulates Fatty Acid Oxidation and Ketogenesis via Intervention of PPAR-γ." Cellular Physiology and Biochemistry 48, no. 3 (2018): 1317–31. http://dx.doi.org/10.1159/000492091.

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Background/Aims: Systemic hyperlipidemia and intracellular lipid accumulation induced by chronic high fat diet (HFD) leads to enhanced fatty acid oxidation (FAO) and ketogenesis. The present study was aimed to determine whether activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) by surplus free fatty acids (FA) in hyperlipidemic condition, has a positive feedback regulation over FAO and ketogenic enzymes controlling lipotoxicity and cardiac apoptosis. Methods: 8 weeks old C57BL/6 wild type (WT) or PPAR-γ-/- mice were challenged with 16 weeks 60% HFD to induce obesity mediated type 2 diabetes mellitus (T2DM) and diabetic cardiomyopathy. Treatment course was followed by echocardiographic measurements, glycemic and lipid profiling, immunoblot, qPCR and immunohistochemistry (IHC) analysis of PPAR-γ and following mitochondrial metabolic enzymes 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2), mitochondrial β- hydroxy butyrate dehydrogenase (BDH1) and pyruvate dehydrogenase kinase isoform 4 (PDK4). In vivo model was translated in vitro, with neonatal rat cardiomyocytes (NRCM) treated with PPAR-γ agonist/antagonist and PPAR-γ overexpression adenovirus in presence of palmitic acid (PA). Apoptosis was determined in vivo from left ventricular heart by TUNEL assay and immunoblot analysis. Results: We found exaggerated circulating ketone bodies production and expressions of the related mitochondrial enzymes HMGCS2, BDH1 and PDK4 in HFD-induced diabetic hearts and in PA-treated NRCM. As a mechanistic approach we found HFD mediated activation of PPAR-γ is associated with the above-mentioned mitochondrial enzymes. HFD-fed PPAR-γ-/-mice display decreased hyperglycemia, hyperlipidemia associated with increased insulin responsiveness as compared to HFD-fed WT mice PPAR-γ-/–HFD mice demonstrated a more robust functional recovery after diabetes induction, as well as significantly reduced myocyte apoptosis and improved cardiac function. Conclusions: PPAR-γ has been described previously to regulate lipid metabolism and adipogenesis. The present study suggests for the first time that increased PPAR-γ expression by HFD is responsible for cardiac dysfunction via upregulation of mitochondrial enzymes HMGCS2, BDH1 and PDK4. Targeting PPAR-γ and its downstream mitochondrial enzymes will provide novel strategies in preventing metabolic and myocardial dysfunction in diabetes mellitus.

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Maraqa, L., M. Cummings, M. Peter, A. Shaaban, A. Hanby, K. Horgan, and V. Speirs. "P3 Evaluating the expression of HMGCS2 in human breast cancer relapses." Breast 16 (March 2007): S13. http://dx.doi.org/10.1016/s0960-9776(07)70068-1.

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Steele, M. A., S. L. Greenwood, J. Croom, and B. W. McBride. "An increase in dietary non-structural carbohydrates alters the structure and metabolism of the rumen epithelium in lambs." Canadian Journal of Animal Science 92, no. 2 (June 2012): 123–30. http://dx.doi.org/10.4141/cjas2011-095.

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Steele, M. A., Greenwood, S. L., Croom, J. and McBride, B. W. 2012. An increase in dietary non-structural carbohydrates alters the structure and metabolism of the rumen epithelium in lambs. Can. J. Anim. Sci. 92: 123–130. This study investigated the effect of a grain challenge on the structure and metabolism of the rumen epithelium in lambs. In a randomized design, lambs (n = 8) received either a control diet [30% dry matter (DM) grain], or a diet of increasing amounts of grain to a maximum inclusion of 79% of DM for 12 d prior to slaughter. Rumen papillae were collected from the ventral sac on day 13 and prepared for histological and gene expression analyses. All lambs fed the high-grain diet were diagnosed with ruminal parakeratosis as the thickness of the corneum was higher (P<0.01) compared with control lambs (51.0±2.3 vs. 17.3±2.5 µm). Plasma beta-hydroxybutyric acid concentrations increased linearly (P<0.05) with increased grain consumption compared with the control. However, the relative mRNA expression of the ketogenic enzyme 3-hydroxy-3-methyl-glutaryl CoA-synthase (HMGCS2) in rumen papillae was not different between treatments. The expression of cholesterolgenic enzyme HMGCS1 was down-regulated by 0.70±0.06 (P<0.05) fold in lambs fed the high-grain diet compared with the control. These results suggest that a short-term grain challenge in lambs is associated with altered rumen epithelium metabolism and structural changes indicative of ruminal parakeratosis.

