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":"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。","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":"{\"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. 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Hepatocyte Deubiquitinating Enzyme OTUD5 Deficiency Is a Key Aggravator for Metabolic Dysfunction-Associated Steatohepatitis by Disturbing Mitochondrial Homeostasis
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.
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.
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