Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells

Clemens Röhrl, Karin Eigner, Katharina Winter, Melanie Korbelius, Sascha Obrowsky, Dagmar Kratky, Werner J. Kovacs, Herbert Stangl

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

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 effl ux 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 effl ux. Liver X receptor, a key regulator of ABCA1 in peripheral cells, was not involved in this process. Despite reduced cholesterol effl ux, 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.

Original languageEnglish
Pages (from-to)94-103
Number of pages10
JournalJournal of Lipid Research
Volume55
Issue number1
DOIs
Publication statusPublished - Jan 2014
Externally publishedYes

Keywords

  • 3-hydroxy-3-methylglutarylcoenzyme A reductase
  • Apolipoprotein A-I
  • ATP-binding cassette transporter A1
  • HepG2
  • High density lipoprotein
  • Humans
  • Male
  • Liver/metabolism
  • Liver X Receptors
  • Gene Expression
  • Hydroxymethylglutaryl CoA Reductases/metabolism
  • Orphan Nuclear Receptors/genetics
  • Mice, Inbred C57BL
  • Gene Expression Regulation
  • Lipid Metabolism
  • Cholesterol/biosynthesis
  • Glycosylation
  • Hep G2 Cells
  • Animals
  • Hepatocytes/metabolism
  • Endoplasmic Reticulum Stress
  • ATP Binding Cassette Transporter 1/genetics
  • Mice
  • Protein Processing, Post-Translational
  • Sterol Regulatory Element Binding Protein 2

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