ArticleMolecular and cellular biology2016
A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes.
Article in Molecular and cellular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 42 citations in OpenAlex.
- Protein M of NADC30-like PRRSV induces MARCH6-mediated K33-linked polyubiquitination of SLA-DRA.The Journal of biological chemistry · 2026Article
- Review
- Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis.Molecular metabolism · 2026Article
- The role of ER-associated degradation and ER-phagy in health and disease.Signal transduction and targeted therapy · 2026Review
- Review
- Role of MARCH E3 ubiquitin ligases in cancer development.Cancer metastasis reviews · 2024Review
- Polyphenols alleviate metabolic disorders: the role of ubiquitin-proteasome system.Frontiers in nutrition · 2024Review
- HECT, UBA and WWE domain containing 1 represses cholesterol efflux during CD4Frontiers in pharmacology · 2023Article
- Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome.Chemical research in toxicology · 2022Article
- The HDL particle composition determines its antitumor activity in pancreatic cancer.Life science alliance · 2022Article
- Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context.Biomedicines · 2021Article
- MARCH6 promotes hepatocellular carcinoma development through up-regulation of ATF2.BMC cancer · 2021Article
- How Is the Fidelity of Proteins Ensured in Terms of Both Quality and Quantity at the Endoplasmic Reticulum? Mechanistic Insights into E3 Ubiquitin Ligases.International journal of molecular sciences · 2021Review
- MARCH6 promotes Papillary Thyroid Cancer development by destabilizing DHX9.International journal of biological sciences · 2021Article
- MARCH Proteins Mediate Responses to Antitumor Antibodies.Journal of immunology (Baltimore, Md. : 1950) · 2020Article
- IDOL gene variant is associated with hyperlipidemia in Han population in Xinjiang, China.Scientific reports · 2020Article
- Mechanisms and regulation of cholesterol homeostasis.Nature reviews. Molecular cell biology · 2020Review
- The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6.The Biochemical journal · 2020Article
- Proteostasis Regulation in the Endoplasmic Reticulum: An Emerging Theme in the Molecular Pathology and Therapeutic Management of Familial Hypercholesterolemia.Frontiers in genetics · 2020Review
- FBXW7 regulates endothelial barrier function by suppression of the cholesterol synthesis pathway and prenylation of RhoB.Molecular biology of the cell · 2019Article
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Authors and funding
10 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cholesterol synthesis and lipoprotein uptake are tightly coordinated to ensure that the cellular level of cholesterol is adequately maintained. Hepatic dysregulation of these processes is associated with pathological conditions, most notably cardiovascular disease. Using a genetic approach, we have recently identified the E3 ubiquitin ligase MARCH6 as a regulator of cholesterol biosynthesis, owing to its ability to promote degradation of the rate-limiting enzymes 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR) and squalene epoxidase (SQLE). Here, we present evidence for MARCH6 playing a multifaceted role in the control of cholesterol homeostasis in hepatocytes. We identify MARCH6 as an endogenous inhibitor of the sterol regulatory element binding protein (SREBP) transcriptional program. Accordingly, loss of MARCH6 increases expression of SREBP-regulated genes involved in cholesterol biosynthesis and lipoprotein uptake. Unexpectedly, this is associated with a decrease in cellular lipoprotein uptake, induced by enhanced lysosomal degradation of the low-density lipoprotein receptor (LDLR). Finally, we provide evidence that induction of the E3 ubiquitin ligase IDOL represents the molecular mechanism underlying this MARCH6-induced phenotype. Our study thus highlights a MARCH6-dependent mechanism to direct cellular cholesterol accretion that relies on uncoupling of cholesterol synthesis from lipoprotein uptake.
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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.