LXRα activation inhibits autophagy and lipophagy in hepatocytes by dysregulating ATG4B and Rab-8B, reducing mitochondrial fuel oxidation.

BACKGROUND & AIMS Fat accumulation results from increased fat absorption and/or defective fat metabolism. Currently, the lipid-sensing nuclear receptor that controls fat utilization in hepatocytes is elusive. Liver X receptor-α (LXRα) promotes the accumulation of lipids through the induction of several lipogenic genes. However, its effect on lipid degradation is unknown. Here, we investigated the inhibitory role of LXRα in autophagy/lipophagy in hepatocytes and the underlying basis. Approach and Results In LXRα knockout mice fed a high-fat diet, or cell models, LXRα activation suppressed the function of mitochondria by inhibiting autophagy/lipophagy and induced hepatic steatosis. Gene sets associated with 'autophagy' were enriched in hepatic transcriptome data. Autophagy flux was markedly augmented in the LXRα knockout mouse liver and primary hepatocytes. Mechanistically, LXRα suppressed ATG4B and Rab-8B, responsible for autophagosome and autolysosome formation, by inducing let-7a and miR-34a. Chromatin immunoprecipitation assay enabled us to find LXRα as a transcription factor of let-7a and miR-34a. Moreover, 3'UTR luciferase assay substantiated the direct inhibitory effects of let-7a and miR-34a on ATG4B and Rab-8B. Consistently, either LXRα activation or the let-7a/miR-34a transfection lowered mitochondrial oxygen consumption rate and mitochondrial transmembrane potential and increased fat levels. In obese animals or non-alcoholic fatty liver disease patients, let-7a and miR-34a levels were elevated with simultaneous decreases in ATG4B and Rab-8B levels. CONCLUSIONS LXRα inhibits autophagy in hepatocytes through downregulating ATG4B and Rab-8B by transcriptionally activating MIRLET7A2 and MIR34A genes and suppresses mitochondrial biogenesis and fuel consumption. This highlights a new function of LXRα, which culminates in the progression of liver steatosis and steatohepatitis, and the identified targets may be applied for a therapeutic strategy in the treatment of non-alcoholic fatty liver disease.