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GRP78 expression inhibits insulin and ER stress–induced SREBP-1c activation and reduces hepatic steatosis in mice
Hélène L. Kammoun, … , Pascal Ferré, Fabienne Foufelle
Hélène L. Kammoun, … , Pascal Ferré, Fabienne Foufelle
Published April 13, 2009
Citation Information: J Clin Invest. 2009;119(5):1201-1215. https://doi.org/10.1172/JCI37007.
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Research Article Metabolism Article has an altmetric score of 4

GRP78 expression inhibits insulin and ER stress–induced SREBP-1c activation and reduces hepatic steatosis in mice

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Abstract

Hepatic steatosis is present in insulin-resistant obese rodents and is concomitant with active lipogenesis. Hepatic lipogenesis depends on the insulin-induced activation of the transcription factor SREBP-1c. Despite prevailing insulin resistance, SREBP-1c is activated in the livers of genetically and diet-induced obese rodents. Recent studies have reported the presence of an ER stress response in the livers of obese ob/ob mice. To assess whether ER stress promotes SREBP-1c activation and thus contributes to lipogenesis, we overexpressed the chaperone glucose-regulated protein 78 (GRP78) in the livers of ob/ob mice using an adenoviral vector. GRP78 overexpression reduced ER stress markers and inhibited SREBP-1c cleavage and the expression of SREBP-1c and SREBP-2 target genes. Furthermore, hepatic triglyceride and cholesterol contents were reduced, and insulin sensitivity improved, in GRP78-injected mice. These metabolic improvements were likely mediated by restoration of IRS-2 expression and tyrosine phosphorylation. Interestingly, GRP78 overexpression also inhibited insulin-induced SREBP-1c cleavage in cultured primary hepatocytes. These findings demonstrate that GRP78 inhibits both insulin-dependent and ER stress–dependent SREBP-1c proteolytic cleavage and explain the role of ER stress in hepatic steatosis in obese rodents.

Authors

Hélène L. Kammoun, Hervé Chabanon, Isabelle Hainault, Serge Luquet, Christophe Magnan, Tatsuro Koike, Pascal Ferré, Fabienne Foufelle

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Figure 2

Effect of ER stress on SREBP-1c proteolytic cleavage and SREBP-1c target genes in cultured rat hepatocytes.

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Effect of ER stress on SREBP-1c proteolytic cleavage and SREBP-1c target...
(A and B) Hepatocytes were incubated for 6 h in M199 medium supplemented with the LXR agonist TO-901317 (TO; 10 μM) and then treated for 1 h with 100 nM insulin (Ins), 300 nM thapsigargin (Thp), 1 μg/ml tunicamycin (Tu), 500 μM DTT, or 5 mM homocysteine (Hom). (A) Unspliced (u-) and spliced (s-) forms of XBP-1 mRNA, measured by RT-PCR. (B) Immunoblot analysis of SREBP-1c precursor and nuclear SREBP-1c. Quantification of SREBP-1c precursor is shown at right. Results are mean ± SEM of 3 independent cultures of hepatocytes in which 3 plates were collected for each condition. #P < 0.05, ##P < 0.01 versus TO-901317 alone. (C and D) Hepatocytes were treated for 1, 3, 6, and 9 h with 100 nM insulin or 300 nM thapsigargin in medium containing 25 mM glucose. (C) Total RNA from triplicate plates of hepatocytes was analyzed for the expression of GK. For the measurement of nuclear ChREBP, hepatocytes were cultured in the presence of 5 or 25 mM glucose and treated for 3 h in the presence of 100 nM insulin or 300 nM thapsigargin. (D) Total RNA from triplicate plates of hepatocytes was analyzed for expression of SCD1 and FAS mRNA. *P < 0.05, **P < 0.01, ***P < 0.001 versus basal value.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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