title: E4BP4 is an insulin-induced stabilizer of nuclear SREBP-1c and promotes SREBP-1c-mediated lipogenesis.
abstract: Upon food intake, insulin stimulates de novo lipogenesis (DNL) in hepatocytes via the AKT-mTORC1-sterol regulatory element-binding protein (SREBP)-1c pathway. How insulin maintains the maximal SREBP-1c activities during the entire feeding state remains elusive. We previously reported that insulin induced b-ZIP transcription factor, E4-binding protein 4 (E4BP4), in hepatocytes. In the current study, we show that insulin injection increases hepatic E4bp4 expression by activating the AKT-mTORC1-SREBP-1c pathway in hepatocytes. E4bp4-deficient hepatocytes not only fail to maintain robust DNL but also become resistant to SREBP-1c-induced lipogenesis. In vivo, acute depletion of E4bp4 in the liver by adenoviral shRNA reduces the expression of lipogenic enzymes and results in reduced levels of serum triglycerides and cholesterol during the postprandial phase. In hepatocytes, E4BP4 interacts with nuclear SREBP-1c to preserve its acetylation, and subsequently protects it from ubiquitination-dependent degradation. In conclusion, the current studies uncover a novel positive feedback pathway mediated by E4BP4 to augment SREBP-1c-mediated DNL in the liver during the fed state.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48019.
authors.forename: Xin
authors.initials: X
authors.lastname: Tong
authors.affiliation: Xiangya School of Medicine, Central South University, Changsha 410013, People's Republic of China.
authors.forename: Pei
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48019.
authors.forename: Deqiang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48019.
authors.forename: Kyle
authors.initials: K
authors.lastname: VanDommelen
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48019.
authors.forename: Neil
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48019.
authors.forename: Liangyou
authors.initials: L
authors.lastname: Rui
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48019.
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48019 leiyin@umich.edu.
authors.forename: Lei
authors.initials: L
authors.lastname: Yin
mesh_terms: D000818:Animals; D001069:Appetite Regulation / Q000235:genetics; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis / Q000235:genetics; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D019518:Postprandial Period; D059748:Proteolysis; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014280:Triglycerides / Q000096:biosynthesis
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D005227:Fatty Acids; D007328:Insulin; C497441:Nfil3 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides
keywords: E4-binding protein 4; acetylation; de novo lipogenesis; fatty acid synthesis; insulin signaling; lipids; liver; post-prandial; sterol regulatory element-binding protein 1c; transcription; triglycerides; ubiquitination