更新于：2024-05-01

HMGCS1

3-hydroxy-3-methylglutaryl-CoA synthase 1

更新于：2024-05-01

基本信息

别名

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase、3-hydroxy-3-methylglutaryl coenzyme A synthase、3-hydroxy-3-methylglutaryl-CoA synthase 1

+ [6]

简介

Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate, a precursor for cholesterol synthesis.

关联

100 项与 HMGCS1 相关的临床结果

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100 项与 HMGCS1 相关的转化医学

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0 项与 HMGCS1 相关的专利（医药）

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2,300

项与 HMGCS1 相关的文献（医药）

2024-03-01·Molecular medicine reports

Excess phosphate promotes SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation via the SCAP‑SREBP2 signaling pathway.

Article

作者: Mi-Hua Liu ; Xiao-Long Lin ; Le-Le Xiao

Hyperphosphatemia or severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can promote cardiovascular adverse events in patients with chronic kidney disease. Hyperphosphatemia is associated with elevated inflammation and sterol regulatory element binding protein 2 (SREBP2) activation, but the underlying mechanisms in SARS‑CoV‑2 that are related to cardiovascular disease remain unclear. The present study aimed to elucidate the role of excess inorganic phosphate (PI) in SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation and the underlying mechanisms in vascular smooth muscle cells (VSMCs). The expression levels of SARS‑CoV‑2 N protein, SREBP cleavage‑activating protein (SCAP), mature N‑terminal SREBP2, NLRP3, procaspase‑1, cleaved caspase‑1, IL‑1β and IL‑18 were examined by western blotting. The expression levels of SREBP2, HMG‑CoA reductase, HMGCS1, low density lipoprotein receptor, proprotein convertase subtilisin/kexin type 9 (PCSK9), SREBP1c, fatty acid synthase, stearyl coenzyme A desaturase 1, acetyl‑CoA carboxylase α and ATP‑citrate lyase were determined by reverse transcription‑quantitative PCR. The translocation of SCAP or NLRP3 from the endoplasmic reticulum to the Golgi was detected by confocal microscopy. The results showed that excess PI promoted SCAP‑SREBP and NLRP3 complex translocation to the Golgi, potentially leading to NLRP3 inflammasome activation and lipogenic gene expression. Furthermore, PI amplified SARS‑CoV‑2 N protein‑induced inflammation via the SCAP‑SREBP pathway, which facilitates NLRP3 inﬂammasome assembly and activation. Inhibition of phosphate uptake with phosphonoformate sodium alleviated NLRP3 inflammasome activation and reduced SREBP‑mediated lipogenic gene expression in VSMCs stimulated with PI and with SARS‑CoV‑2 N protein overexpression. Inhibition of SREBP2 or small interfering RNA‑induced silencing of SREBP2 effectively suppressed the effect of PI and SARS‑CoV‑2 N protein on NLRP3 inflammasome activation and lipogenic gene expression. In conclusion, the present study identified that PI amplified SARS‑CoV‑2 N protein‑induced NLRP3 inflammasome activation and lipogenic gene expression via the SCAP‑SREBP signaling pathway.

2024-02-19·Biomolecules

Peroxisomal Localization of a Truncated HMG-CoA Reductase under Low Cholesterol Conditions.

Article

作者: Jianqiu Wang ; Markus Kunze ; Andrea Villoria-González ; Isabelle Weinhofer ; Johannes Berger

3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase, HMGCR) is one of the rate-limiting enzymes in the mevalonate pathway required for cholesterol biosynthesis. It is an integral membrane protein of the endoplasmic reticulum (ER) but has occasionally been described in peroxisomes. By co-immunofluorescence microscopy using different HMGCR antibodies, we present evidence for a dual localization of HMGCR in the ER and peroxisomes in differentiated human monocytic THP-1 cells, primary human monocyte-derived macrophages and human primary skin fibroblasts under conditions of low cholesterol and statin treatment. Using density gradient centrifugation and Western blot analysis, we observed a truncated HMGCR variant of 76 kDa in the peroxisomal fractions, while a full-length HMGCR of 96 kDa was contained in fractions of the ER. In contrast to primary human control fibroblasts, peroxisomal HMGCR was not found in fibroblasts from patients suffering from type-1 rhizomelic chondrodysplasia punctata, who lack functional PEX7 and, thus, cannot import peroxisomal matrix proteins harboring a type-2 peroxisomal targeting signal (PTS2). Moreover, in the N-terminal region of the soluble 76 kDa C-terminal catalytic domain, we identified a PTS2-like motif, which was functional in a reporter context. We propose that under sterol-depleted conditions, part of the soluble HMGCR domain, which is released from the ER by proteolytic processing for further turnover, remains sufficiently long in the cytosol for peroxisomal import via a PTS2/PEX7-dependent mechanism. Altogether, our findings describe a dual localization of HMGCR under combined lipid depletion and statin treatment, adding another puzzle piece to the complex regulation of HMGCR.

