title: Calycosin attenuates triglyceride accumulation and hepatic fibrosis in murine model of non-alcoholic steatohepatitis via activating farnesoid X receptor.
abstract: BACKGROUND
  Non-alcoholic steatohepatitis (NASH) represents the more severe end of hepatic steatosis and is associated with progressive liver disease. Calycosin, derived from the root of Radix Astragali, has been demonstrated to have favorable efficacy on acute liver injury.
  
  
  OBJECTIVE
  The present study was to investigate the hepatoprotective effect of calycosin on attenuating triglyceride accumulation and hepatic fibrosis, as well as explore the potential mechanism in murine model of NASH.
  
  
  METHODS
  The C57BL/6 male mice were fed with methionine choline deficient (MCD) diet for 4 weeks to induce NASH and treated with or without calycosin by oral gavage for 4 weeks.
  
  
  METHODS
  The body weight, liver weight and the liver to body weight ratios were measured. Serum ALT, AST, TG, TC, FFA, MCP-1 and mKC levels were accessed by biochemical methods. H&E staining and Oil red O staining were used to identify the amelioration of liver histopathology. Immunohistochemistry of a-SMA, Masson trichrome staining and Sirius red staining were used to identify the amelioration of hepatic fibrosis. The quantitative real-time-PCR and Western blot were applied to observe the expression changes of key factors involved in triglyceride synthesis, free fatty acid β-oxidation and hepatic fibrosis.
  
  
  RESULTS
  Calycosin significantly inhibited body weight loss induced by MCD diet, decreased the ALT and AST activities, MCP-1 and mKC in a dose-dependent manner. The H&E and Oil red O staining indicated calycosin effectively improved hepatic steatosis, improved the degree of triglyceride accumulation. Masson trichrome and Sirius red staining indicated that calycosin treatment remarkably attenuated the degree of hepatic fibrosis. Immunohistochemistry of a-SMA demonstrated that calycosin attenuated hepatic fibrosis by inhibiting hepatic stellate cell activation. Further, calycosin inhibited the expression of SREBP-1c, FASN, ACC and SCD1 involved in triglyceride synthesis, promoted the expression of PPARa, CPT1, Syndecan-1 and LPL involved in free fatty acid β-oxidation. The above effects of calycosin were attributed to FXR activation.
  
  
  CONCLUSIONS
  Calycosin attenuates triglyceride accumulation and hepatic fibrosis to protect against NASH via FXR activation.
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian, Liaoning, China.
authors.forename: Xingping
authors.initials: X
authors.lastname: Duan
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian, Liaoning, China. Electronic address: mengq531@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian, Liaoning, China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian, Liaoning, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian, Liaoning, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian, Liaoning, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian, Liaoning, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian, Liaoning, China.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, Liaoning, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Dalian, Liaoning, China. Electronic address: kexinliu@dlmedu.edu.cn.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000818:Animals; D027883:Astragalus Plant / Q000737:chemistry*; D018932:Chemokine CCL2 / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000737:chemistry*; D007529:Isoflavones / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008517:Phytotherapy; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018932:Chemokine CCL2; D004365:Drugs, Chinese Herbal; D007529:Isoflavones; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C491768:Ccl2 protein, mouse; C121707:7,3'-dihydroxy-4'-methoxyisoflavone
keywords: Calycosin; Farnesoid X receptor; Hepatic fibrosis; Non-alcoholic steatohepatitis; Triglyceride accumulation