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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  Ppargc1β  (peroxisome proliferator‐activated receptor γ coactivator 1‐beta), there was a significant uncoupling of  Ppargc1β  mRNA and microRNA‐378 levels in both sources of fatty livers. Further studies identified a full‐length primary transcript of microRNA‐378. LXRα (liver X receptor alpha) functioned as a transcription activator of microRNA‐378 and a repressor of  Ppargc1β  transcription. It is known that miR‐378 is an inhibitor of fatty acid oxidation (FAO) and the function of  Ppargc1β  is opposite to that of miR‐378. GW3965 treatment (LXRα agonist) of murine hepatocytes and mice increased microRNA‐378 and reduced  Ppargc1β , which subsequently impaired FAO and aggravated hepatosteatosis. In contrast, additional treatment of miR‐378 inhibitor or  Ppargc1β , which knocked down increased miR‐378 or recovered expression of  Ppargc1β , offset the effects of GW3965. Liver‐specific ablation of  Lxrα  led to decreased miR‐378 and increased  Ppargc1β , 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  Ppargc1β . LXRα selectively activates transcription of miR‐378 and inhibits expression of  Ppargc1β,  which synergistically impairs FAO. In addition to lipogenesis, impaired FAO by miR‐378 in part contributes to LXRα‐induced hepatosteatosis.

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