ArticleThe Journal of biological chemistry2016
Contribution of Accelerated Degradation to Feedback Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Cholesterol Metabolism in the Liver.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 49 citations in OpenAlex.
- Trial
- SIRT6 Mediates Sterol-Dependent Feedback Regulation of Cholesterol Biosynthetic Genes in Hepatocytes.Biomolecules & therapeutics · 2026Article
- CXCL6 exacerbates metabolic dysfunction-associated steatohepatitis by suppressing LPIN1-mediated fatty acid oxidation in hepatocytes.International journal of biological sciences · 2026Article
- Allosteric regulation of UBIAD1 trafficking from ER to Golgi revealed by chemical genetic screening.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The SIRT6 Activator MDL-800 Inhibits PPARα and Fatty acid Oxidation-Related Gene Expression in Hepatocytes.Biomolecules & therapeutics · 2025Article
- Taurochenodeoxycholic acid suppresses the progression of glioblastoma via HMGCS1/HMGCR/GPX4 signaling pathway in vitro and in vivo.Cancer cell international · 2025Article
- HMGCR: a malignancy hub - frontiers in cancer diagnosis and therapy.Frontiers in oncology · 2025Review
- Targeted protein degradation: advances in drug discovery and clinical practice.Signal transduction and targeted therapy · 2024Review
- MAMs and Mitochondrial Quality Control: Overview and Their Role in Alzheimer's Disease.Neurochemical research · 2024Review
- Article
- Dimethyloxalylglycine Suppresses SREBP1c and Lipogenic Gene Expressions in Hepatocytes Independently of HIF1A.Current issues in molecular biology · 2024Article
- Direct binding to sterols accelerates endoplasmic reticulum-associated degradation of HMG CoA reductase.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Post-Translational Regulation of HMG CoA Reductase.Cold Spring Harbor perspectives in biology · 2022Review
- Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome.Chemical research in toxicology · 2022Article
- Lowering low-density lipoprotein cholesterol: from mechanisms to therapies.Life metabolism · 2022Review
- Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain.Nature communications · 2022Article
- Revised model of the tissue factor pathway of thrombin generation: Role of the feedback activation of FXI.Journal of thrombosis and haemostasis : JTH · 2022Article
- Synthesis, function, and regulation of sterol and nonsterol isoprenoids.Frontiers in molecular biosciences · 2022Review
- Article
- Association of Insomnia, Depressive Disorders, and Mood Disorders as Risk Factors With Breast Cancer: A Nationwide Population-Based Cohort Study of 232,108 Women in Taiwan.Frontiers in oncology · 2021Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Accumulation of sterols in endoplasmic reticulum membranes stimulates the ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which catalyzes a rate-limiting step in synthesis of cholesterol. This ubiquitination marks HMGCR for proteasome-mediated degradation and constitutes one of several mechanisms for feedback control of cholesterol synthesis. Mechanisms for sterol-accelerated ubiquitination and degradation of HMGCR have been elucidated through the study of cultured mammalian cells. However, the extent to which these reactions modulate HMGCR and contribute to control of cholesterol metabolism in whole animals is unknown. Here, we examine transgenic mice expressing in the liver the membrane domain of HMGCR (HMGCR (TM1-8)), a region necessary and sufficient for sterol-accelerated degradation, and knock-in mice in which endogenous HMGCR harbors mutations that prevent sterol-induced ubiquitination. Characterization of transgenic mice revealed that HMGCR (TM1-8) is appropriately regulated in the liver of mice fed a high cholesterol diet or chow diet supplemented with the HMGCR inhibitor lovastatin. Ubiquitination-resistant HMGCR protein accumulates in the liver and other tissues disproportionately to its mRNA, indicating that sterol-accelerated degradation significantly contributes to feedback regulation of HMGCR in vivo Results of these studies demonstrate that HMGCR is subjected to sterol-accelerated degradation in the liver through mechanisms similar to those established in cultured cells. Moreover, these studies designate sterol-accelerated degradation of HMGCR as a potential therapeutic target for prevention of atherosclerosis and associated cardiovascular disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.