2024-02-17·International journal of molecular sciences

The Complement Component 4 Binding Protein α Gene: A Versatile Immune Gene That Influences Lipid Metabolism in Bovine Mammary Epithelial Cell Lines.

Article

作者: Xuanxu Chen ; Zhihui Zhao ; Xinyi Jiang ; Jing Li ; Fengshuai Miao ; Haibin Yu ; Ziwei Lin ; Ping Jiang

Complement component 4 binding protein α (C4BPA) is an immune gene which is responsible for the complement regulation function of C4BP by binding and inactivating the Complement component C4b (C4b) component of the classical Complement 3 (C3) invertase pathway. Our previous findings revealed that C4BPA was differentially expressed by comparing the transcriptome in high-fat and low-fat bovine mammary epithelial cell lines (BMECs) from Chinese Holstein dairy cows. In this study, a C4BPA gene knockout BMECs line model was constructed via using a CRISPR/Cas9 system to investigate the function of C4BPA in lipid metabolism. The results showed that levels of triglyceride (TG) were increased, while levels of cholesterol (CHOL) and free fatty acid (FFA) were decreased (p < 0.05) after knocking out C4BPA in BMECs. Additionally, most kinds of fatty acids were found to be mainly enriched in the pathway of the biosynthesis of unsaturated fatty acids, linoleic acid metabolism, fatty acid biosynthesis, and regulation of lipolysis in adipocyte. Meanwhile, the RNA-seq showed that most of the differentially expressed genes (DEGs) are related to PI3K-Akt signaling pathway. The expressions of 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 (HMGCS1), Carnitine Palmitoyltransferase 1A (CPT1A), Fatty Acid Desaturase 1 (FADS1), and Stearoyl-Coenzyme A desaturase 1 (SCD1) significantly changed when the C4BPA gene was knocked out. Collectively, C4BPA gene, which is an immune gene, played an important role in lipid metabolism in BMECs. These findings provide a new avenue for animal breeders: this gene, with multiple functions, should be reasonably utilized.

项与 HMGCS1 相关的新闻（医药）

2024-02-05

·生物制品圈

中山大学等团队发现最新肝细胞癌生物标志物和治疗靶点

导读：CSN6（基因名COPS6）是COP9蛋白质复合体的成员，先前已被证明参与信号转导和肿瘤发生，是一种多功能蛋白质，通过Cullin-RING泛素连接酶（CRL）复合物调节真核细胞中的大部分蛋白质周转。2月2日，中山大学李孟鸿、周仲国和暨南大学张海鹏共同通讯在期刊《ADVANCED SCIENCE》上在线发表题为“CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation”的研究论文，研究结果确定了CSN6-HMGCS1-YAP1轴介导HCC的肿瘤生长，并提出了针对非酒精性脂肪肝病相关HCC的治疗策略。研究表明，CSN6-HMGCS1-YAP1通路是HCC的预测性生物标志物，并可作为NAFLD相关HCC治疗的靶点。https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202306827研究背景 01 肝癌在全球范围内呈上升趋势，其中90%为肝细胞癌（HCC），并且是癌症相关死亡的第二大原因。肝脏作为一个中央代谢协调器，具有广泛的重要功能，包括对葡萄糖、脂质代谢和胆酸合成的调节。HCC的主要风险因素包括肝炎病毒感染、黄曲霉素污染和肝代谢疾病。在这些风险因素中，非酒精性脂肪肝病（NAFLD）作为肥胖流行的次要后果，被预测将成为未来肝细胞癌的主要原因。然而，对于与NAFLD相关癌症的治疗仍需进一步探索。胆固醇代谢在维持细胞膜完整性和对抗肥胖、癌症等疾病的发展中起着重要作用。即使在胆固醇丰富的情况下，癌细胞仍然维持胆固醇生物合成以促进其增殖和微环境重塑。然而，针对胆固醇代谢进行癌症治疗的有效性总是受到限制。研究发现 02 在这项研究中，研究人员发现CSN6在肝细胞癌（HCC）中高表达，并与不良生存率相关。CSN6通过YAP1核转位和激活，在体外和体内促进HCC癌细胞的生长。通过IP-质谱和定量蛋白质组学分析，研究人员确定了68个潜在的CSN6直接靶点，并发现CSN6直接调节HMGCS1蛋白的稳定性。进一步研究表明，CSN6通过阻止SPOP介导的HMGCS1泛素化和降解来稳定HMGCS1蛋白。机制研究显示MDM2是SPOP的新型E3连接酶。研究表明，CSN6-HMGCS1-YAP1通路是HCC的预测性生物标志物，并可作为NAFLD相关HCC治疗的靶点。靶向HMGCS1-YAP1轴可抑制HCC生长研究结果 03 综上所述，研究结果确定了CSN6-HMGCS1-YAP1轴介导HCC的肿瘤生长，并提出了针对非酒精性脂肪肝病相关HCC的治疗策略。研究表明，CSN6-HMGCS1-YAP1通路是HCC的预测性生物标志物，并可作为NAFLD相关HCC治疗的靶点。参考资料：https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202306827识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

