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.

Dysregulations in hepatic lipid synthesis are often associated with obesity and type 2 diabetes, and therefore a perfect understanding of the regulation of this metabolic pathway appears essential to identify potential therapeutic targets. Recently, the transcription factor ChREBP (carbohydrate-responsive element-binding protein) has emerged as a major mediator of glucose action on lipogenic gene expression and as a key determinant of lipid synthesis in vivo. Indeed, liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in obese ob/ob mice. Since ChREBP cellular localization is a determinant of its functional activity, a better knowledge of the mechanisms involved in regulating its nucleo-cytoplasmic shuttling and/or its post-translational activation is crucial in both physiology and physiopathology. Here, we review some of the studies that have begun to elucidate the regulation and function of this key transcription factor in liver.

In the last years, several lines of evidence have shown that cell cycle regulatory proteins also can modulate metabolic processes. The transcription factor E2F1 is a central player involved in cell cycle progression, DNA-damage response and apoptosis. Its crucial role in the control of cell fate has been extensively studied and reviewed before, however, here we focus on the participation of E2F1 in the regulation of metabolism. We summarize recent findings about the cell cycle independent roles of E2F1 in various tissues that contribute to global metabolic homeostasis and highlight that E2F1 activity is increased during obesity. Finally, coming back to the pivotal role of E2F1 in cancer development, we discuss how E2F1 links cell cycle progression with different metabolic adaptations required for cell growth and survival.

β-catenin signaling can be both a physiological and oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20%-40% of hepatocellular carcinomas (HCCs) with specific metabolic features. We decipher the molecular determinants of β-catenin-dependent zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by T-cell factor (Tcf)−4 and β-catenin, transcriptome, and metabolome. We find that Tcf-4 DNA bindings depend on β-catenin. Tcf-4/β-catenin binds Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, genes repressed by β-catenin bind Tcf-4 on hepatocyte nuclear factor 4 (Hnf-4)-responsive elements. β-Catenin, Tcf-4, and Hnf-4α interact, dictating β-catenin transcription, which is antagonistic to that elicited by Hnf-4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by β-catenin, partly through xenobiotic nuclear receptors. Conclusions: β-catenin patterns the zonal liver together with Tcf-4, Hnf-4α, and xenobiotic nuclear receptors. This network represses lipid metabolism and exacerbates glutamine, drug, and bile metabolism, mirroring HCCs with β-catenin mutational activation. (Hepatology 2014;59:2344–2357)