title: Contribution of Accelerated Degradation to Feedback Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Cholesterol Metabolism in the Liver.
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.
authors.affiliation: From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
authors.forename: Seonghwan
authors.initials: S
authors.lastname: Hwang
authors.affiliation: From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
authors.forename: Isamu Z
authors.initials: IZ
authors.lastname: Hartman
authors.affiliation: From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
authors.forename: Leona N
authors.initials: LN
authors.lastname: Calhoun
authors.affiliation: From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
authors.forename: Kristina
authors.initials: K
authors.lastname: Garland
authors.affiliation: From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
authors.forename: Gennipher A
authors.initials: GA
authors.lastname: Young
authors.affiliation: From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Mitsche
authors.affiliation: From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: McDonald
authors.affiliation: From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.affiliation: From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046.
authors.forename: Luke
authors.initials: L
authors.lastname: Engelking
authors.affiliation: From the Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9046 Russell.DeBose-Boyd@utsouthwestern.edu.
authors.forename: Russell A
authors.initials: RA
authors.lastname: DeBose-Boyd
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D017434:Protein Structure, Tertiary; D059748:Proteolysis
chemical_list: D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: cholesterol metabolism; endoplasmic reticulum (ER); endoplasmic-reticulum-associated protein degradation (ERAD); isoprenoid; lipid metabolism