HIF-1α/miR-185 axis regulates lipid accumulation and metabolism involved in alcohol-related liver disease in mice.

Abstract

Background: Hypoxia is a major driver of alcohol-related liver disease (ARLD), with hypoxia-inducible factor 1-alpha (HIF-1α) central to this response. Emerging evidence suggests HIF-1α regulates hepatic lipid metabolism via microRNA-185 (miR-185), though the mechanism remains unclear.Objectives: This work aims to unravel the molecular mechanisms by which the HIF-1α/miR-185 pathway regulates lipid uptake and transport in ARLD, and to explore its potential as a therapeutic target.Methods: Male C57BL/6J mice were administered a chronic ethanol-containing Lieber-DeCarli liquid diet for six weeks to induce ARLD, along with adeno-associated virus-mediated silencing of HIF-1α. Serum levels of liver function markers and lipid profile components were measured for biochemical analysis. ELISA evaluation was carried out for liver inflammatory markers. Liver sections were evaluated with H&E oil red O staining. HIF-1α, miR-185, scavenger receptor class B type I (SR-BI), and low-density lipoprotein receptor (LDLR) expressions were evaluated using RT-PCR and Western Blot.Results: Chronic alcohol exposure to mice was responsible for inducing liver steatosis, inducing HIF-1α, and increasing miR-185 (p < 0. 05, η² = 0.32). In alcohol-fed wild-type mice, the mRNA and protein levels of SR-BI decreased significantly (p < 0.05, η² = 0.29), while LDLR levels were enhanced (p < .05, η² = 0.25). HIF-1α silencing downregulated LDLR mRNA and protein expression in alcohol-fed mice (p < 0. 05, η² = 0.23).Conclusions:Alcohol-induced activation of the HIF-1α/miR-185 pathway disrupts hepatic lipid metabolism by modulating SR-BI and LDLR transcription, presenting a potential therapeutic target for lipid disorders in ARLD.