title: Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis.
abstract: gp78 is a membrane-anchored ubiquitin ligase mediating the degradation of HMG-CoA reductase (HMGCR) and Insig-1. As a rate-limiting enzyme in cholesterol biosynthesis, HMGCR undergoes rapid sterol-promoted degradation. In contrast, destruction of Insig-1 releases its inhibition on SREBP and stimulates the expression of lipogenic genes. Thus, gp78 has opposite effects on lipid biosynthesis. We here generated liver-specific gp78 knockout (L-gp78(-/-)) mice and showed that although the degradation of HMGCR was blunted, SREBP was suppressed due to the elevation of Insig-1/-2, and therefore the lipid biosynthesis was decreased. The L-gp78(-/-) mice were protected from diet-/age-induced obesity and glucose intolerance. The livers of L-gp78(-/-) mice produced more FGF21, which activated thermogenesis in brown adipocytes and enhanced energy expenditure. Together, the major function of gp78 in liver is regulating lipid biosynthesis through SREBP pathway. Ablation of gp78 decreases the lipid levels and increases FGF21, and is beneficial to patients with metabolic diseases.
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Tong-Fei
authors.initials: TF
authors.lastname: Liu
authors.forename: Jing-Jie
authors.initials: JJ
authors.lastname: Tang
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Jia-Gui
authors.initials: JG
authors.lastname: Li
authors.forename: Hong-Hua
authors.initials: HH
authors.lastname: Miao
authors.forename: Bo-Liang
authors.initials: BL
authors.lastname: Li
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Song
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002853:Chromatography, Liquid; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006949:Hyperlipidemias / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D060285:Receptors, Autocrine Motility Factor / Q000172:deficiency* / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000037:antagonists & inhibitors*
chemical_list: D001786:Blood Glucose; C506119:Insig1 protein, mouse; D008055:Lipids; D008565:Membrane Proteins; D051779:Sterol Regulatory Element Binding Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D006903:Hydroxymethylglutaryl CoA Reductases; C555002:Amfr protein, mouse; D060285:Receptors, Autocrine Motility Factor