LXRα Promotes Hepatosteatosis in Part Through Activation of MicroRNA-378 Transcription and Inhibition of Ppargc1β Expression

Nonalcoholic fatty liver disease (NAFLD) is a major risk factor of many end-stage liver diseases. Alterations in microRNA expression have been reported in patients with NAFLD. However, the transcriptional mechanism(s) of dysregulated microRNAs under the state of NAFLD is poorly described, and microRNAs that regulate the pathogenesis of NAFLD synergistically with their regulators remain unknown. Here we report that microRNA-378 expression is significantly increased in fatty livers of mice and patients with NAFLD. Although microRNA-378 locates within the intron of Ppargc1 beta (peroxisome proliferator-activated receptor gamma coactivator 1-beta), there was a significant uncoupling of Ppargc1 beta mRNA and microRNA-378 levels in both sources of fatty livers. Further studies identified a full-length primary transcript of microRNA-378. LXR alpha (liver X receptor alpha) functioned as a transcription activator of microRNA-378 and a repressor of Ppargc1 beta transcription. It is known that miR-378 is an inhibitor of fatty acid oxidation (FAO) and the function of Ppargc1 beta is opposite to that of miR-378. GW3965 treatment (LXR alpha agonist) of murine hepatocytes and mice increased microRNA-378 and reduced Ppargc1 beta, which subsequently impaired FAO and aggravated hepatosteatosis. In contrast, additional treatment of miR-378 inhibitor or Ppargc1 beta, which knocked down increased miR-378 or recovered expression of Ppargc1 beta, offset the effects of GW3965. Liver-specific ablation of Lxr alpha led to decreased miR-378 and increased Ppargc1 beta, which subsequently improved FAO and reduced hepatosteatosis. Conclusion: Our findings indicated that miR-378 possesses its own transcription machinery, which challenges the well-established dogma that miR-378 transcription is controlled by the promoter of Ppargc1 beta. LXR alpha selectively activates transcription of miR-378 and inhibits expression of Ppargc1 beta, which synergistically impairs FAO. In addition to lipogenesis, impaired FAO by miR-378 in part contributes to LXR alpha-induced hepatosteatosis.