Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells

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

doi:10.1194/jlr.m043299

Cited by 62 publications

(51 citation statements)

References 65 publications

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“…6, C-E). Others have reported that TM blocks de novo cholesterol synthesis via direct inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (59) and reduces cholesterol efflux (60). However, a model FIGURE 6.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress and Ca2+ Depletion Differentially Modulate the Sterol Regulatory Protein PCSK9 to Control Lipid Metabolism

Lebeau

Al‐Hashimi

Sood

et al. 2017

Journal of Biological Chemistry

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Edited by Roger J. ColbranAccumulating evidence implicates endoplasmic reticulum (ER) stress as a mediator of impaired lipid metabolism, thereby contributing to fatty liver disease and atherosclerosis. Previous studies demonstrated that ER stress can activate the sterol regulatory element-binding protein-2 (SREBP2), an ER-localized transcription factor that directly up-regulates sterol regulatory genes, including PCSK9. Given that PCSK9 contributes to atherosclerosis by targeting low density lipoprotein (LDL) receptor (LDLR) degradation, this study investigates a novel mechanism by which ER stress plays a role in lipid metabolism by examining its ability to modulate PCSK9 expression. Herein, we demonstrate the existence of two independent effects of ER stress on PCSK9 expression and secretion. In cultured HuH7 and HepG2 cells, agents or conditions that cause ER Ca 2؉ depletion, including thapsigargin, induced SREBP2-dependent up-regulation of PCSK9 expression. In contrast, a significant reduction in the secreted form of PCSK9 protein was observed in the media from both thapsigargin-and tunicamycin (TM)-treated HuH7 cells, mouse primary hepatocytes, and in the plasma of TMtreated C57BL/6 mice. Furthermore, TM significantly increased hepatic LDLR expression and reduced plasma LDL concentrations in mice. Based on these findings, we propose a model in which ER Ca 2؉ depletion promotes the activation of SREBP2 and subsequent transcription of PCSK9. However, conditions that cause ER stress regardless of their ability to dysregulate ER Ca 2؉ inhibit PCSK9 secretion, thereby reducing PCSK9-mediated LDLR degradation and promoting LDLR-dependent hepatic cholesterol uptake. Taken together, our studies provide evidence that the retention of PCSK9 in the ER may serve as a potential strategy for lowering LDL cholesterol levels.

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Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress and Ca2+ Depletion Differentially Modulate the Sterol Regulatory Protein PCSK9 to Control Lipid Metabolism

Lebeau

Al‐Hashimi

Sood

et al. 2017

Journal of Biological Chemistry

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“…Cholesterol efflux was measured as described previously [31]. Briefly, HepG2 cells were cultured in DMEM media containing 15% FBS, trace labeled with 1 µCi/ml 3 H-cholesterol (Perkin-Elmer, USA) overnight.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia Induces Dysregulation of Lipid Metabolism in HepG2 Cells via Activation of HIF-2a

Cao

Zhao

et al. 2014

Cell Physiol Biochem

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Background: Hypoxia is a risk factor for non-alcoholic fatty liver diseases, leading to permanent imbalance of liver lipid homeostasis and steatohepatitis. The current study examined the effect of HIF-2α, an oxygen-sensitive heterodimeric transcription factor, on hypoxia-induced dysregulation of lipid metabolism in HepG2 cells. Methods: Studies were conducted in C57BL/6 male mice and human HepG2 cells under hypoxic conditions, transfected with HIF-2α-targeted shRNA. The mRNA and protein expressions of key genes relevant to lipid metabolism were determined via RT-qPCR and western blot, respectively. Intracellular lipid accumulation was determined by Nile red, filipin staining and quantitative assay kits. Results: HIF-2α protein was quantified in both HepG2 cells and C57BL/6 mice under hypoxic conditions. Intracellular lipid accumulation and increased lipid levels induced by hypoxia were significantly reduced by silence of HIF-2α expression, associated with reversed expression of ABCA1 and ADRP, key genes in involved cholesterol excretion and fatty acid uptake respectively. However, HIF-2α had no effect on enzymatic activity and expression of key genes involved in fatty acid β-oxidation or cholesterol metabolism. Conclusion: Inhibition of HIF-2α protein reversed lipid metabolism dysregulation induced by acute hypoxia in HepG2 cells, which suggested that HIF-2α signaling may be relevant to oxygen-dependent lipid homeostasis in the liver.

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“…Excess unesterified cellular cholesterol is known to induce ER stress in a number of cell types, including hepatocytes [48–50]. Conversely, ER stress reduces ABCA1 and SR-BI and impairs cholesterol efflux in cultured hepatocytes [51]. Similar to G5G8, AdGRP78 increased ABCA1 and SR-BI in db/db mice, suggesting that ER dysfunction perturbs multiple facets of hepatic sterol metabolism in db/db mice.…”

Section: Discussionmentioning

confidence: 99%

GRP78 rescues the ABCG5 ABCG8 sterol transporter in db/db mice

et al. 2015

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Objective Mice lacking leptin (ob/ob) or its receptor (db/db) are obese, insulin resistant, and have reduced levels of biliary cholesterol due, in part, to reduced levels of hepatic G5G8. Chronic leptin replacement restores G5G8 abundance and increases biliary cholesterol concentrations, but the molecular mechanisms responsible for G5G8 regulation remain unclear. In the current study, we used a series of mouse models to address potential mechanisms for leptin-mediated regulation of G5G8. Methods and Results We acutely replaced leptin in ob/ob mice and deleted hepatic leptin receptors in lean mice. Neither manipulation altered G5G8 abundance or biliary cholesterol. Similarly, hepatic vagotomy had no effect on G5G8. Alternatively, G5G8 may be decreased in ob/ob and db/db mice due to ER dysfunction, the site of G5G8 complex assembly. Overexpression of the ER chaperone GRP78 using an adenoviral vector restores ER function and reduces steatosis in ob/ob mice. Therefore, we determined if AdGRP78 could rescue G5G8 in db/db mice. As in ob/ob mice, AdGRP78 reduced expression of lipogenic genes and plasma triglycerides in the db/db strain. Both G5 and G8 protein levels increased as did total biliary cholesterol, but in the absence of changes in G5 or G8 mRNAs. The increase in G5G8 was associated with increases in a number of proteins, including the ER lectin chaperone, calnexin, a key regulator of G5G8 complex assembly. Conclusions Leptin signaling does not directly regulate G5G8 abundance. The loss of G5G8 in mice harboring defects in the leptin axis is likely associated with compromised ER function.

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Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells

Cited by 62 publications

References 65 publications

Endoplasmic Reticulum Stress and Ca2+ Depletion Differentially Modulate the Sterol Regulatory Protein PCSK9 to Control Lipid Metabolism

Endoplasmic Reticulum Stress and Ca2+ Depletion Differentially Modulate the Sterol Regulatory Protein PCSK9 to Control Lipid Metabolism

Hypoxia Induces Dysregulation of Lipid Metabolism in HepG2 Cells via Activation of HIF-2a

GRP78 rescues the ABCG5 ABCG8 sterol transporter in db/db mice

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