2024-02-04

·今日头条

【Adv. Sci.】中山大学等团队发现最新肝细胞癌生物标志物和治疗靶点

本文为转化医学网原创，转载请注明出处作者：Rainbow 导读： CSN6（基因名COPS6）是COP9蛋白质复合体的成员，先前已被证明参与信号转导和肿瘤发生，是一种多功能蛋白质，通过Cullin-RING泛素连接酶（CRL）复合物调节真核细胞中的大部分蛋白质周转。 2月2日，中山大学李孟鸿、周仲国和暨南大学张海鹏共同通讯在期刊《ADVANCED SCIENCE》上在线发表题为“CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation”的研究论文，研究结果确定了CSN6-HMGCS1-YAP1轴介导HCC的肿瘤生长，并提出了针对非酒精性脂肪肝病相关HCC的治疗策略。研究表明，CSN6-HMGCS1-YAP1通路是HCC的预测性生物标志物，并可作为NAFLD相关HCC治疗的靶点。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202306827 研究背景 01 肝癌在全球范围内呈上升趋势，其中90%为肝细胞癌（HCC），并且是癌症相关死亡的第二大原因。肝脏作为一个中央代谢协调器，具有广泛的重要功能，包括对葡萄糖、脂质代谢和胆酸合成的调节。HCC的主要风险因素包括肝炎病毒感染、黄曲霉素污染和肝代谢疾病。在这些风险因素中，非酒精性脂肪肝病（NAFLD）作为肥胖流行的次要后果，被预测将成为未来肝细胞癌的主要原因。然而，对于与NAFLD相关癌症的治疗仍需进一步探索。胆固醇代谢在维持细胞膜完整性和对抗肥胖、癌症等疾病的发展中起着重要作用。即使在胆固醇丰富的情况下，癌细胞仍然维持胆固醇生物合成以促进其增殖和微环境重塑。然而，针对胆固醇代谢进行癌症治疗的有效性总是受到限制。研究发现 02 在这项研究中，研究人员发现CSN6在肝细胞癌（HCC）中高表达，并与不良生存率相关。CSN6通过YAP1核转位和激活，在体外和体内促进HCC癌细胞的生长。通过IP-质谱和定量蛋白质组学分析，研究人员确定了68个潜在的CSN6直接靶点，并发现CSN6直接调节HMGCS1蛋白的稳定性。进一步研究表明，CSN6通过阻止SPOP介导的HMGCS1泛素化和降解来稳定HMGCS1蛋白。机制研究显示MDM2是SPOP的新型E3连接酶。研究表明，CSN6-HMGCS1-YAP1通路是HCC的预测性生物标志物，并可作为NAFLD相关HCC治疗的靶点。靶向HMGCS1-YAP1轴可抑制HCC生长研究结果 03 综上所述，研究结果确定了CSN6-HMGCS1-YAP1轴介导HCC的肿瘤生长，并提出了针对非酒精性脂肪肝病相关HCC的治疗策略。研究表明，CSN6-HMGCS1-YAP1通路是HCC的预测性生物标志物，并可作为NAFLD相关HCC治疗的靶点。参考资料： https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202306827 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！点击对应文字查看详情

2022-10-31

·BioSpace

Sagimet Biosciences Announces Late-Breaking, Oral and Poster Presentations for Denifanstat (TVB-2640), a First-in-Class Fatty Acid Synthase Inhibitor, in NASH at AASLD’s The Liver Meeting

