Hepatocyte Deubiquitinating Enzyme OTUD5 Deficiency Is a Key Aggravator for Metabolic Dysfunction-Associated Steatohepatitis by Disturbing Mitochondrial Homeostasis

IF 7.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2024-01-01 DOI:10.1016/j.jcmgh.2023.11.014

Jingjing Dai , Liren Zhang , Ruizhi Zhang , Jing Ge , Feifan Yao , Suiqing Zhou , Jiali Xu , Kai Yu , Jing Xu , Longfeng Jiang , Ke Jin , Xinzheng Dai , Jun Li , Qing Li

{"title":"Hepatocyte Deubiquitinating Enzyme OTUD5 Deficiency Is a Key Aggravator for Metabolic Dysfunction-Associated Steatohepatitis by Disturbing Mitochondrial Homeostasis","authors":"Jingjing Dai , Liren Zhang , Ruizhi Zhang , Jing Ge , Feifan Yao , Suiqing Zhou , Jiali Xu , Kai Yu , Jing Xu , Longfeng Jiang , Ke Jin , Xinzheng Dai , Jun Li , Qing Li","doi":"10.1016/j.jcmgh.2023.11.014","DOIUrl":null,"url":null,"abstract":"<div><h3>Background & Aims</h3><p>Metabolic dysfunction–associated steatohepatitis (MASH) is a common chronic liver disease worldwide. No effective pharmacologic therapies for MASH have been developed; to develop such promising drugs, the underlying mechanisms regulating MASH need to be elucidated. Here, we aimed to determine the role of ovarian tumor domain-containing protein 5 (OTUD5) in MASH progression and identify a specific mechanism.</p></div><div><h3>Methods</h3><p>The expression levels of OTUD subfamily under palmitic acid/oleic acid (PAOA) stimulation were screened. OTUD5 expression was assessed in human liver tissues without steatosis, those with simple steatosis, and those with MASH. MASH models were developed in hepatocyte-specific <em>Otud5</em>-knockout mice that were fed high-fat high-cholesterol and high-fat high-cholesterol plus high-fructose/sucrose diet for 16 weeks.</p></div><div><h3>Results</h3><p>The expression of OTUD5 was down-regulated in fatty liver and was negatively related to the progression of MASH. Lipid accumulation and inflammation were exacerbated by <em>Otud5</em> knockdown but attenuated by <em>Otud5</em> overexpression under PAOA treatment. Hepatocyte-specific <em>Otud5</em> deletion markedly exacerbated steatosis, inflammation, and fibrosis in the livers of 2 MASH mouse models. We identified voltage-dependent anion channel 2 (VDAC2) as an OTUD5-interacting partner; OTUD5 cleaved the K48-linked polyubiquitin chains from VDAC2, and it inhibited subsequent proteasomal degradation. The anabolic effects of OTUD5 knockdown on PAOA-induced lipid accumulation were effectively reversed by VDAC2 overexpression in primary hepatocytes. Metabolomic results revealed that VDAC2 is required for OTUD5-mediated protection against hepatic steatosis by maintaining mitochondrial function.</p></div><div><h3>Conclusions</h3><p>OTUD5 may ameliorate MASH progression via VDAC2-maintained mitochondrial homeostasis. Targeting OTUD5 may be a viable MASH-treatment strategy.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X23002138/pdfft?md5=5c42777cb99d32033c1f7fbc97118eee&pid=1-s2.0-S2352345X23002138-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular and Molecular Gastroenterology and Hepatology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2352345X23002138","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background & Aims

Metabolic dysfunction–associated steatohepatitis (MASH) is a common chronic liver disease worldwide. No effective pharmacologic therapies for MASH have been developed; to develop such promising drugs, the underlying mechanisms regulating MASH need to be elucidated. Here, we aimed to determine the role of ovarian tumor domain-containing protein 5 (OTUD5) in MASH progression and identify a specific mechanism.

Methods

The expression levels of OTUD subfamily under palmitic acid/oleic acid (PAOA) stimulation were screened. OTUD5 expression was assessed in human liver tissues without steatosis, those with simple steatosis, and those with MASH. MASH models were developed in hepatocyte-specific Otud5-knockout mice that were fed high-fat high-cholesterol and high-fat high-cholesterol plus high-fructose/sucrose diet for 16 weeks.

Results

The expression of OTUD5 was down-regulated in fatty liver and was negatively related to the progression of MASH. Lipid accumulation and inflammation were exacerbated by Otud5 knockdown but attenuated by Otud5 overexpression under PAOA treatment. Hepatocyte-specific Otud5 deletion markedly exacerbated steatosis, inflammation, and fibrosis in the livers of 2 MASH mouse models. We identified voltage-dependent anion channel 2 (VDAC2) as an OTUD5-interacting partner; OTUD5 cleaved the K48-linked polyubiquitin chains from VDAC2, and it inhibited subsequent proteasomal degradation. The anabolic effects of OTUD5 knockdown on PAOA-induced lipid accumulation were effectively reversed by VDAC2 overexpression in primary hepatocytes. Metabolomic results revealed that VDAC2 is required for OTUD5-mediated protection against hepatic steatosis by maintaining mitochondrial function.

Conclusions

OTUD5 may ameliorate MASH progression via VDAC2-maintained mitochondrial homeostasis. Targeting OTUD5 may be a viable MASH-treatment strategy.

Abstract Image

查看原文本刊更多论文

肝细胞去泛素化酶OTUD5缺乏是代谢功能障碍相关脂肪性肝炎的关键加重因素，因为它扰乱了线粒体稳态。

背景与目的:代谢功能障碍相关脂肪性肝炎(MASH)是世界范围内常见的慢性肝病。目前尚未开发出有效的药物治疗MASH;为了开发这些有前景的药物，需要阐明调节MASH的潜在机制。在这里，我们的目的是确定OTUD5在MASH进展中的作用，并确定一个特定的机制。方法:筛选棕榈酸/油酸(PAOA)刺激下OTUD亚家族的表达水平。评估了OTUD5在无脂肪变性、单纯性脂肪变性和MASH患者肝组织中的表达。在肝细胞特异性otud5敲除小鼠中建立MASH模型，这些小鼠被喂食高脂肪高胆固醇(HFHC)和高脂肪高胆固醇加高果糖/蔗糖(HFF)饮食16周。结果:OTUD5在脂肪肝中表达下调，与MASH进展呈负相关。在PAOA治疗下，Otud5基因下调会加重脂质积累和炎症，而Otud5基因过表达则会减轻脂质积累和炎症。肝细胞特异性Otud5缺失显著加重了两种MASH小鼠模型的肝脏脂肪变性、炎症和纤维化。我们确定了电压依赖性阴离子通道2 (VDAC2)作为otud5相互作用的伙伴;OTUD5从VDAC2上切割k48连接的多泛素链，并抑制随后的蛋白酶体降解。原代肝细胞中VDAC2过表达可有效逆转OTUD5敲低对paoa诱导的脂质积累的合成代谢作用。代谢组学结果显示，VDAC2是otud5通过维持线粒体功能介导的肝脂肪变性保护所必需的。结论:OTUD5可能通过vdac2维持线粒体稳态来改善MASH进展。靶向OTUD5可能是一种可行的mash治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cellular and Molecular Gastroenterology and Hepatology Medicine-Gastroenterology

CiteScore

13.00

自引率

2.80%

发文量

246

审稿时长

42 days

期刊介绍： "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.