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

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