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 9

Improved Akt phosphorylation in livers of HFD-fed ChREBP mice.

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Improved Akt phosphorylation in livers of HFD-fed ChREBP mice. All analy...
All analyses were carried out in HFD-fed GFP and ChREBP mice, as described in the Methods section. GFP mice maintained on a standard CD for a similar number of weeks were used as controls. Mice were sacrificed in the fasted state. (A) Ser473, Thr308 Akt phosphorylation, and Ser9 GSK3β phosphorylation in livers of overnight fasted CD-fed GFP, HFD-fed GFP, and HFD-fed ChREBP mice. Total protein content of Akt, GSK3β ChREBP, SCD1, CRTC2, and GFP are shown. Representative Western blots are shown. β-Actin was used as a loading control. Samples were run on the same gel, but lanes were not contiguous. (B) Quantification of the ratios of Ser473 and Thr308 Akt phosphorylation compared with total Akt protein content are shown. (C) Phosphorylation of Akt substrates (ranging from 55 to 250 kDa). A representative Western blot is shown. Samples were run on the same gel, but lanes were not contiguous. (D) Liver pyruvate concentrations. (E) qRT-PCR analysis of genes involved in the gluconeogenic pathway (G6pc, Pck1, Ppargc1a). Results are the mean ± SEM (n = 8–10/group). #P < 0.05 HFD-fed GFP versus CD-fed GFP mice; *P < 0.05, **P < 0.01 HFD-fed ChREBP versus HFD-fed GFP mice.