[Cajanolactone A ameliorates hepatocyte steatosis by regulating mitochondrial quality control via PGC-1α].

To explore the effects and mechanisms of cajanolactone A(CLA) on hepatocyte steatosis, with a focus on mitochondrial quality control(MQC) regulated by peroxisome proliferator-activated receptor-γ-coactivator-1α(PGC-1α). Human liver HHL-5 cells were induced with fatty acids(oleic acid-palmitic acid=2∶1) to develop steatosis, followed by exposure to different concentrations(2, 4, and 8 μmol·L~(-1)) of CLA. Lovastatin(LOV), the PGC-1α agonist ZLN005, and the PGC-1α inhibitor SR18292 served as control groups. Lipid accumulation was assessed by BODIPY staining, and flow cytometry. The levels of triglycerides(TG), total cholesterol(TC), and non-esterified fatty acids(NEFA) were measured by corresponding kits. The mitochondrial DNA(mtDNA) levels were determined by qPCR. The number and morphology of mitochondria(Mt) were observed by transmission electron microscopy. The mitochondrial quality was detected by Mt-specific fluorescent probe labeling. The functions of Mt were evaluated by JC-1 mitochondrial membrane potential and the ATP assay. The expression levels of PGC-1α and its associated transcription factors, including peroxisome proliferator-activated receptor α(PPARA), nuclear respiratory factor 1(NRF1), nuclear respiratory factor 2(NRF2), mitochondrial transcription factor A(TFAM), mitofusion 2(MFN2), optic atrophy 1(OPA1), autophagy receptor protein p62, beclin 1, and microtubule-associated protein 1 light chain 3β(LC3B), were quantified by RT-qPCR and Western blot. The results showed that CLA significantly reduced lipid accumulation, promoted lipolysis, increased Mt quantity, and improved the mitochondrial morphology, structure, and function in hepatocytes with steatosis. Furthermore, CLA up-regulated the expression of PGC-1α, PPARA, NRF1, NRF2, TFAM, MFN2, OPA1, p62, beclin 1, and LC3B. In conclusion, CLA may ameliorate hepatic steatosis by regulating the PGC-1α pathway and maintaining mitochondrial homeostasis.