Multiple MicroRNAs Ameliorate Hepatocyte Steatosis and Injury by Suppressing FABP1 Expression.

ABSTRACT

BACKGROUND/AIMS: Liver fatty acid-binding protein (FABP1) is a key regulator of hepatic lipid metabolism. MicroRNAs (miRNAs) are thought to be involved in nonalcoholic fatty liver disease (NAFLD), and the underlying mechanism is largely unclear. We investigated whether miRNAs influence hepatocyte steatosis by regulating the FABP1 gene. METHODS: Candidate FABP1-targeting miRNAs were evaluated using luciferase reporter assay. FABP1 expression was measured using western blotting and quantitative reverse transcription-PCR. Intracellular lipid accumulation was measured based on Oil Red O staining and intracellular triglyceride content. Hepatocyte injury was evaluated based on culture supernatant levels of alanine aminotransferase, aspartate aminotransferase, and intracellular adenosine triphosphate, and mitochondrial membrane potential. RESULTS: Dicer1 knockdown significantly elevated FABP1 expression. In total, 68 miRNAs potentially targeting FABP1 were selected; of these, miR-3941, miR-4517, and miR-4672 directly targeted the FABP1 3' untranslated region. Mimics of the three miRNAs substantially repressed FABP1 expression at translational level and led to HepG2 cell resistance to steatosis and cell injury induced by free fatty acids mixture, which rescue of FABP1 overexpression reversed. CONCLUSION: Our findings identify a novel mechanism by which miRNAs protect against hepatocyte steatosis and injury by downregulating FABP1 expression.