title: Sortilin 1 Modulates Hepatic Cholesterol Lipotoxicity in Mice via Functional Interaction with Liver Carboxylesterase 1.
abstract: The liver plays a key role in cholesterol metabolism. Impaired hepatic cholesterol homeostasis causes intracellular free cholesterol accumulation and hepatocyte injury. Sortilin 1 (SORT1) is a lysosomal trafficking receptor that was identified by genome-wide association studies (GWAS) as a novel regulator of cholesterol metabolism in humans. Here we report that SORT1 deficiency protected against cholesterol accumulation-induced liver injury and inflammation in mice. Using an LC-MS/MS-based proteomics approach, we identified liver carboxylesterase 1 (CES1) as a novel SORT1-interacting protein. Mechanistic studies further showed that SORT1 may regulate CES1 lysosomal targeting and degradation and that SORT1 deficiency resulted in higher liver CES1 protein abundance. Previous studies have established an important role of hepatic CES1 in promoting intracellular cholesterol mobilization, cholesterol efflux, and bile acid synthesis. Consistently, high cholesterol atherogenic diet-challenged Sort1 knock-out mice showed less hepatic free cholesterol accumulation, increased bile acid synthesis, decreased biliary cholesterol secretion, and the absence of gallstone formation. SORT1 deficiency did not alter hepatic ceramide and fatty acid metabolism in high cholesterol atherogenic diet-fed mice. Finally, knockdown of liver CES1 in mice markedly increased the susceptibility to high cholesterol diet-induced liver injury and abolished the protective effect against cholesterol lipotoxicity in Sort1 knock-out mice. In summary, this study identified a novel SORT1-CES1 axis that regulates cholesterol-induced liver injury, which provides novel insights that improve our current understanding of the molecular links between SORT1 and cholesterol metabolism. This study further suggests that therapeutic inhibition of SORT1 may be beneficial in improving hepatic cholesterol homeostasis in metabolic and inflammatory liver diseases.
authors.affiliation: From the Department of Pharmacology, Toxicology and Therapeutics, Kansas University Medical Center, Kansas City, Kansas 66160 and.
authors.forename: Jibiao
authors.initials: J
authors.lastname: Li
authors.affiliation: From the Department of Pharmacology, Toxicology and Therapeutics, Kansas University Medical Center, Kansas City, Kansas 66160 and.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Pharmacology, Toxicology and Therapeutics, Kansas University Medical Center, Kansas City, Kansas 66160 and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Matye
authors.affiliation: From the Department of Pharmacology, Toxicology and Therapeutics, Kansas University Medical Center, Kansas City, Kansas 66160 and.
authors.forename: Hemantkumar
authors.initials: H
authors.lastname: Chavan
authors.affiliation: From the Department of Pharmacology, Toxicology and Therapeutics, Kansas University Medical Center, Kansas City, Kansas 66160 and.
authors.forename: Partha
authors.initials: P
authors.lastname: Krishnamurthy
authors.affiliation: the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: From the Department of Pharmacology, Toxicology and Therapeutics, Kansas University Medical Center, Kansas City, Kansas 66160 and tli@kumc.edu.
authors.forename: Tiangang
authors.initials: T
authors.lastname: Li
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D002784:Cholesterol / Q000633:toxicity*; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002265:Carboxylic Ester Hydrolases; D002784:Cholesterol; D034741:RNA, Small Interfering; D000099183:Sortilin; C545375:carboxylesterase 1, mouse
keywords: CES1; CYP7A1; FXR; bile acid; fatty liver; hypercholesterolemia; lipid metabolism; liver injury; nuclear receptor; protein trafficking (Golgi); steatohepatitis