Matrine Protects Against MCD-Induced Development of NASH via Upregulating HSP72 and Downregulating mTOR in a Manner Distinctive From Metformin

Abstract

The present study investigated the effects of matrine on non-alcoholic steatohepatitis (NASH) in mice induced by a methionine choline-deficient (MCD) diet and the mechanism involved. The study was performed in C57B/6J mice fed a MCD diet for 6 weeks to induce NASH with or without the treatment of matrine (100 mg/kg/day in diet). Metformin was used (250 mg/kg/day in diet) as a comparator for mechanistic investigation. Administration of matrine significantly reduced MCD-induced elevations in plasma ALT and AST but without changing body or liver fat content. Along with alleviating liver injury, matrine suppressed MCD-induced hepatic inflammation (indicated by TNFα, CD68, MCP-1, and NLRP3) and fibrosis (indicated by collagen 1, TGFβ, Smad3, and sirius-red staining). In comparison, metformin treatment did not show any clear sign of effects on these parameters indicative of NASH. Further examination of the liver showed that matrine treatment rescued the suppressed HSP72 (a chaperon protein against cytotoxicity) and blocked the induction of mTOR (a key protein in a stress pathway). In keeping with the lack of the improvement of the NASH features, metformin did not show any significant effect against MCD-induced changes in HSP72 and mTOR. Matrine protects against MCD-induced development of NASH which is refractory to metformin treatment. Its anti-NASH effects involve enhancing HSP72 and downregulating mTOR but do not rely on amelioration of hepatosteatosis.

Val‐Val‐Tyr‐Pro protects against non‐alcoholic steatohepatitis in mice by modulating the gut microbiota and gut‐liver axis activation

“…Previous studies demonstrated that another crucial participator in the progression of NASH is the network of pro‐inflammatory chemokines and cytokines 82,83 . Several inflammatory factors, such as TNF‐α, IL‐1β and IL‐6, have been proved to enable steatosis and liver damage, thus promoting the occurrence and progression of NASH 84,85 . In addition, TNF‐α was supposed to be a pivotal mediator of NASH development, 86 and inhibition of TNF‐α activity by anti‐inflammatory drugs ameliorated inflammation, liver damage and NASH 87 .…”

“…82,83 Several inflammatory factors, such as TNF-α, IL-1β and IL-6, have been proved to enable steatosis and liver damage, thus promoting the occurrence and progression of NASH. 84,85 In addition, TNF-α was supposed to be a pivotal mediator of NASH development, 86 and inhibition of TNF-α activity by anti-inflammatory drugs ameliorated inflammation, liver damage and NASH. 87 Consistent with previous researches, mice fed a MCD diet effectively developed marked hepatic inflammation that simulated the natural development of NASH in human.…”

Natural Products that Target the NLRP3 Inflammasome to Treat Fibrosis

“…Various in vivo studies have demonstrated the role of alkaloids in treating fibrosis. In NASH mice fed an MCD diet, matrine decreases the expression of TGF-β, collagen Ⅰ, and Smad3 by inhibiting the NLRP3 inflammasome, at least partially (Mahzari et al, 2019). In CCl 4 -induced liver injury in rats, tetramethylpyrazine possesses an antifibrotic role in alleviating liver injury and fibrogenesis through the involvement of PDGF-βR/NLRP3 signaling pathway.…”

Metformin and Fibrosis: A Review of Existing Evidence and Mechanisms

“…Decreased NOX4 activity and mitochondrial oxidative stress and inhibited protein kinase C α (PKC α ) activity, which accounted for the effect of metformin on Gal-3 expression, may be a consequence of increased levels of TSC2 phosphorylation and subsequent inactivation of the mTOR-S6K signaling pathway [ 29 ]. However, metformin treatment did not show any effects on methionine-choline-deficient- (MCD-) induced increases in mTOR activity or the NASH phenotype, such as inflammation and collagen deposition, in NASH mice [ 90 ].…”