Nobiletin mitigates hepatocytes death, liver inflammation, and fibrosis in a murine model of NASH through modulating hepatic oxidative stress and mitochondrial dysfunction †

This study aimed to investigate the therapeutic effects of nobiletin (NOB) on nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice and to elucidate its underlying molecular mechanisms. BALB/c mice were fed a normal chow diet or a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 8 wks and treated with NOB (50 mg/kg) or vehicle by daily intraperitoneally injection for the last 4 wks. In vitro, we used palmitate (PA) stimulated AML12 cells as the model of hepatocyte lipotoxicity to dissect the effect and molecular mechanisms of NOB ' action. Our results exhibited that NOB dramatically reduced hepatic steatosis, lipid accumulation and hepatocyte apoptosis, and inhibited the infiltration of F4/80 + macrophages into the NASH livers. Furthermore, NOB limited liver fibrosis and hepatic stellate cells activation in NASH mice. In parallel, NOB alleviated hepatocytes apoptosis and lipid accumulation in PA-treated AML12 cells. Most importantly, these histological ameliorations in NASH and fibrosis in NOB-treated NASH mice were associated with improvement hepatic oxidative stress, lipid peroxidation product, mitochondrial respiratory chain complexes I and restored ATP production. Similarly, NOB attenuated PA-induced reactive oxygen species (ROS) generation and mitochondrial disfunction in cultured AML12 cells. Additionally, NOB diminished the expression of mitochondrial Ca2+ uniporter (MCU) both in NASH livers and in PA-treated AML12. Taken together, our results indicate that NOB mitigated NASH development and fibrosis through modulating hepatic oxidative stress and attenuating mitochondrial dysfunction. Therefore, NOB might be a novel and promising agent for treatment of NASH and liver fibrosis. (C) 2021 Elsevier Inc. All rights reserved.