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Vilà-Brau, Anna, Ana Luísa De Sousa-Coelho, Cristina Mayordomo, Diego Haro, and Pedro F. Marrero. "Human HMGCS2 Regulates Mitochondrial Fatty Acid Oxidation andFGF21Expression in HepG2 Cell Line." Journal of Biological Chemistry 286, no. 23 (April 18, 2011): 20423–30. http://dx.doi.org/10.1074/jbc.m111.235044.

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Mohr, Alex E., Rebecca A. Reiss, Monique Beaudet, Johnny Sena, Jay S. Naik, Benjimen R. Walker, and Karen L. Sweazea. "Short-term high fat diet alters genes associated with metabolic and vascular dysfunction during adolescence in rats: a pilot study." PeerJ 9 (July 9, 2021): e11714. http://dx.doi.org/10.7717/peerj.11714.

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Background Diet-induced metabolic dysfunction precedes multiple disease states including diabetes, heart disease, and vascular dysfunction. The critical role of the vasculature in disease progression is established, yet the details of how gene expression changes in early cardiovascular disease remain an enigma. The objective of the current pilot project was to evaluate whether a quantitative assessment of gene expression within the aorta of six-week old healthy male Sprague-Dawley rats compared to those exhibiting symptoms of metabolic dysfunction could reveal potential mediators of vascular dysfunction. Methods RNA was extracted from the aorta of eight rats from a larger experiment; four animals fed a high-fat diet (HFD) known to induce symptoms of metabolic dysfunction (hypertension, increased adiposity, fasting hyperglycemia) and four age-matched healthy animals fed a standard chow diet (CHOW). The bioinformatic workflow included Gene Ontology (GO) biological process enrichment and network analyses. Results The resulting network contained genes relevant to physiological processes including fat and protein metabolism, oxygen transport, hormone regulation, vascular regulation, thermoregulation, and circadian rhythm. The majority of differentially regulated genes were downregulated, including several associated with circadian clock function. In contrast, leptin and 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) were notably upregulated. Leptin is involved in several major energy balance signaling pathways and Hmgcs2 is a mitochondrial enzyme that catalyzes the first reaction of ketogenesis. Conclusion Together, these data describe changes in gene expression within the aortic wall of HFD rats with early metabolic dysfunction and highlight potential pathways and signaling intermediates that may impact the development of early vascular dysfunction.

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Liput, Kamila P., Adam Lepczyński, Agata Nawrocka, Ewa Poławska, Magdalena Ogłuszka, Aneta Jończy, Weronika Grzybek, et al. "Effects of Three-Month Administration of High-Saturated Fat Diet and High-Polyunsaturated Fat Diets with Different Linoleic Acid (LA, C18:2n–6) to α-Linolenic Acid (ALA, C18:3n–3) Ratio on the Mouse Liver Proteome." Nutrients 13, no. 5 (May 15, 2021): 1678. http://dx.doi.org/10.3390/nu13051678.

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The aim of the study was to evaluate the effect of different types of high-fat diets (HFDs) on the proteomic profile of mouse liver. The analysis included four dietary groups of mice fed a standard diet (STD group), a high-fat diet rich in SFAs (SFA group), and high-fat diets dominated by PUFAs with linoleic acid (LA, C18:2n–6) to α-linolenic acid (ALA, C18:3n–3) ratios of 14:1 (14:1 group) and 5:1 (5:1 group). After three months of diets, liver proteins were resolved by two-dimensional gel electrophoresis (2DE) using 17 cm non-linear 3–10 pH gradient strips. Protein spots with different expression were identified by MALDI-TOF/TOF. The expression of 13 liver proteins was changed in the SFA group compared to the STD group (↓: ALB, APOA1, IVD, MAT1A, OAT and PHB; ↑: ALDH1L1, UniProtKB—Q91V76, GALK1, GPD1, HMGCS2, KHK and TKFC). Eleven proteins with altered expression were recorded in the 14:1 group compared to the SFA group (↓: ARG1, FTL1, GPD1, HGD, HMGCS2 and MAT1A; ↑: APOA1, CA3, GLO1, HDHD3 and IVD). The expression of 11 proteins was altered in the 5:1 group compared to the SFA group (↓: ATP5F1B, FTL1, GALK1, HGD, HSPA9, HSPD1, PC and TKFC; ↑: ACAT2, CA3 and GSTP1). High-PUFA diets significantly affected the expression of proteins involved in, e.g., carbohydrate metabolism, and had varying effects on plasma total cholesterol and glucose levels. The outcomes of this study revealed crucial liver proteins affected by different high-fat diets.

