Pablo Fernández-Tussy, Magdalena P Cardelo, Hanming Zhang, Jonathan Sun, Nathan L Price, Nabil E Boutagy, Leigh Goedeke, Martí Cadena-Sandoval, Chrysovalantou E Xirouchaki, Wendy A Brown, Xiaoyong Yang, Oscar Pastor-Rojo, Rebecca A Haeusler, Anton M Bennett, Tony Tiganis, Yajaira Suárez, Carlos Fernández-Hernando
{"title":"肝细胞中的 miR-33 缺失可减轻 NAFLD-NASH-HCC 的进展。","authors":"Pablo Fernández-Tussy, Magdalena P Cardelo, Hanming Zhang, Jonathan Sun, Nathan L Price, Nabil E Boutagy, Leigh Goedeke, Martí Cadena-Sandoval, Chrysovalantou E Xirouchaki, Wendy A Brown, Xiaoyong Yang, Oscar Pastor-Rojo, Rebecca A Haeusler, Anton M Bennett, Tony Tiganis, Yajaira Suárez, Carlos Fernández-Hernando","doi":"10.1172/jci.insight.168476","DOIUrl":null,"url":null,"abstract":"<p><p>The complexity of the mechanisms underlying non-alcoholic fatty liver disease (NAFLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of NAFLD and the development of hepatocellular carcinoma (HCC). We report that miR-33 is elevated in the livers of humans and mice with NAFLD and that its deletion in hepatocytes (miR-33 HKO) improves multiple aspects of the disease, including steatosis and inflammation, limiting the progression to non-alcoholic steatohepatitis (NASH), fibrosis and HCC. Mechanistically, hepatic miR-33 deletion reduces lipid synthesis and promotes mitochondrial fatty acid oxidation, reducing lipid burden. Additionally, absence of miR-33 alters the expression of several known miR-33 target genes involved in metabolism and results in improved mitochondrial function and reduced oxidative stress. The reduction in lipid accumulation and liver injury resulted in decreased YAP/TAZ pathway activation, which may be involved in the reduced HCC progression in HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach to temper the development of NAFLD, NASH, and HCC in obesity.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3000,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"miR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression.\",\"authors\":\"Pablo Fernández-Tussy, Magdalena P Cardelo, Hanming Zhang, Jonathan Sun, Nathan L Price, Nabil E Boutagy, Leigh Goedeke, Martí Cadena-Sandoval, Chrysovalantou E Xirouchaki, Wendy A Brown, Xiaoyong Yang, Oscar Pastor-Rojo, Rebecca A Haeusler, Anton M Bennett, Tony Tiganis, Yajaira Suárez, Carlos Fernández-Hernando\",\"doi\":\"10.1172/jci.insight.168476\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The complexity of the mechanisms underlying non-alcoholic fatty liver disease (NAFLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of NAFLD and the development of hepatocellular carcinoma (HCC). We report that miR-33 is elevated in the livers of humans and mice with NAFLD and that its deletion in hepatocytes (miR-33 HKO) improves multiple aspects of the disease, including steatosis and inflammation, limiting the progression to non-alcoholic steatohepatitis (NASH), fibrosis and HCC. Mechanistically, hepatic miR-33 deletion reduces lipid synthesis and promotes mitochondrial fatty acid oxidation, reducing lipid burden. Additionally, absence of miR-33 alters the expression of several known miR-33 target genes involved in metabolism and results in improved mitochondrial function and reduced oxidative stress. The reduction in lipid accumulation and liver injury resulted in decreased YAP/TAZ pathway activation, which may be involved in the reduced HCC progression in HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach to temper the development of NAFLD, NASH, and HCC in obesity.</p>\",\"PeriodicalId\":14722,\"journal\":{\"name\":\"JCI insight\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.3000,\"publicationDate\":\"2024-08-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JCI insight\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1172/jci.insight.168476\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"JCI insight","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1172/jci.insight.168476","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
miR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression.
The complexity of the mechanisms underlying non-alcoholic fatty liver disease (NAFLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of NAFLD and the development of hepatocellular carcinoma (HCC). We report that miR-33 is elevated in the livers of humans and mice with NAFLD and that its deletion in hepatocytes (miR-33 HKO) improves multiple aspects of the disease, including steatosis and inflammation, limiting the progression to non-alcoholic steatohepatitis (NASH), fibrosis and HCC. Mechanistically, hepatic miR-33 deletion reduces lipid synthesis and promotes mitochondrial fatty acid oxidation, reducing lipid burden. Additionally, absence of miR-33 alters the expression of several known miR-33 target genes involved in metabolism and results in improved mitochondrial function and reduced oxidative stress. The reduction in lipid accumulation and liver injury resulted in decreased YAP/TAZ pathway activation, which may be involved in the reduced HCC progression in HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach to temper the development of NAFLD, NASH, and HCC in obesity.
期刊介绍:
JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.