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

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posted on 2022-12-12, 16:29 authored by Sujuan Wang, Meichan Yang, Pei Li, Julian Sit, Audrey Wong, Kyle Rodrigues, Daniel Lank, Deqiang Zhang, Kezhong Zhang, Lei Yin, Xin Tong

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 E4bp4 deficiency (E4bp4-LKO) 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 Fsp27 in the liver of E4bp4-LKO mice. E4BP4 is both necessary and sufficient to activate Fsp27 expression and lipid droplet formation in primary mouse hepatocytes. Overexpression of Fsp27 increased lipid droplets and triglycerides in E4bp4-LKO primary mouse hepatocytes and restored hepatic steatosis in HFD-fed E4bp4-LKO mice. Mechanistically, E4BP4 enhances the transactivation of Fsp27 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 Fsp27 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. 

Funding

This work was supported by R01 (DK121170) to X.T.. Part of the work was also supported by pilot grants from Michigan Nutrition Obesity Research Center (P30 DK089503) to L.Y., Michigan Diabetes Research Training Center (P60 DK020572) to X.T.. Julian Sit and Audrey Wong were supported by the MIP STEP program (R25DK088752).

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