Inhibition of Dexamethasone-induced Fatty Liver Development by Reducing miR-17-5p Levels

Steatosis is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD) which can be driven by peroxisonne proliferator-activated receptor-alpha (PPAR-alpha) dysregulation. Through examining the effect of PPAR-alpha on fatty liver development, we found that PPAR-alpha is a target of miR-17-5p. Transgenic mice expressing miR-17 developed fatty liver and produced higher levels of triglyceride and cholesterol but lower levels of PPAR-alpha. Ectopic expression of nniR-17 enhanced cellular steatosis. Gain-of-function and loss-of-function experiments confirmed PPAR-alpha as a target of miR-17-5p. On the other hand, PPAR-alpha bound to the promoter of miR-17 and promoted its expression. The feed-back loop between miR-17-.5p and PPAR-alpha played a key role in the induction of steatosis and fatty liver development. Mice with high levels of miR-17-5p were sensitive to Dexamethasone-induced fatty liver formation. Inhibition of miR-17-5p suppressed this process and enhanced PPAR-alpha expression in mice treated with Dexamethasone. Clofibrate, Ciprofibrate, and WY-14643: three agents used for treatment of metabolic disorders, were found to promote PPAR-alpha expression while decreasing miR-17-5p levels and inhibiting steatosis. Our studies show that miR-17-5p inhibitor and agents used in metabolic disorders may be applied in combination with Dexamethasone in the treatment of anti-inflammation, immunosuppression, and cancer patients.