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

Röhrl C, Eigner K, Winter K, Korbelius M, Obrowsky S, Kratky D, Kovacs WJ, Stangl H - J. Lipid Res. (2013)

Bottom Line: 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.However, HDL cholesterol levels were unaltered, presumably because of scavenger receptor class B, type I downregulation under ER stress.

View Article: PubMed Central - PubMed

Affiliation: 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.

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ER stress reduces ABCA1 expression in the murine liver. C57BL/6 mice were intraperitoneally injected with 1 mg/kg bodyweight tunicamycin or solvent (n = 4). Mice were euthanized after 48 h. Liver RNA and protein were isolated after 48 h and analyzed by qRT-PCR (A) and Western blot analysis (B). Expression of ABCA1, apoA-I, and SR-BI are decreased upon ER stress induction. Plasma total cholesterol was quantified (C), and relative cholesterol distribution was analyzed in pooled plasma after separation by fast-protein liquid chromatography (D). The reduction of plasma cholesterol can be attributed to decreased VLDL/LDL cholesterol levels.
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fig9: ER stress reduces ABCA1 expression in the murine liver. C57BL/6 mice were intraperitoneally injected with 1 mg/kg bodyweight tunicamycin or solvent (n = 4). Mice were euthanized after 48 h. Liver RNA and protein were isolated after 48 h and analyzed by qRT-PCR (A) and Western blot analysis (B). Expression of ABCA1, apoA-I, and SR-BI are decreased upon ER stress induction. Plasma total cholesterol was quantified (C), and relative cholesterol distribution was analyzed in pooled plasma after separation by fast-protein liquid chromatography (D). The reduction of plasma cholesterol can be attributed to decreased VLDL/LDL cholesterol levels.

Mentions: We aimed to validate our key findings obtained in hepatic cells lines in mice. We injected tunicamycin, which is widely used to exert ER stress in vivo, into mice. Tunicamycin treatment induced expression of CHOP and GRP-78 in the liver, indicating hepatic ER stress (Fig. 9A). In addition, ABCA1 and apoA-I protein expression levels were strongly reduced (Fig. 9B), which confirms the in vitro data. Moreover, SR-BI expression was markedly decreased. Plasma total cholesterol was lower in mice treated with tunicamycin compared with untreated controls (79 vs. 110 mg/dl). However, this decrease was due to reduced cholesterol content in the VLDL/LDL fraction, whereas HDL cholesterol was unaltered (Fig. 9C, D).


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

Röhrl C, Eigner K, Winter K, Korbelius M, Obrowsky S, Kratky D, Kovacs WJ, Stangl H - J. Lipid Res. (2013)

ER stress reduces ABCA1 expression in the murine liver. C57BL/6 mice were intraperitoneally injected with 1 mg/kg bodyweight tunicamycin or solvent (n = 4). Mice were euthanized after 48 h. Liver RNA and protein were isolated after 48 h and analyzed by qRT-PCR (A) and Western blot analysis (B). Expression of ABCA1, apoA-I, and SR-BI are decreased upon ER stress induction. Plasma total cholesterol was quantified (C), and relative cholesterol distribution was analyzed in pooled plasma after separation by fast-protein liquid chromatography (D). The reduction of plasma cholesterol can be attributed to decreased VLDL/LDL cholesterol levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927476&req=5

fig9: ER stress reduces ABCA1 expression in the murine liver. C57BL/6 mice were intraperitoneally injected with 1 mg/kg bodyweight tunicamycin or solvent (n = 4). Mice were euthanized after 48 h. Liver RNA and protein were isolated after 48 h and analyzed by qRT-PCR (A) and Western blot analysis (B). Expression of ABCA1, apoA-I, and SR-BI are decreased upon ER stress induction. Plasma total cholesterol was quantified (C), and relative cholesterol distribution was analyzed in pooled plasma after separation by fast-protein liquid chromatography (D). The reduction of plasma cholesterol can be attributed to decreased VLDL/LDL cholesterol levels.
Mentions: We aimed to validate our key findings obtained in hepatic cells lines in mice. We injected tunicamycin, which is widely used to exert ER stress in vivo, into mice. Tunicamycin treatment induced expression of CHOP and GRP-78 in the liver, indicating hepatic ER stress (Fig. 9A). In addition, ABCA1 and apoA-I protein expression levels were strongly reduced (Fig. 9B), which confirms the in vitro data. Moreover, SR-BI expression was markedly decreased. Plasma total cholesterol was lower in mice treated with tunicamycin compared with untreated controls (79 vs. 110 mg/dl). However, this decrease was due to reduced cholesterol content in the VLDL/LDL fraction, whereas HDL cholesterol was unaltered (Fig. 9C, D).

Bottom Line: 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.However, HDL cholesterol levels were unaltered, presumably because of scavenger receptor class B, type I downregulation under ER stress.

View Article: PubMed Central - PubMed

Affiliation: 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.

Show MeSH
Related in: MedlinePlus