The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans
Fadila Benhamed, … , Hervé Guillou, Catherine Postic
Fadila Benhamed, … , Hervé Guillou, Catherine Postic
Published May 1, 2012
Citation Information: J Clin Invest. 2012;122(6):2176-2194. https://doi.org/10.1172/JCI41636.
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Research Article Metabolism

The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans

Abstract

Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element–binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism.

Authors

Fadila Benhamed, Pierre-Damien Denechaud, Maud Lemoine, Céline Robichon, Marthe Moldes, Justine Bertrand-Michel, Vlad Ratziu, Lawrence Serfaty, Chantal Housset, Jacqueline Capeau, Jean Girard, Hervé Guillou, Catherine Postic

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Figure 1

Overexpression of ChREBP in livers of mice leads to the induction of the entire lipogenic and esterification program.

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Overexpression of ChREBP in livers of mice leads to the induction of the...
C57BL/6J mice were injected intravenously with a single dose of 5 × 109 pfu of GFP or ChREBP adenovirus at day 1. Four weeks later, mice were sacrificed and analyses were performed. (A) Ser196 phosphorylation level of ChREBP in livers of overnight fasted GFP and ChREBP mice. A representative Western blot is shown (n = 10–12 group). (B) Quantification of the ratio of Ser196 ChREBP phosphorylation compared with total ChREBP protein content is shown. ***P < 0.001 ChREBP versus GFP mice. (C) Nuclear ChREBP and SREBP-1c protein content in nuclear extracts from fed GFP versus ChREBP mice. Lamin A/C antibody was used as a loading control. A representative Western blot is shown (n = 10–12/group). mSREBP-1c, mature SREBP-1c. (D) Total ACACA, FASN, and SCD1 protein content in liver lysates from fed GFP and ChREBP mice. β-Actin antibody was used as a loading control. A representative Western blot is shown (n = 10–12/group). (E) qRT-PCR analysis of ChREBP, SREBP-1c, LXR, Pparg, Gck, Pklr, Acaca, Fasn, Scd1, Elovl6, and GPAT in livers of GFP versus ChREBP mice. Results are the mean ± SEM (n = 10–12/group). *P < 0.05, **P < 0.01 ChREBP versus GFP mice.