Hepatic miR-20b promotes nonalcoholic fatty liver disease by suppressing PPARα

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic metabolic reprogramming that leads to excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic metabolic reprogramming, the underlying mechanisms of NR regulation in NAFLD remain largely unclear. Methods Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in NAFLD patients, we revealed that miR-20b specifically targets PPARα. miR-20b mimic and anti-miR-20b were administered to hepatocytes as well as high fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of miR-20b in NAFLD. We tested the inhibition of the therapeutic effect of a PPARα agonist, fenofibrate, by miR-20b. Results We revealed that miR-20b specifically targets PPARα through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of miR-20b was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of miR-20b significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, miR-20b significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARα. In miR-20b-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of miR-20b significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Conclusions Taken together, our results demonstrate that the novel miR-20b targets PPARα, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD. Funding This research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340), the Future-leading Project Research Fund (1.210034.01) of UNIST and the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1I1A1A01074940).