Diabetologia ( IF 8.4 ) Pub Date : 2024-07-22 , DOI: 10.1007/s00125-024-06224-2 Yao Wu 1, 2 , Min Yang 1, 2 , Shao-Bo Wu 2 , Pei-Qi Luo 2 , Cheng Zhang 2 , Chang-Shun Ruan 2 , Wei Cui 3 , Qiu-Rong Zhao 3 , Lin-Xin Chen 3 , Juan-Juan Meng 3 , Qiang Song 3 , Wen-Jin Zhang 2 , Qin-Qin Pei 3 , Fang Li 1, 2 , Ting Zeng 1 , Hong-Xin Du 1 , Li-Xin Xu 4 , Weizhen Zhang 5, 6 , Xian-Xiang Zhang 2 , Xiao-He Luo 1, 2, 3, 4
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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).
Graphical Abstract
中文翻译：
含有 3 的锌指 BED 型通过与聚嘧啶束结合蛋白 1 相互作用促进肝脂肪变性
目标/假设
代谢功能障碍相关的脂肪肝病 (MASLD) 与 2 型糖尿病、胰岛素抵抗和代谢综合征之间的关系已明确。虽然锌指 BED 型含 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 背景下的功能。
方法
在患有 MASLD 的个体以及 MASLD 的细胞和动物模型中评估了 ZBED3 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。采用 RNA-seq 和生物信息学分析来检查 ZBED3 调节脂质积累的途径。这些下一代转录组测序研究的结果表明，ZBED3 控制SREBP1c （也称为SREBF1 ；一种参与脂肪酸从头合成的基因）；因此，利用免疫共沉淀和LC-MS/MS来研究ZBED3调节甾醇调节元件结合蛋白1c（SREBP1c）的分子机制。
结果
在这项研究中，我们发现 ZBED3 在 MASLD 个体和 MASLD 动物模型的肝脏中显着上调。 ZBED3 过表达促进体外肝细胞中 NEFA 诱导的甘油三酯积累。此外， Zbed3的肝细胞特异性过度表达促进了肝脂肪变性。相反， Zbed3的肝细胞特异性敲除导致对 HFD 诱导的肝脂肪变性的抵抗。从机制上讲，ZBED3 直接与聚嘧啶束结合蛋白 1 (PTBP1) 相互作用，并影响其与SREBP1c mRNA 前体的结合，从而调节SREBP1c mRNA 稳定性和选择性剪接。
结论/解释
这项研究表明，ZBED3 促进肝脏脂肪变性，并作为 MASLD 进展的关键调节因子。
数据可用性
RNA-seq 数据已存入 NCBI 基因表达综合库 (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 (https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041743) 存入 ProteomeXchange 联盟。
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