Jiye Zhang, Wenling Mou, Shiru Chen, Zhenting Wu, Shujie Zhang, Ping Liu, Haobo Sun, Hang Zhou, Ying Liu
{"title":"酒精相关肝病中HDL代谢的调节:HIF-1α和miR-185在SR-BI抑制中的作用","authors":"Jiye Zhang, Wenling Mou, Shiru Chen, Zhenting Wu, Shujie Zhang, Ping Liu, Haobo Sun, Hang Zhou, Ying Liu","doi":"10.1080/00952990.2025.2506529","DOIUrl":null,"url":null,"abstract":"<p><p><i>Background:</i> Alcohol-associated liver disease (ALD) results from excessive alcohol consumption, leading to liver damage such as steatosis and inflammation. Hypoxia and altered lipid metabolism contribute to ALD pathogenesis. HIF-1α, a key hypoxia regulator, and miR-185, a microRNA associated with ALD, are potential contributors to the disease.<i>Objectives:</i> To explore how HIF-1α and miR-185 regulate SR-BI and HDL metabolism in ethanol-exposed hepatocytes and their role in ALD-related lipid dysfunction.<i>Methods:</i> HL-7702 cells were treated with ethanol (25-200 mm) or hypoxia (1-2% O<sub>2</sub>) for 24-72 hours to identify optimal conditions. miR-185 or HIF-1α inhibitors were used to assess SR-BI expression. Co-localization of HIF-1α and SR-BI was evaluated by immunofluorescence, and high-density lipoprotein cholesterol (HDL-C), which is critical in lipid metabolism, and triglyceride (TG) levels were measured by ELISA.<i>Results:</i> Ethanol exposure reduced cell viability in a dose- and time-dependent manner (200 mm for 72 h reduced viability by 43.7% ± 4.1%, <i>p</i> = .003). Exposure to 1% oxygen for 72 hours was confirmed as the optimal hypoxia model. Ethanol (200 mm) or hypoxia significantly increased HIF-1α (<i>p</i> = .002) and miR-185 expression (<i>p</i> = .001). These changes were accompanied by reduced SR-BI expression and elevated HDL-C and TG levels. miR-185 knockdown restored SR-BI expression (<i>p</i> = .003) and normalized HDL-C (<i>p</i> = .004) and TG levels (<i>p</i> = .005).<i>Conclusions:</i> Ethanol-induced HIF-1α and miR-185 upregulation disrupts HDL metabolism by suppressing SR-BI, impairing hepatic HDL uptake in ALD. Targeting this axis may offer new therapeutic strategies for ALD.</p>","PeriodicalId":48957,"journal":{"name":"American Journal of Drug and Alcohol Abuse","volume":" ","pages":"1-11"},"PeriodicalIF":2.7000,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Regulation of HDL metabolism in alcohol-associated liver disease: the role of HIF-1α and miR-185 in SR-BI suppression.\",\"authors\":\"Jiye Zhang, Wenling Mou, Shiru Chen, Zhenting Wu, Shujie Zhang, Ping Liu, Haobo Sun, Hang Zhou, Ying Liu\",\"doi\":\"10.1080/00952990.2025.2506529\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><i>Background:</i> Alcohol-associated liver disease (ALD) results from excessive alcohol consumption, leading to liver damage such as steatosis and inflammation. Hypoxia and altered lipid metabolism contribute to ALD pathogenesis. HIF-1α, a key hypoxia regulator, and miR-185, a microRNA associated with ALD, are potential contributors to the disease.<i>Objectives:</i> To explore how HIF-1α and miR-185 regulate SR-BI and HDL metabolism in ethanol-exposed hepatocytes and their role in ALD-related lipid dysfunction.<i>Methods:</i> HL-7702 cells were treated with ethanol (25-200 mm) or hypoxia (1-2% O<sub>2</sub>) for 24-72 hours to identify optimal conditions. miR-185 or HIF-1α inhibitors were used to assess SR-BI expression. Co-localization of HIF-1α and SR-BI was evaluated by immunofluorescence, and high-density lipoprotein cholesterol (HDL-C), which is critical in lipid metabolism, and triglyceride (TG) levels were measured by ELISA.<i>Results:</i> Ethanol exposure reduced cell viability in a dose- and time-dependent manner (200 mm for 72 h reduced viability by 43.7% ± 4.1%, <i>p</i> = .003). Exposure to 1% oxygen for 72 hours was confirmed as the optimal hypoxia model. Ethanol (200 mm) or hypoxia significantly increased HIF-1α (<i>p</i> = .002) and miR-185 expression (<i>p</i> = .001). These changes were accompanied by reduced SR-BI expression and elevated HDL-C and TG levels. miR-185 knockdown restored SR-BI expression (<i>p</i> = .003) and normalized HDL-C (<i>p</i> = .004) and TG levels (<i>p</i> = .005).