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Hepler, Chelsea, Caroline E. Foy, Mark R. Higgins, and Benjamin J. Renquist. "The hypophagic response to heat stress is not mediated by GPR109A or peripheral β-OH butyrate." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 310, no. 10 (May 15, 2016): R992—R998. http://dx.doi.org/10.1152/ajpregu.00513.2015.

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Rising temperatures resulting from climate change will increase the incidence of heat stress, negatively impacting the labor force and food animal production. Heat stress elevates circulating β-OH butyrate, which induces vasodilation through GPR109a. Interestingly, both heat stress and intraperitoneal β-OH butyrate administration induce hypophagia. Thus, we aimed to investigate the role of β-OH butyrate in heat stress hypophagia in mice. We found that niacin, a β-OH butyrate mimetic that cannot be oxidized to generate ATP, also reduces food intake. Interestingly, the depression in food intake as a result of 8-h intraperitoneal niacin or 48-h heat exposure did not result from changes in hypothalamic expression of orexigenic or anorexigenic signals (AgRP, NPY, or POMC). Genetically eliminating GPR109a expression did not prevent the hypophagic response to heat exposure, intraperitoneal β-OH butyrate (5.7 mmol/kg), or niacin (0.8 mmol/kg). Hepatic vagotomy eliminated the hypophagic response to β-OH butyrate and niacin but did not affect the hypophagic response to heat exposure. We subsequently hypothesized that the hypophagic response to heat stress may depend on direct effects of β-OH butyrate at the central nervous system: β-OH butyrate induced hormonal changes (hyperinsulinemia, hypercorticosteronemia, and hyperleptinemia), or gene expression changes. To test these possibilities, we blocked expression of hepatic hydroxyl methyl glutaryl CoA synthase II (HMGCS2) to prevent hepatic β-OH butyrate synthesis. Mice that lack HMGCS2 maintain a hypophagic response to heat stress. Herein, we establish that the hypophagia of heat stress is independent of GPR109a, the hepatic vagus afferent nerve, and hepatic ketone body synthesis.

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Liu, Mei Hui, Jun Li, Ping Shen, B. Husna, E. Shyong Tai, and E. L. Yong. "A Natural Polymorphism in Peroxisome Proliferator-Activated Receptor-α Hinge Region Attenuates Transcription due to Defective Release of Nuclear Receptor Corepressor from Chromatin." Molecular Endocrinology 22, no. 5 (May 1, 2008): 1078–92. http://dx.doi.org/10.1210/me.2007-0547.

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Abstract Peroxisome proliferator-activated receptor-α (PPARα) is a central regulator of lipid metabolism. Fibrate drugs act on PPARα to modulate dyslipidemias. A natural variant (V227A) affecting the PPARα hinge region was associated with perturbations in blood lipid levels in Asian populations. In this study, we investigated the functional significance of the V227A substitution. The variant significantly attenuated PPARα-mediated transactivation of the cytochrome P450 4A6 and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) genes in the presence of fibrate ligands. Screening of a panel of PPARα coregulators revealed that V227A enhanced recruitment of the nuclear corepressor NCoR. Transactivation activity of V227A could be restored by silencing NCoR or by inhibition of its histone deacetylase activity. Deletion studies indicated that PPARα interacted with NCoR receptor-interacting domain 1 (ID1) but not ID2 or ID3. These interactions were dependent on the intact consensus nonapeptide nuclear receptor interaction motif in NCoR ID1 and were enhanced by the adjacent 24 N-terminal residues. Novel corepressor interaction determinants involving PPARα helices 1 and 2 were identified. In hepatic cells, the V227A substitution stabilized PPARα/NCoR interactions and caused defective release of NCoR in the presence of agonists on the HMGCS2 promoter. These results provide the first indication that defective function of a natural PPARα variant was due, at least partially, to increased corepressor binding. Our data suggest that the PPARα/NCoR interaction is physiologically relevant and can produce a discernable phenotype when the magnitude of the interaction is altered by a naturally occurring variation.

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Wang, Pengfei, Michael R. Bowl, Stephanie Bender, Jun Peng, Leslie Farber, Jindong Chen, Asif Ali, et al. "Parafibromin, a Component of the Human PAF Complex, Regulates Growth Factors and Is Required for Embryonic Development and Survival in Adult Mice." Molecular and Cellular Biology 28, no. 9 (January 22, 2008): 2930–40. http://dx.doi.org/10.1128/mcb.00654-07.

