miR-148a promotes the expression of multiple alcohol dehydrogenase genes by activating an ADH4 enhancer element

Alcohol dehydrogenases (ADHs) play a central role in alcohol metabolism, with approximately 90 % of absorbed alcohol metabolized by these enzymes in the liver. The ADH family comprises 7 genes, ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6, and ADH7, which are arranged in a cluster on chromosome 4. Although the expression of this cluster is crucial for alcohol-induced liver injury, regulatory mechanisms governing remain largely unexplored. In the present study, we identified a strong positive correlation between miR-148a levels and the expression of 4 ADH genes (ADH1A, ADH1B, ADH4, and ADH6) in human liver tissues, including those from patients with alcoholic hepatitis. Functional assays showed that miR-148a promoted the expression of these ADH genes under both normal and ethanol-exposed conditions. Mechanistically, miR-148a activated an enhancer element within the ADH4 gene by targeting a specific motif, as evidenced by luciferase reporter assays. Additionally, miR-148a aggravated acute ethanol-induced cytotoxicity in hepatocytes. Together, our study reveals a novel regulatory mechanism in which miR-148a coordinates the expression of multiple ADH genes through enhancer activation, providing new insight into the transcriptional regulation of alcohol metabolism.