title: A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes.
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.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Anke
authors.initials: A
authors.lastname: Loregger
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Emma Claire Laura
authors.initials: EC
authors.lastname: Cook
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jessica Kristin
authors.initials: JK
authors.lastname: Nelson
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Martina
authors.initials: M
authors.lastname: Moeton
authors.affiliation: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia.
authors.forename: Laura Jane
authors.initials: LJ
authors.lastname: Sharpe
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Engberg
authors.affiliation: AstraZeneca R&D, Gothenburg, Sweden.
authors.forename: Madina
authors.initials: M
authors.lastname: Karimova
authors.affiliation: Laboratoire Inserm UMR 1188, Université de la Réunion, Sainte-Clothilde, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Lambert
authors.affiliation: School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW, Australia.
authors.forename: Andrew John
authors.initials: AJ
authors.lastname: Brown
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands n.zelcer@amc.uva.nl.
authors.forename: Noam
authors.initials: N
authors.lastname: Zelcer
mesh_terms: D053898:Biosynthetic Pathways; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D020868:Gene Silencing; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D008074:Lipoproteins; D008565:Membrane Proteins; D011973:Receptors, LDL; D002784:Cholesterol; C504816:MARCHF6 protein, human; C403126:MYLIP protein, human; D044767:Ubiquitin-Protein Ligases