High-fat diet-induced deSUMOylation of E4BP4 promotes lipid droplet biogenesis and liver steatosis in mice

Abstract

<p>Dysregulated lipid droplet accumulation has been identified as one of the main contributors to liver steatosis during nonalcoholic fatty liver disease (NAFLD). However, the underlying molecular mechanisms for excessive lipid droplet formation in the liver remain largely unknown. In the current study, hepatic E4 promoter-binding protein 4 (E4BP4) plays a critical role in promoting lipid droplet formation and liver steatosis in a high-fat diet (HFD)-induced NAFLD mouse model. Hepatic <em>E4bp4</em> deficiency (<em>E4bp4-LKO</em>) protects mice from HFD-induced liver steatosis independently of obesity and insulin resistance. Our microarray study showed a markedly reduced expression of lipid droplet binding genes such as <em>Fsp27</em> in the liver of <em>E4bp4-LKO</em> mice. E4BP4 is both necessary and sufficient to activate <em>Fsp27</em> expression and lipid droplet formation in primary mouse hepatocytes. Overexpression of <em>Fsp27</em> increased lipid droplets and triglycerides in <em>E4bp4-LKO</em> primary mouse hepatocytes and restored hepatic steatosis in HFD-fed <em>E4bp4-LKO</em> mice. Mechanistically, E4BP4 enhances the transactivation of <em>Fsp27</em> by CREBH in hepatocytes. Furthermore, E4BP4 is modified by SUMOylation and HFD feeding induces deSUMOylation of hepatic E4BP4. SUMOylation of five lysine residues of E4BP4 is critical for the downregulation of <em>Fsp27 </em>and lipid droplets by the cAMP signaling in hepatocytes. Taken together, this study revealed that E4BP4 drives liver steatosis in HFD-fed mice through its regulation of lipid-droplet binding proteins. Our study also highlights the critical role of deSUMOylation of hepatic E4BP4 in promoting NAFLD. </p>