Additional Preclinical Data on Denifanstat Published in Scientific Reports SAN MATEO, Calif.--(BUSINESS WIRE)--Sagimet Biosciences, a clinical-stage biopharmaceutical company developing novel therapeutics targeting dysfunctional metabolic pathways, announced today that it will present three abstracts at The Liver Meeting of the American Association for the Study of Liver Diseases (AASLD), taking place November 4-8, 2022, in Washington, DC. The presentations are focused on identifying non-invasive tests correlated with AI-based digital pathology to ultimately minimize unnecessary biopsies and serum profiling that reveals metabolic benefits of denifanstat, the company’s lead product candidate, in non-alcoholic steatohepatitis (NASH) patients. Additional Phase 2 biomarker data aimed at better identifying potential patient responders will also be presented. “Selecting patients for Phase 2b/3 NASH clinical trials currently requires liver biopsy, an invasive and costly procedure that is subject to variability that can result in a high rate of screen failures,” said Stephen Harrison, MD, visiting professor, University of Oxford, founder and chairman of Pinnacle Clinical Research. “Using AI-based digital pathology from the FASCINATE-2 study, we have identified readily available non-invasive tests that could help reduce the number of patients having unnecessary liver biopsies.” Separately, Sagimet announced the publication of preclinical data, “FASN Inhibition Targets Multiple Drivers of NASH by Reducing Steatosis, Inflammation and Fibrosis in Preclinical Models,” in the September 19, 2022, edition of Scientific Reports, an online peer-reviewed open access scientific journal published by Nature. Details for AASLD presentations are: ORAL PRESENTATION Abstract Title: "Correlation Between AI-based Digital Pathology and Non-invasive Tests (NITS) of NASH Fibrosis Stage: Baseline Data from the FASCINATE-2 Phase 2b Clinical Study of Denifanstat in Patients with F2/F3 NASH” Abstract Number: 99 Presenting Author: Stephen Harrison, MD, FAASLD, University of Oxford, Pinnacle Research Center Session Title: NASH Therapeutics and OMICs Date and Time: Sunday, November 6, 2022, 2:00-3:30 PM EST Presentation Time: 3:00 PM EST Location: Room 146, Walter E. Washington Convention Center LATE-BREAKING POSTER PRESENTATION Abstract Title: “Serum Proteomic Profiling Reveals that the Fatty Acid Synthase (FASN) Inhibitor Denifanstat Provides Metabolic Benefits via Increasing Fibroblast Growth Factor 19 (FGF-19) and Decreasing 3-Hydroxy-3-Methylglutaryl-COA Synthase 1 (HMGCS1) in NASH Patients” Abstract Number: 38967 Presenting Author: Wen-Wei Tsai, PhD, Director, R&D, Sagimet Biosciences Date and Time: Monday, November 7, 2022, 1:00 PM – 2:00 PM EST Location: Poster Hall, Walter E. Washington Convention Center POSTER PRESENTATION Abstract Title: “A Baseline Metabolomic Signature Predicts Liver Fat Response to Denifanstat (DFS), A First-in-class Fatty Acid Synthase (FASN) Inhibitor: Analysis in FASCINATE-1 and FASCINATE-2 Clinical Studies” Abstract Number: 2370 Presenting Author: Rohit Loomba, MD, FAASLD, University of California, San Diego, NAFLD Research Center, Division of Gastroenterology and Epidemiology Date and Time: Saturday, November 5, 2022, 1:00-2:00 PM EST Location: Poster Hall, Walter E. Washington Convention Center Denifanstat is an oral, once daily, selective, fatty acid synthase (FASN) inhibitor that directly targets three key NASH drivers by blocking accumulation of excess liver fat, reducing inflammation and blunting fibrosis. Sagimet recently completed patient enrollment of its FASCINATE-2 Phase 2b liver biopsy-based clinical trial with denifanstat in NASH patients and expects to report interim data in the fourth quarter of 2022. About Sagimet Biosciences Sagimet is a clinical-stage biopharmaceutical company developing novel therapeutics targeting dysfunctional metabolic pathways in diseases such as nonalcoholic steatohepatitis, certain cancers and acne. Sagimet compounds are designed to inhibit FASN, an enzyme involved in the production of fatty acids normally used for energy storage. In NASH, the activity of FASN enzyme is upregulated, resulting in excess accumulation of liver fat, inflammation, and fibrosis. FASN dysregulation has also been implicated in multiple cancers with lipogenic phenotypes.

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