High-Fat Diet–Induced DeSUMOylation of E4BP4 Promotes Lipid Droplet Biogenesis and Liver Steatosis in Mice
Year: 2022
Type: article
Abstract: 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 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.
Source: Diabetes
DOI: 10.2337/db22-0332
Authors: Sujuan Wang, Meichan Yang, Pei Li, Julian Sit, Audrey Wong, Kyle Rodrigues, Daniel Lank, Deqiang Zhang, Kezhong Zhang, Lei Yin, Xin Tong
Institutions: Central South University, University of Michigan, Michigan Medicine, Second Xiangya Hospital of Central South University, Xiangya Hospital Central South University, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Rutgers, The State University of New Jersey, University of Virginia, Wayne State University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G1650628242, A novel CREBH-derived hepatokine regulates triglyceride metabolism, Michigan Diabetes Research and Training Center, Regulation of Rhythmic m6A RNA Modification by ER‐associated Degradation, Interfacing computation and engineering with digestive and metabolic physiology, G643570424, Role and Mechanisms of E4BP4 over-activation in diet-induced fatty liver disease, G9000231952, G9000301509, Michigan Diabetes Research Center (MDRC), Michigan Nutrition Obesity Research Center
OpenAlex ID: W4311200024