NDLI: Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Röhrl, Clemens Eigner, Karin Winter, Katharina Korbelius, Melanie Obrowsky, Sascha Kratky, Dagmar Kovacs, Werner J. Stangl, Herbert
Description	Country affiliation: Austria Author Affiliation: Röhrl C ( Institute of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria.)
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.
File Format	HTM / HTML
ISSN	00222275
e-ISSN	15397262
DOI	10.1194/jlr.M043299
Journal	The Journal of Lipid Research
Issue Number	1
Volume Number	55
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2014-01-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Biochemistry Cholesterol Biosynthesis Endoplasmic Reticulum Stress Hepatocytes Metabolism Atp Binding Cassette Transporter 1 Genetics Animals Secretion Gene Expression Gene Expression Regulation Glycosylation Hep G2 Cells Hydroxymethylglutaryl Coa Reductases Lipid Metabolism Liver Mice Mice, Inbred C57bl Orphan Nuclear Receptors Protein Processing, Post-translational Sterol Regulatory Element Binding Protein 2 Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Endocrinology

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