miR-27a Suppresses Mitochondrial Function to Promote Hepatic Steatosis in High-Fat-Diet-Induced Obesity

Non-coding RNAs are pivotal regulators of metabolic disease pathogenesis, yet the role of microRNA-27a (miR-27a) in obesity-associated hepatic steatosis remains incompletely characterized. This study examined the functional contribution and molecular mechanism of miR-27a in regulating hepatocyte mitochondrial homeostasis and lipid metabolism. Utilizing in vivo mouse models, including low-fat diet controls, high-fat diet (HFD)-induced obesity, and gain- and loss-of-function approaches, miR-27a was found to be markedly upregulated in the serum and liver of obese mice, correlating with disrupted glucose and lipid homeostasis as well as hepatic steatosis. Mechanistically, miR-27a overexpression recapitulated HFD-induced mitochondrial dysfunction, manifested by decreased mitochondrial biogenesis and elevated reactive oxygen species (ROS) production. Conversely, genetic silencing of miR-27a restored mitochondrial integrity and mitigated lipid accumulation. In vitro experiments using HepG2 cells confirmed that miR-27a directly suppresses nuclear factor erythroid 2-related factor 2 (NFE2L2), and NFE2L2 overexpression counteracted miR-27a-induced mitochondrial damage and steatosis. Collectively, these results demonstrate that miR-27a promotes hepatic steatosis by targeting NFE2L2, leading to mitochondrial impairment and oxidative stress, highlighting miR-27a as a potential biomarker and therapeutic target for obesity-associated liver metabolic disorders.