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ABSTRACT Parafibromin, a transcription factor associated with the PAF complex, is encoded by the HRPT2 gene, mutations of which cause the hyperparathyroidism-jaw tumor syndrome (OMIM145001). To elucidate the function of parafibromin, we generated conventional and conditional Hrpt2 knockout mice and found that Hrpt2 −/− mice were embryonic lethal by embryonic day 6.5 (E6.5). Controlled deletion of Hrpt2 after E8.5 resulted in apoptosis and growth retardation. Deletion of Hrpt2 in adult mice led to severe cachexia and death within 20 days. To explore the mechanism underlying the embryonic lethality and death of adult mice, mouse embryonic fibroblasts (MEFs) were cultured and Hrpt2 was deleted in vitro. Hrpt2 −/− MEFs underwent apoptosis, while Hrpt2 +/+ and Hrpt2 +/− MEFs grew normally. To study the mechanism of this apoptosis, Hrpt2 +/+ and Hrpt2 −/− MEFs were used in cDNA microarray, semiquantitative reverse transcription-PCR, and chromatin immunoprecipitation assays to identify genes regulated by parafibromin. These revealed that Hrpt2 expression and the parafibromin/PAF complex directly regulate genes involved in cell growth and survival, including H19, Igf1, Igf2, Igfbp4, Hmga1, Hmga2, and Hmgcs2. Thus, our results show that expression of Hrpt2 and parafibromin is pivotal in mammalian development and survival in adults and that these functions are likely mediated by the transcriptional regulation of growth factors.

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Xu, Wenfang, Zhen Chen, Gang Liu, Yuping Dai, Xuanfu Xu, Duan Ma, and Lei Liu. "Identification of a Potential PPAR-Related Multigene Signature Predicting Prognosis of Patients with Hepatocellular Carcinoma." PPAR Research 2021 (March 12, 2021): 1–10. http://dx.doi.org/10.1155/2021/6642939.

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Peroxisome proliferator-activated receptors (PPARs) and part of their target genes have been reported to be related to the progression of hepatocellular carcinoma (HCC). The prognosis of HCC is not optimistic, and more accurate prognostic markers are needed. This study focused on discovering potential prognostic markers from the PPAR-related gene set. The mRNA data and clinical information of HCC were collected from TCGA and GEO platforms. Univariate Cox and lasso Cox regression analyses were used to screen prognostic genes of HCC. Three genes (MMP1, HMGCS2, and SLC27A5) involved in the PPAR signaling pathway were selected as the prognostic signature of HCC. A formula was established based on the expression values and multivariate Cox regression coefficients of selected genes, that was, risk score = 0.1488 ∗ expression value of M M P 1 + − 0.0393 ∗ expression value of H M G C S 2 + − 0.0479 ∗ expression value of S L C 27 A 5 . The prognostic ability of the three-gene signature was assessed in the TCGA HCC dataset and verified in three GEO sets (GSE14520, GSE36376, and GSE76427). The results showed that the risk score based on our signature was a risk factor with a HR (hazard ratio) of 2.72 ( 95 % CI Confidence Interval = 1.87 ~ 3.95 , p < 0.001 ) for HCC survival. The signature could significantly ( p < 0.0001 ) distinguish high-risk and low-risk patients with poor prognosis for HCC. In addition, we further explored the independence and applicability of the signature with other clinical indicators through multivariate Cox analysis ( p < 0.001 ) and nomogram analysis ( C ‐ index = 0.709 ). The above results indicate that the combination of MMP1, HMGCS2, and SLC27A5 selected from the PPAR signaling pathway could effectively, independently, and applicatively predict the prognosis of HCC. Our research provided new insights to the prognosis of HCC.

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Tang, Hong, Yufeng Wu, Yanru Qin, Hongyan Wang, Yongxu Jia, Shujun Yang, Suxia Luo, and Qiming Wang. "Predictive significance of HMGCS2 for prognosis in resected Chinese esophageal squamous cell carcinoma patients." OncoTargets and Therapy Volume 10 (May 2017): 2553–60. http://dx.doi.org/10.2147/ott.s132543.

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Kim, Ji Tae, Chang Li, Heidi L. Weiss, Qingding Wang, and B. Mark Evers. "Sa1127 THE KETOGENIC ENZYME, HMGCS2, PROTECTS INTESTINAL CELLS FROM TNFα-INDUCED INFLAMMATION AND APOPTOSIS." Gastroenterology 158, no. 6 (May 2020): S—285. http://dx.doi.org/10.1016/s0016-5085(20)31401-3.

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Wan, Song, Ming Xi, Hai-Bo Zhao, Wei Hua, Yuan-Ling Liu, Yu-Lin Zhou, Yang-Jia Zhuo, et al. "HMGCS2 functions as a tumor suppressor and has a prognostic impact in prostate cancer." Pathology - Research and Practice 215, no. 8 (August 2019): 152464. http://dx.doi.org/10.1016/j.prp.2019.152464.

