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.

Automated summary

The study demonstrated that nobiletin (NOB) effectively alleviated nonalcoholic steatohepatitis (NASH) and liver fibrosis by reducing hepatic oxidative stress and attenuating mitochondrial dysfunction. This suggests that NOB may be a promising agent for the treatment of NASH and liver fibrosis.