Alisol B 23-acetate protects against non-alcoholic steatohepatitis in mice via farnesoid X receptor activation

Abstract

Alisol B 23-acetate (AB23A) is a natural triterpenoid isolated from the traditional Chinese medicine rhizoma alismatis, which exhibits a number of pharmacological activities, including anti-hepatitis virus, anti-cancer and antibacterial effects. In this study we examined whether AB23A protected against non-alcoholic steatohepatitis (NASH) in mice, and the mechanisms underlying the protective effects. NASH was induced in mice fed a methionine and choline-deficient (MCD) diet for 4 weeks. The mice were simultaneously treated with AB23A (15, 30, and 60 mg·kg·d, ig) for 4 weeks. On the last day, blood samples and livers were collected. Serum liver functional enzymes, inflammatoru markers were assessed. The livers were histologically examined using H&E, Oil Red O, Masson's trichrome and Sirius Red staining. Mouse primary hepatocytes were used for in vitro experiments. The mechanisms underlying AB23A protection were analyzed using siRNA, qRT-PCR, and Western blot assays. AB23A treatment significantly and dose-dependently decreased the elevated levels of serum ALT and AST in MCD diet-fed mice. Furthermore, AB23A treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration and hepatic fibrosis in the mice. AB23A-induced decreases in serum and hepatic lipids were related to decreased hepatic lipogenesis through decreasing hepatic levels of SREBP-1c, FAS, ACC1 and SCD1 and increased lipid metabolism via inducing PPARα, CPT1α, ACADS and LPL. The reduction in inflammatory cell infiltration corresponded to deceased serum levels of mKC and MCP-1 and decreased hepatic gene expression of MCP-1 and VCAM-1. The reduction in hepatic fibrosis was correlated with decreased hepatic gene expression of fibrosis markers. The protective effects of AB23A were FXR-dependent, because treatment with the FXR agonist CDCA mimicked AB23A-induced hepato-protection in the mice, whereas co-administration of FXR antagonist guggulsterone abrogated AB23A-induced hepato-protection. In mouse primary hepatocytes, FXR gene silencing abrogated AB23A-induced changes in gene expression of Apo C-II, CPT1α, ACADS and LPL. AB23A produces protective effects against NASH in mice via FXR activation.

Protection by the Total Flavonoids from Rosa laevigata Michx Fruit against Lipopolysaccharide-Induced Liver Injury in Mice via Modulation of FXR Signaling

“…Farnesoid X receptor (FXR), a ligand-activated transcription factor which belongs to the nuclear hormone receptor superfamily, is highly expressed in hepatic tissue [ 10 ]. The activation of hepatic FXR can regulate the expression levels of various genes, including nuclear erythroid factor 2-related factor 2 (Nrf2), forkhead box O3 (FOXO3a), and sterol regulatory element-binding proteins-1c (SREBP-1c) [ 11 , 12 , 13 ]. Briefly, Nrf2 is present in the cytoplasm and binds to Kelch-like epichlorohydrin (ECH)-associated protein 1 (Keap1) in normal conditions.…”

Dahuang Zexie Decoction Protects against High‐Fat Diet‐Induced NAFLD by Modulating Gut Microbiota‐Mediated Toll‐Like Receptor 4 Signaling Activation and Loss of Intestinal Barrier

“…Huang et al demonstrated that gallic acid could improve high-fat diet- (HFD-) induced dyslipidaemia and hepatosteatosis [ 56 ]. Meng et al reported that alisol B protected against nonalcoholic steatohepatitis in mice by activating farnesoid X receptor [ 57 ]. Rhein and emodin also can improve NAFLD induced by HFD [ 58 , 59 ], and emodin can restore the increased intestinal permeability by inhibiting inflammation response [ 60 ].…”

Pharmacological Activities of Alisma orientale against Nonalcoholic Fatty Liver Disease and Metabolic Syndrome: Literature Review

“…Its role as FXR agonist is expanded to its protective activities against NASH in mice. Indeed, it played a critical action in TG and fatty acid synthesis and metabolism, thus preventing inflammation and fibrogenesis in MCD-diet mice via FXR stimulation [46]. Its antioxidant [47, 77] and hepatoprotective [46] effects are also likely associated with downstream target genes of FXR.…”

“…Indeed, it played a critical action in TG and fatty acid synthesis and metabolism, thus preventing inflammation and fibrogenesis in MCD-diet mice via FXR stimulation [46]. Its antioxidant [47, 77] and hepatoprotective [46] effects are also likely associated with downstream target genes of FXR. Hence, Alisol B 23-acetate is anticipated to show pharmacological effects similar to FXR agonists such as obeticholic acid and ursodeoxycholic acid in NAFLD treatment.…”