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Shizu, Ryota, Kanako Ezaki, Takumi Sato, Ayaka Sugawara, Takuomi Hosaka, Takamitsu Sasaki, and Kouichi Yoshinari. "PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α." Cells 10, no. 12 (December 16, 2021): 3550. http://dx.doi.org/10.3390/cells10123550.

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Background: PXR is a xenobiotic-responsive nuclear receptor that controls the expression of drug-metabolizing enzymes. Drug-induced activation of PXR sometimes causes drug–drug interactions due to the induced metabolism of co-administered drugs. Our group recently reported a possible drug–drug interaction mechanism via an interaction between the nuclear receptors CAR and PPARα. As CAR and PXR are structurally and functionally related receptors, we investigated possible crosstalk between PXR and PPARα. Methods: Human hepatocyte-like HepaRG cells were treated with various PXR ligands, and mRNA levels were determined by quantitative reverse transcription PCR. Reporter assays using the HMGCS2 promoter containing a PPARα-binding motif and mammalian two-hybrid assays were performed in HepG2 or COS-1 cells. Results: Treatment with PXR activators reduced the mRNA levels of PPARα target genes in HepaRG cells. In reporter assays, PXR suppressed PPARα-dependent gene expression in HepG2 cells. In COS-1 cells, co-expression of PGC1α, a common coactivator of PPARα and PXR, enhanced PPARα-dependent gene transcription, which was clearly suppressed by PXR. Consistently, in mammalian two-hybrid assays, the interaction between PGC1α and PPARα was attenuated by ligand-activated PXR. Conclusion: The present results suggest that ligand-activated PXR suppresses PPARα-dependent gene expression by inhibiting PGC1α recruitment.

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Qian, Xiaoli, Ting Wang, Jiahong Gong, Li Wang, Xuyan Chen, Haiyan Lin, Wenzhan Tu, Songhe Jiang, and Shengcun Li. "Exercise in mice ameliorates high-fat diet-induced nonalcoholic fatty liver disease by lowering HMGCS2." Aging 13, no. 6 (March 1, 2021): 8960–74. http://dx.doi.org/10.18632/aging.202717.

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Kang, Dong Young, Nipin S.P., Pramod Darvin, Youn Hee Joung, Hyo Joo Byun, Chang Hee Do, Kyung Do Park, Mi Na Park, Kwang Hyun Cho, and Young Mok Yang. "Momilactone B Inhibits Ketosis In Vitro by Regulating the ANGPTL3-LPL Pathway and Inhibiting HMGCS2." Animal Biotechnology 28, no. 3 (November 22, 2016): 189–97. http://dx.doi.org/10.1080/10495398.2016.1252769.

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Hu, Li-Tian, Bing-Lin Zhu, Yu-Jie Lai, Yan Long, Jing-Si Zha, Xiao-Tong Hu, John H. Zhang, and Guo-Jun Chen. "HMGCS2 promotes autophagic degradation of the amyloid-β precursor protein through ketone body-mediated mechanisms." Biochemical and Biophysical Research Communications 486, no. 2 (April 2017): 492–98. http://dx.doi.org/10.1016/j.bbrc.2017.03.069.

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Sasaki, Yusuke, Sana Raza-Iqbal, Toshiya Tanaka, Kentaro Murakami, Motonobu Anai, Tsuyoshi Osawa, Yoshihiro Matsumura, Juro Sakai, and Tatsuhiko Kodama. "Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate." International Journal of Molecular Sciences 20, no. 22 (November 13, 2019): 5682. http://dx.doi.org/10.3390/ijms20225682.

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Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces HMGCS2 and PDK4, which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes. This suggests that PPARα plays a crucial role in nutrient flux in the human liver. Additionally, pemafibrate induces clinically favorable genes, such as ABCA1, FGF21, and VLDLR. Furthermore, pemafibrate shows anti-inflammatory effects in vascular endothelial cells. Pemafibrate is predicted to exhibit beneficial effects in patients with atherogenic dyslipidemia and diabetic microvascular complications.

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Bagheri-Fam, Stefan, Huijun Chen, Sean Wilson, Katie Ayers, James Hughes, Frederique Sloan-Bena, Pierre Calvel, et al. "The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice." PLOS ONE 15, no. 1 (January 7, 2020): e0227411. http://dx.doi.org/10.1371/journal.pone.0227411.

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Su, Shu-Guang, Mei Yang, Mei-Fang Zhang, Quan-zhou Peng, Ming-yue Li, Li-ping Liu, and Shi-yun Bao. "miR-107-mediated decrease of HMGCS2 indicates poor outcomes and promotes cell migration in hepatocellular carcinoma." International Journal of Biochemistry & Cell Biology 91 (October 2017): 53–59. http://dx.doi.org/10.1016/j.biocel.2017.08.016.