<i>Conclusions:</i> Ethanol-induced HIF-1α and miR-185 upregulation disrupts HDL metabolism by suppressing SR-BI, impairing hepatic HDL uptake in ALD. Targeting this axis may offer new therapeutic strategies for ALD.</p>\",\"PeriodicalId\":48957,\"journal\":{\"name\":\"American Journal of Drug and Alcohol Abuse\",\"volume\":\" \",\"pages\":\"1-11\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2025-05-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American Journal of Drug and Alcohol Abuse\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/00952990.2025.2506529\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PSYCHOLOGY, CLINICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Drug and Alcohol Abuse","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/00952990.2025.2506529","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PSYCHOLOGY, CLINICAL","Score":null,"Total":0}
Regulation of HDL metabolism in alcohol-associated liver disease: the role of HIF-1α and miR-185 in SR-BI suppression.
Background: Alcohol-associated liver disease (ALD) results from excessive alcohol consumption, leading to liver damage such as steatosis and inflammation. Hypoxia and altered lipid metabolism contribute to ALD pathogenesis. HIF-1α, a key hypoxia regulator, and miR-185, a microRNA associated with ALD, are potential contributors to the disease.Objectives: To explore how HIF-1α and miR-185 regulate SR-BI and HDL metabolism in ethanol-exposed hepatocytes and their role in ALD-related lipid dysfunction.Methods: HL-7702 cells were treated with ethanol (25-200 mm) or hypoxia (1-2% O2) for 24-72 hours to identify optimal conditions. miR-185 or HIF-1α inhibitors were used to assess SR-BI expression. Co-localization of HIF-1α and SR-BI was evaluated by immunofluorescence, and high-density lipoprotein cholesterol (HDL-C), which is critical in lipid metabolism, and triglyceride (TG) levels were measured by ELISA.Results: Ethanol exposure reduced cell viability in a dose- and time-dependent manner (200 mm for 72 h reduced viability by 43.7% ± 4.1%, p = .003). Exposure to 1% oxygen for 72 hours was confirmed as the optimal hypoxia model. Ethanol (200 mm) or hypoxia significantly increased HIF-1α (p = .002) and miR-185 expression (p = .001). These changes were accompanied by reduced SR-BI expression and elevated HDL-C and TG levels. miR-185 knockdown restored SR-BI expression (p = .003) and normalized HDL-C (p = .004) and TG levels (p = .005).Conclusions: Ethanol-induced HIF-1α and miR-185 upregulation disrupts HDL metabolism by suppressing SR-BI, impairing hepatic HDL uptake in ALD. Targeting this axis may offer new therapeutic strategies for ALD.
期刊介绍:
The American Journal of Drug and Alcohol Abuse (AJDAA) is an international journal published six times per year and provides an important and stimulating venue for the exchange of ideas between the researchers working in diverse areas, including public policy, epidemiology, neurobiology, and the treatment of addictive disorders. AJDAA includes a wide range of translational research, covering preclinical and clinical aspects of the field. AJDAA covers these topics with focused data presentations and authoritative reviews of timely developments in our field. Manuscripts exploring addictions other than substance use disorders are encouraged. Reviews and Perspectives of emerging fields are given priority consideration.
Areas of particular interest include: public health policy; novel research methodologies; human and animal pharmacology; human translational studies, including neuroimaging; pharmacological and behavioral treatments; new modalities of care; molecular and family genetic studies; medicinal use of substances traditionally considered substances of abuse.