{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T03:06:28Z","timestamp":1789095988885,"version":"build-2803163510"},"reference-count":72,"publisher":"American Diabetes Association","issue":"3","license":[{"start":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T00:00:00Z","timestamp":1670803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"national institute of health","award":["DK020572"],"award-info":[{"award-number":["DK020572"]}]},{"name":"national institute of health","award":["DK088752"],"award-info":[{"award-number":["DK088752"]}]},{"name":"national institute of health","award":["DK089503"],"award-info":[{"award-number":["DK089503"]}]},{"name":"national institute of health","award":["DK121170"],"award-info":[{"award-number":["DK121170"]}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,3,1]]},"abstract":"<jats: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\u2013binding protein 4 (E4BP4) plays a critical role in promoting lipid droplet formation and liver steatosis in a high-fat diet (HFD)\u2013induced 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.<\/jats:p>","DOI":"10.2337\/db22-0332","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T11:36:10Z","timestamp":1670844970000},"page":"348-361","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":19,"title":["High-Fat Diet\u2013Induced DeSUMOylation of E4BP4 Promotes Lipid Droplet Biogenesis and Liver Steatosis in Mice"],"prefix":"10.2337","volume":"72","author":[{"given":"Sujuan","family":"Wang","sequence":"first","affiliation":[{"name":"1Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI"},{"name":"2Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, People\u2019s Republic of 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