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Gromov, Pavel, Jaime A. Espinoza, Maj-Lis Talman, Naoko Honma, Niels Kroman, Vera Timmermans Wielenga, José M. A. Moreira, and Irina Gromova. "FABP7 and HMGCS2 Are Novel Protein Markers for Apocrine Differentiation Categorizing Apocrine Carcinoma of the Breast." PLoS ONE 9, no. 11 (November 12, 2014): e112024. http://dx.doi.org/10.1371/journal.pone.0112024.

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Li, Jie, Ming-han Li, Tian-tian Wang, Xiao-ning Liu, Xiao-ting Zhu, Yun-zhang Dai, Ke-chao Zhai, et al. "SLC38A4 functions as a tumour suppressor in hepatocellular carcinoma through modulating Wnt/β-catenin/MYC/HMGCS2 axis." British Journal of Cancer 125, no. 6 (July 17, 2021): 865–76. http://dx.doi.org/10.1038/s41416-021-01490-y.

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Cao, Yanan, Bin Duan, Xiaowei Gao, E. Wang, and Zhitao Dong. "iTRAQ-Based Comparative Proteomics Analysis of Urolithiasis Rats Induced by Ethylene Glycol." BioMed Research International 2020 (May 16, 2020): 1–10. http://dx.doi.org/10.1155/2020/6137947.

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Nephrolithiasis is a frequent chronic urological condition with a high prevalence and recurrence rate. Proteomics studies on urolithiasis rat models are highly important in characterizing the pathophysiology of kidney stones and identifying potential approaches for preventing and treating kidney stones. The isobaric tags for relative and absolute quantification (iTRAQ) were performed to identify differentially expressed proteins (DEPs) in the kidney between urolithiasis rats and control rats. The results showed that 127 DEPs (85 upregulated and 42 downregulated) were identified in urolithiasis and control rats. The functions of DEPs were predicted by Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein–protein interaction (PPI) network analysis. The expression of four upregulated proteins (Tagln, Akr1c9, Spp1, and Fbn1) and four downregulated proteins (Hbb, Epb42, Hmgcs2, and Ca1) were validated by parallel reaction monitoring (PRM). Proteomics studies of ethylene glycol-induced urolithiasis rat models using iTRAQ and PRM helped to elucidate the molecular mechanism governing nephrolithiasis and to identify candidate proteins for the treatment of kidney stones.

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Zafar, Rafia, Javeria Syeda, and Suzan Saber. "PSUN274 Chlorthalidone-Induced Diabetic Ketoacidosis." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A401. http://dx.doi.org/10.1210/jendso/bvac150.834.

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Abstract Introduction A variety of pharmacological agents affect glucose homeostasis resulting in hypo- or hyperglycemia. Several antihypertensives, including thiazide diuretics, are implicated in hyperglycemia. Clinical Case A 56 years old African American male with a history of type 2 diabetes mellitus, hypertension, and hyperlipidemia presented to the emergency department with diabetic ketoacidosis 3 weeks after initiation of chlorthalidone. His HbA1c at the time of chlorthalidone initiation was 6.8%. On presentation, his serum glucose was 870 mg/dL, beta-hydroxybutyrate was 34.70 (0.02–0.27), and HbA1c was 15.5%. The patient received aggressive IV fluid resuscitation and insulin infusion. Twenty hours later, DKA resolved and subcutaneous insulin was started. He was discharged home on MDI of insulin and chlorthalidone was discontinued. Metformin was restarted while insulin was tapered and stopped. Of note, the patient was diagnosed with diabetes mellitus 7 years before this presentation after an episode of DKA. After his first DKA, LADA was ruled out. His C-peptide level was intact and he was switched from MDI of insulin to metformin. The patient was maintained on metformin 1000 mg twice daily for 7 years with his HbA1c ranging from 6.1% to 6.4%. One year after his second DKA episode, he was still on metformin monotherapy with HbA1c of 6.8%. This is a case of DKA-prone diabetes and we believe that the use of thiazides precipitated his second episode due to the temporal relation and the lack of other contributing factors. There are several suggested mechanisms for thiazide diuretic-related hyperglycemia and other metabolic adverse effects. Genome Wide Association Study (GWAS) identifies the HMGCS2 locus to be associated with chlorthalidone induced glucose increase in hypertensive patients. Thiazide diuretics, especially chlorthalidone-associated DKA is not well documented and this entity may need further research. We found only one case report in the literature search. Conclusion Thiazide diuretics can worsen diabetes control in diabetic patients and may even lead to hyperglycemic emergencies, such as DKA in susceptible individuals. Patients should be closely monitored for some time after initiation of such medications to avoid hyperglycemia and related complications. References Qiao, X., & Moses, L. (2018). AN INTERESTING CAUSE OF DIABETIC KETOACIDOSIS: CASE REPORT, REVIEW OF LITERATURE AND POSSIBLE PATHOPHYSIOLOGY OF THIAZIDE DIURETICS-INDUCED DKA. Chest, 154(4), 265A.) Singh, S., McDonough, C. W., Gong, Y., Alghamdi, W. A., Arwood, M. J., Bargal, S. A., … & Johnson, J. A. (2018). Genome wide association study identifies the HMGCS2 locus to be associated with chlorthalidone induced glucose increase in hypertensive patients. Journal of the American Heart Association, 7(6), e007339. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

