title: 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-1·d-1, 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.
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.|Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China.
authors: Qiang
authors: Q
authors: Meng
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.
authors: Xing-Ping
authors: XP
authors: Duan
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.|Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China.
authors: Chang-Yuan
authors: CY
authors: Wang
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.|Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China.
authors: Zhi-Hao
authors: ZH
authors: Liu
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.|Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China.
authors: Peng-Yuan
authors: PY
authors: Sun
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.
authors: Xiao-Kui
authors: XK
authors: Huo
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.|Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China.
authors: Hui-Jun
authors: HJ
authors: Sun
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.
authors: Jin-Yong
authors: JY
authors: Peng
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.|Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China.
authors: Ke-Xin
authors: KX
authors: Liu
mesh_terms: D000818:Animals; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002783:Cholestenones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002796:Choline Deficiency; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000517:prevention & control*; D011282:Pregnenediones / Q000494:pharmacology; D061251:Primary Cell Culture; D020011:Protective Agents / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000037:antagonists & inhibitors; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D002783:Cholestenones; D008715:Methionine; D011282:Pregnenediones; D020011:Protective Agents; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C526957:alisol B 23-acetate; C023617:pregna-4,17-diene-3,16-dione