Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Röhrl, C; Eigner, K; Winter, K; Korbelius, M; Obrowsky, S; Kratky, D; Kovacs, WJ; Stangl, H.
Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells.
J Lipid Res. 2014; 55(1):94-103
Doi: 10.1194/jlr.M043299
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- Co-authors Med Uni Graz
- Korbelius Melanie
- Kratky Dagmar
- Obrowsky Sascha
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- ATP Binding Cassette Transporter 1 - genetics
- ATP Binding Cassette Transporter 1 - metabolism
- Animals -
- Cholesterol - biosynthesis
- Cholesterol - metabolism
- Endoplasmic Reticulum Stress -
- Gene Expression -
- Gene Expression Regulation -
- Glycosylation -
- Hep G2 Cells -
- Hepatocytes - metabolism
- Humans -
- Hydroxymethylglutaryl CoA Reductases - metabolism
- Lipid Metabolism -
- Liver - metabolism
- Liver X Receptors -
- Male -
- Mice -
- Mice, Inbred C57BL -
- Orphan Nuclear Receptors - genetics
- Orphan Nuclear Receptors - metabolism
- Protein Processing, Post-Translational -
- Sterol Regulatory Element Binding Protein 2 -
- Find related publications in this database (Keywords)
- ATP-binding cassette transporter A1
- apolipoprotein A-I
- high density lipoprotein
- 3-hydroxy-3-methylglutaryl-coenzyme A reductase
- HepG2