1. Zinc finger BED-type containing 3 promotes hepatic steatosis by interacting with polypyrimidine tract-binding protein 1.
- Author
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Wu, Yao, Yang, Min, Wu, Shao-bo, Luo, Pei-qi, Zhang, Cheng, Ruan, Chang-shun, Cui, Wei, Zhao, Qiu-rong, Chen, Lin-xin, Meng, Juan-juan, Song, Qiang, Zhang, Wen-jin, Pei, Qin-qin, Li, Fang, Zeng, Ting, Du, Hong-xin, Xu, Li-xin, Zhang, Weizhen, Zhang, Xian-xiang, and Luo, Xiao-he
- Abstract
Aims/hypothesis: The relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus, insulin resistance and the metabolic syndrome is well established. While zinc finger BED-type containing 3 (ZBED3) has been linked to type 2 diabetes mellitus and the metabolic syndrome, its role in MASLD remains unclear. In this study, we aimed to investigate the function of ZBED3 in the context of MASLD. Methods: Expression levels of ZBED3 were assessed in individuals with MASLD, as well as in cellular and animal models of MASLD. In vitro and in vivo analyses were conducted using a cellular model of MASLD induced by NEFA and an animal model of MASLD induced by a high-fat diet (HFD), respectively, to investigate the role of ZBED3 in MASLD. ZBED3 expression was increased by lentiviral infection or tail-vein injection of adeno-associated virus. RNA-seq and bioinformatics analysis were employed to examine the pathways through which ZBED3 modulates lipid accumulation. Findings from these next-generation transcriptome sequencing studies indicated that ZBED3 controls SREBP1c (also known as SREBF1; a gene involved in fatty acid de novo synthesis); thus, co-immunoprecipitation and LC-MS/MS were utilised to investigate the molecular mechanisms by which ZBED3 regulates the sterol regulatory element binding protein 1c (SREBP1c). Results: In this study, we found that ZBED3 was significantly upregulated in the liver of individuals with MASLD and in MASLD animal models. ZBED3 overexpression promoted NEFA-induced triglyceride accumulation in hepatocytes in vitro. Furthermore, the hepatocyte-specific overexpression of Zbed3 promoted hepatic steatosis. Conversely, the hepatocyte-specific knockout of Zbed3 resulted in resistance of HFD-induced hepatic steatosis. Mechanistically, ZBED3 interacts directly with polypyrimidine tract-binding protein 1 (PTBP1) and affects its binding to the SREBP1c mRNA precursor to regulate SREBP1c mRNA stability and alternative splicing. Conclusions/interpretation: This study indicates that ZBED3 promotes hepatic steatosis and serves as a critical regulator of the progression of MASLD. Data availability: RNA-seq data have been deposited in the NCBI Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231875). MS proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository (https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041743). [ABSTRACT FROM AUTHOR]
- Published
- 2024
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