Zinc finger BED-type containing 3 promotes hepatic steatosis by interacting with polypyrimidine tract-binding protein 1.

IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetologia Pub Date : 2024-10-01 Epub Date: 2024-07-22 DOI:10.1007/s00125-024-06224-2
Yao Wu, Min Yang, Shao-Bo Wu, Pei-Qi Luo, Cheng Zhang, Chang-Shun Ruan, Wei Cui, Qiu-Rong Zhao, Lin-Xin Chen, Juan-Juan Meng, Qiang Song, Wen-Jin Zhang, Qin-Qin Pei, Fang Li, Ting Zeng, Hong-Xin Du, Li-Xin Xu, Weizhen Zhang, Xian-Xiang Zhang, Xiao-He Luo
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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 ).

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含锌指 BED 型 3 通过与多嘧啶束结合蛋白 1 相互作用促进肝脏脂肪变性。
目的/假设:代谢功能障碍相关性脂肪性肝病(MASLD)与2型糖尿病、胰岛素抵抗和代谢综合征之间的关系已得到公认。虽然锌指 BED 型含锌 3(ZBED3)与 2 型糖尿病和代谢综合征有关,但其在 MASLD 中的作用仍不清楚。在本研究中,我们旨在研究 ZBED3 在 MASLD 中的功能:方法:评估ZBED3在MASLD患者以及MASLD细胞和动物模型中的表达水平。分别使用NEFA诱导的MASLD细胞模型和高脂饮食(HFD)诱导的MASLD动物模型进行了体外和体内分析,以研究ZBED3在MASLD中的作用。慢病毒感染或尾静脉注射腺相关病毒可增加ZBED3的表达。研究人员采用RNA-seq和生物信息学分析来研究ZBED3调节脂质积累的途径。这些新一代转录组测序研究的结果表明,ZBED3控制着SREBP1c(又称SREBF1,一种参与脂肪酸从头合成的基因);因此,我们利用共免疫沉淀和LC-MS/MS研究了ZBED3调控固醇调节元件结合蛋白1c(SREBP1c)的分子机制:本研究发现,ZBED3在MASLD患者肝脏和MASLD动物模型中显著上调。ZBED3 的过表达促进了 NEFA 诱导的甘油三酯在体外肝细胞中的积累。此外,肝细胞特异性过表达 Zbed3 会促进肝脏脂肪变性。相反,肝细胞特异性敲除 Zbed3 则可抵抗 HFD 诱导的肝脂肪变性。从机理上讲,ZBED3与多嘧啶束结合蛋白1(PTBP1)直接相互作用,影响其与SREBP1c mRNA前体的结合,从而调控SREBP1c mRNA的稳定性和替代剪接:这项研究表明,ZBED3可促进肝脏脂肪变性,是MASLD进展的关键调控因子:RNA-seq数据已存入NCBI基因表达总库( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231875 )。MS蛋白质组学数据已通过iProX合作伙伴存储库存入ProteomeXchange Consortium ( https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041743 )。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Diabetologia
Diabetologia 医学-内分泌学与代谢
CiteScore
18.10
自引率
2.40%
发文量
193
审稿时长
1 months
期刊介绍: Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
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