miR-205-5p Promotes Hepatic Fat Accumulation as a Downstream Effector of PPARγ Signaling.

Hepatic peroxisome proliferator-activated receptor gamma (PPARγ) promotes fat accumulation in the liver of leptin-deficient (ob/ob) mice. However, the mechanism underlying PPARγ-dependent fat accumulation remains unclear. In this study, we identified miR-205-5p as a liver-enriched microRNA regulated by PPARγ. miR-205-5p was significantly upregulated in the ob/ob mouse livers and induced by treatment with the PPARγ-specific agonist rosiglitazone. In contrast, its expression was markedly reduced in liver-specific PPARγ knockout mice. In both nonalcoholic fatty liver and nonalcoholic steatohepatitis models, hepatic miR-205-5p levels were elevated, whereas serum levels were decreased. In HepG2 cells treated with a mixture of oleic and palmitic acids to induce fat accumulation, overexpression of miR-205-5p increased the expression of lipogenic gene (ACC) and decreased the expression of the rate-limiting enzyme for fatty acid β-oxidation (ACOX1) and transcription factors involved in fatty acid oxidation and oxidative stress (HNF4A and NRF2). Furthermore, forced expression of miR-205-5p significantly increased fat levels in HepG2 cells. These findings suggest that the PPARγ-miR-205-5p axis plays a key role in the promotion of hepatic fat accumulation. Collectively, our data indicate that miR-205-5p has potential as a downstream effector of hepatic PPARγ signaling and may serve as a biomarker and therapeutic target for nonalcoholic fatty liver disease.