title: Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells.
abstract: Metabolic disorders such as type 2 diabetes cause hepatic endoplasmic reticulum (ER) stress, which affects neutral lipid metabolism. However, the role of ER stress in cholesterol metabolism is incompletely understood. Here, we show that induction of acute ER stress in human hepatic HepG2 cells reduced ABCA1 expression and caused ABCA1 redistribution to tubular perinuclear compartments. Consequently, cholesterol efflux to apoA-I, a key step in nascent HDL formation, was diminished by 80%. Besides ABCA1, endogenous apoA-I expression was reduced upon ER stress induction, which contributed to reduced cholesterol efflux. Liver X receptor, a key regulator of ABCA1 in peripheral cells, was not involved in this process. Despite reduced cholesterol efflux, cellular cholesterol levels remained unchanged during ER stress. This was due to impaired de novo cholesterol synthesis by reduction of HMG-CoA reductase activity by 70%, although sterol response element-binding protein-2 activity was induced. In mice, ER stress induction led to a marked reduction of hepatic ABCA1 expression. However, HDL cholesterol levels were unaltered, presumably because of scavenger receptor class B, type I downregulation under ER stress. Taken together, our data suggest that ER stress in metabolic disorders reduces HDL biogenesis due to impaired hepatic ABCA1 function.
authors.affiliation: Institute of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Röhrl
authors.forename: Karin
authors.initials: K
authors.lastname: Eigner
authors.forename: Katharina
authors.initials: K
authors.lastname: Winter
authors.forename: Melanie
authors.initials: M
authors.lastname: Korbelius
authors.forename: Sascha
authors.initials: S
authors.lastname: Obrowsky
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Kovacs
authors.forename: Herbert
authors.initials: H
authors.lastname: Stangl
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D015870:Gene Expression; D005786:Gene Expression Regulation; D006031:Glycosylation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051782:Sterol Regulatory Element Binding Protein 2
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: 3-hydroxy-3-methylglutaryl- coenzyme A reductase; ATP-binding cassette transporter A1; HepG2; apolipoprotein A-I; high density lipoprotein