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.