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Kang, Dong Young, Nipin Sp, Kyung Do Park, Hak Kyo Lee, Ki-Duk Song, and Young Mok Yang. "Silibinin inhibits in vitro ketosis by regulating HMGCS2 and NF-kB: elucidation of signaling molecule relationship under ketotic conditions." In Vitro Cellular & Developmental Biology - Animal 55, no. 5 (April 25, 2019): 368–75. http://dx.doi.org/10.1007/s11626-019-00351-6.

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Lee, Ying-En, Hong-Lin He, Yow-Ling Shiue, Sung-Wei Lee, Li-Ching Lin, Ting-Feng Wu, I.-Wei Chang, Hao-Hsien Lee, and Chien-Feng Li. "The prognostic impact of lipid biosynthesis-associated markers, HSD17B2 and HMGCS2, in rectal cancer treated with neoadjuvant concurrent chemoradiotherapy." Tumor Biology 36, no. 10 (May 1, 2015): 7675–83. http://dx.doi.org/10.1007/s13277-015-3503-2.

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Miller, Aubrey L., Patrick L. Garcia, Samuel C. Fehling, Tracy L. Gamblin, Rebecca B. Vance, Leona N. Council, Dongquan Chen, Eddy S. Yang, Robert C. A. M. van Waardenburg, and Karina J. Yoon. "The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer." Cancers 13, no. 14 (July 11, 2021): 3470. http://dx.doi.org/10.3390/cancers13143470.

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Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cell cycle dysregulation and DNA damage augment the efficacy of gemcitabine. BET inhibitors arrest cells in G1 and allow increases in DNA damage, likely due to inhibition of expression of DNA repair proteins Ku80 and RAD51. BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. JQ1 + gemcitabine was more effective in vivo than either drug alone in patient-derived xenograft models (P < 0.01). Increases in the apoptosis marker cleaved caspase 3 and DNA damage marker γH2AX paralleled antitumor efficacy. Notably, RNA-seq data showed that JQ1 + gemcitabine selectively inhibited HMGCS2 and APOC1 ~6-fold, compared to controls. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine.

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Chen, Shih-Wen, Chiang-Ting Chou, Cheng-Chi Chang, Yue-Ju Li, Szu-Ta Chen, I.-Ching Lin, Sang-Heng Kok, et al. "HMGCS2 enhances invasion and metastasis via direct interaction with PPARα to activate Src signaling in colorectal cancer and oral cancer." Oncotarget 8, no. 14 (November 1, 2016): 22460–76. http://dx.doi.org/10.18632/oncotarget.13006.

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Liu, Hao, Yixin Zhang, Kaijun Long, Fandi Wang, Xingxing Zeng, Yuanfu Lu, Yuqi He, and Yanliu Lu. "Metabolomics Studies into The Role of Dendrobium nobile Lindl. in Lipid Metabolism." Current Topics in Nutraceutical Research 19, no. 3 (October 10, 2020): 248–54. http://dx.doi.org/10.37290/ctnr2641-452x.19:248-254.

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In an earlier study, we had demonstrated ameliorative effects of Dendrobium nobile Lindl. on dyslipidemia and fatty liver in mouse fed a high fat diet. In the present study, we have examined the effect of D. nobile on the lipid metabolism in normal healthy rats after intragastric treatment for four times a day for five days. The treatment followed a metabolomics analysis of the plasma samples for metabolites by ultra-performance liquid chromatography-mass spectroscopy and the expression levels of genes for lipid metabolism. The metabolite profiles were substantially altered by D. nobile. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis, metabolic pathways were ranked first in terms of the number of referenced metabolites. There were 112 metabolites that were changed significantly in the pathways. The results revealed that D. nobile increased the content of epoxy-octadecenoic acids in plasma more than 19-folds. Moreover, the expression of genes Cyp1a2, Cyp2e1, Cyp2j2, Cyp3a1, Pparγ, Lpl, Acsl1, and Hmgcs2 were all induced in D. nobile treatment group (P < 0.05). Our results supported that D. nobile has a significant role in regulating lipid metabolism in healthy rats. Therefore, it is tempting to speculate that D. nobile would be beneficial in protecting human against the disorders of lipid metabolism.

