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

IF 2.7 3区 医学 Q2 PSYCHOLOGY, CLINICAL
Jiye Zhang, Wenling Mou, Shiru Chen, Zhenting Wu, Shujie Zhang, Ping Liu, Haobo Sun, Hang Zhou, Ying Liu
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引用次数: 0

摘要

背景:酒精相关性肝病(ALD)是由过度饮酒引起的,可导致肝脏损伤,如脂肪变性和炎症。缺氧和脂质代谢改变有助于ALD的发病。HIF-1α(一种关键的缺氧调节因子)和miR-185(一种与ALD相关的microRNA)是该疾病的潜在诱因。目的:探讨HIF-1α和miR-185如何调节乙醇暴露肝细胞中SR-BI和HDL代谢及其在ald相关脂质功能障碍中的作用。方法:用乙醇(25-200 mm)或缺氧(1-2% O2)处理HL-7702细胞24-72小时,确定最佳处理条件。miR-185或HIF-1α抑制剂用于评估SR-BI的表达。免疫荧光法检测HIF-1α和SR-BI的共定位,ELISA法检测脂质代谢关键的高密度脂蛋白胆固醇(HDL-C)和甘油三酯(TG)水平。结果:乙醇暴露使细胞活力呈剂量和时间依赖关系(200mm暴露72h使细胞活力降低43.7%±4.1%,p = 0.003)。暴露于1%氧气72小时被证实为最佳缺氧模型。乙醇(200 mm)或缺氧显著增加HIF-1α (p = 0.002)和miR-185的表达(p = 0.001)。这些变化伴随着SR-BI表达减少和HDL-C和TG水平升高。miR-185敲低恢复SR-BI表达(p = 0.003),并使HDL-C (p = 0.004)和TG水平正常化(p = 0.005)。结论:乙醇诱导的HIF-1α和miR-185上调通过抑制SR-BI破坏HDL代谢,损害ALD中肝脏HDL摄取。靶向这一轴可能为ALD提供新的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
CiteScore
4.70
自引率
3.70%
发文量
68
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.
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