Nomilin and its analogue obacunone alleviate NASH and hepatic fibrosis in mice via enhancing antioxidant and anti‐inflammation capacity

Abstract

Nonalcoholic steatohepatitis (NASH) and hepatic fibrosis are leading causes of cirrhosis with rising morbidity and mortality worldwide. Currently, there is no appropriate treatment for NASH and hepatic fibrosis. Many studies have shown that oxidative stress is a main factor inducing NASH. Nomilin (NML) and obacunone (OBA) are limonoid compounds naturally occurring in citrus fruits with various biological properties. However, whether OBA and NML have beneficial effects on NASH remains unclear. Here, we demonstrated that OBA and NML inhibited hepatic tissue necrosis, inflammatory infiltration and liver fibrosis progression in methionine and choline‐deficient (MCD) diet, carbon tetrachloride (CCl4)‐treated and bile duct ligation (BDL) NASH and hepatic fibrosis mouse models. Mechanistic studies showed that NML and OBA enhanced anti‐oxidative effects, including reduction of malondialdehyde (MDA) level, increase of catalase (CAT) activity and the gene expression of glutathione S‐transferases (GSTs) and Nrf2‐keap1 signaling. Additional, NML and OBA inhibited the expression of inflammatory gene interleukin 6 (Il‐6), and regulated the bile acid metabolism genes Cyp3a11, Cyp7a1, multidrug resistance‐associated protein 3 (Mrp3). Overall, these findings indicate that NML and OBA may alleviate NASH and liver fibrosis in mice via enhancing antioxidant and anti‐inflammation capacity. Our study proposed that NML and OBA may be potential strategies for NASH treatment.

Obacunone, a Promising Phytochemical Triterpenoid: Research Progress on Its Pharmacological Activity and Mechanism

“…In a CCl 4 -induced liver fibrosis model, obacunone (1.5, 3, and 6 mg/kg) decreased alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels and reversed the pathological changes in the liver tissue, with reduced expression levels of epithelialmesenchymal transition-related proteins (e.g., α-smooth muscle actin and connective tissue growth factor) and lipid oxidation factors and enhanced expression of glutathione peroxi-dase 4 Gene (GPx-4). The administration of obacunone also inhibited pulmonary fibrosis in bleomycin-induced mice [41] and bile-duct ligation-induced cholestatic fibrogenesis mice [42]. Mechanistic studies revealed that the antifibrotic effect was not only related to anti-inflammatory and antioxidant properties of obacunone but also its regulation of the expression and production of GPx-4, the inhibition of TGF-β/SMAD signaling pathway [43,44], and the maintenance of the homeostasis of bile acids.…”