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Men, Lihui, Wenting Hui, Xin Guan, Tongtong Song, Xuan Wang, Siwei Zhang, and Xia Chen. "Cardiac Transcriptome Analysis Reveals Nr4a1 Mediated Glucose Metabolism Dysregulation in Response to High-Fat Diet." Genes 11, no. 7 (June 29, 2020): 720. http://dx.doi.org/10.3390/genes11070720.

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Obesity is associated with an increased risk of developing cardiovascular disease (CVD), with limited alterations in cardiac genomic characteristics known. Cardiac transcriptome analysis was conducted to profile gene signatures in high-fat diet (HFD)-induced obese mice. A total of 184 differentially expressed genes (DEGs) were identified between groups. Based on the gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs, the critical role of closely interlocked glucose metabolism was determined in HFD-induced cardiac remodeling DEGs, including Nr4a1, Fgf21, Slc2a3, Pck1, Gck, Hmgcs2, and Bpgm. Subsequently, the expression levels of these DEGs were evaluated in both the myocardium and palmitic acid (PA)-stimulated H9c2 cardiomyocytes using qPCR. Nr4a1 was highlighted according to its overexpression resulting from the HFD. Additionally, inhibition of Nr4a1 by siRNA reversed the PA-induced altered expression of glucose metabolism-related DEGs and hexokinase 2 (HK2), the rate-limiting enzyme in glycolysis, thus indicating that Nr4a1 could modulate glucose metabolism homeostasis by regulating the expression of key enzymes in glycolysis, which may subsequently influence cardiac function in obesity. Overall, we provide a comprehensive understanding of the myocardium transcript molecular framework influenced by HFD and propose Nr4a1 as a key glucose metabolism target in obesity-induced CVD.

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Bragoszewski, Piotr, Andrzej Habior, Bozena Walewska-Zielecka, and Jerzy Ostrowski. "Expression of genes encoding mitochondrial proteins can distinguish nonalcoholic steatosis from steatohepatitis." Acta Biochimica Polonica 54, no. 2 (May 15, 2007): 341–48. http://dx.doi.org/10.18388/abp.2007_3255.

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In patients without substantial alcohol use, triglyceride accumulation in the liver can lead to nonalcoholic fatty liver disease (NAFLD) that may progress to nonalcoholic steatohepatitis (NASH). The differential diagnosis between NAFLD and NASH can be accomplished only by morphological examination. Although the relationship between mitochondrial dysfunction and the progression of liver pathologic changes has been described, the exact mechanisms initiating primary liver steatosis and its progression to NASH are unknown. We selected 16 genes encoding mitochondrial proteins which expression was compared by quantitative RT-PCR in liver tissue samples taken from patients with NAFLD and NASH. We found that 6 of the 16 examined genes were differentially expressed in NAFLD versus NASH patients. The expression of hepatic HK1, UCP2, ME2, and ME3 appeared to be higher in NASH than in NAFLD patients, whereas HMGCS2 and hnRNPK expression was lower in NASH patients. Although the severity of liver morphological injury in the spectrum of NAFLD-NASH may be defined at the molecular level, expression of these selected 6 genes cannot be used as a molecular marker aiding histological examination. Moreover, it is still unclear whether these differences in hepatic gene expression profiles truly reflect the progression of morphological abnormalities or rather indicate various metabolic and hormonal states in patients with different degrees of fatty liver disease.

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Chen, Donglin, Xiang Ruan, Yu Liu, and Yan He. "HMGCS2 silencing attenuates high glucose-induced in vitro diabetic cardiomyopathy by increasing cell viability, and inhibiting apoptosis, inflammation, and oxidative stress." Bioengineered 13, no. 5 (May 2, 2022): 11417–29. http://dx.doi.org/10.1080/21655979.2022.2063222.

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Zhou, Tong, Guangyu Xu, Luyao Sun, Zhenxiang Yu, and Guixia Wang. "Improving Energy Metabolism of Deproteinized Extract of Calf Blood Through Regulation of Hmgcs2, Cpt1a, Angptl4, Cyp8b1, and Ehhadh Genes in Mice." Chemical Research in Chinese Universities 35, no. 3 (May 8, 2019): 427–33. http://dx.doi.org/10.1007/s40242-019-9021-9.

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Journal articles on the topic 'HMGCS2'

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