Berberine alleviates hepatic inflammation of nonalcoholic steatohepatitis mice by inhibiting oxidative stress and endoplasmic reticulum stress

Abstract

Objective To evaluate the alleviating effect of berberine（BBR）on hepatic inflammation in nonalcoholic steatohepatitis（NASH）mice from the perspectives of oxidative stress and endoplasmic reticulum stress. Methods A total of 24 C57BL/6J mice were randomly divided into 4 groups. Mice in the NASH and NASH+BBR groups were fed with high-fat，high-fructose，and high-cholesterol diets for 28 weeks to induce the NASH disease models，whereas mice in the CD and CD+BBR groups were given with normal diets，and mice in the CD+BBR and NASH+BBR groups were given with 200 mg/（kg·d）of BBR by gavage once a day starting from the 25th week for 4 consecutive weeks. The body weight of mice was recorded weekly. Glucose tolerance test and insulin resistance test were performed at the 3rd week of administration. Serum alanine aminotransferase，aspartate aminotransferase，triglyceride，total cholesterol，LDL cholesterol，and HDL cholesterol levels，and hepatic triglyceride and total cholesterol levels were measured at the end of treatment. Liver samples were treated with HE，Oil-Red O and Masson staining. The expression levels of liver inflammatory factors of TNF-α and IL-1β mRNA were detected by qPCR. The levels of malondialdehyde，total superoxide dismutase activity and total antioxidant capacity，indicators of oxidative stress in liver tissues were assessed by colorimetric assay. The expression levels of proteins in the endoplasmic reticulum stress-related pathways in liver tissues were detected by Western blot. Results NASH mouse models were successfully established. Compared with the mice in the NASH group，weight gain was inhibited，glucose tolerance abnormality was mitigated，insulin sensitivity was increased and liver function and hyperlipidemia were improved after treatment with BBR in the NASH+BBR group（all P < 0.05）. Hepatic pathological slices showed a reduction in steatosis ，and a decrease in inflammatory cell infiltration，but there was no significant alleviation in fibrosis. The mRNA expression levels of liver inflammatory factors were down-regulated（all P < 0.05）. The levels of hepatic tissue oxidative stress factor of malondialdehyde were decreased，whereas those of antioxidant factors of total superoxide dismutase activity and total antioxidant capacity were increased（all P < 0.05）. The expression levels of endoplasmic reticulum stress marker of GRP78 protein and PERK/eIF2α/ATF4/CHOP endoplasmic reticulum stress signaling pathway were significantly down-regulated（all P < 0.05）. Conclusions BBR can alleviate overweight，glycolipid metabolism disorder and liver function abnormality in NASH mice. Besides，it can also mitigate hepatic steatosis and inflammation，but it has no significant effect on the alleviation of fibrosis. BBR mitigates inflammatory response in NASH mice probably by suppressing oxidative stress and endoplasmic reticulum stress in the liver.

Keywords

• berberine|nonalcoholic steatohepatitis|inflammation|oxidative stress|endoplasmic reticulum stress