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Planta Med 2007; 73(8): 718-724
DOI: 10.1055/s-2007-981552
Pharmacology
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Osthole Improves Fat Milk-Induced Fatty Liver in Rats: Modulation of Hepatic PPAR-alpha/gamma-Mediated Lipogenic Gene Expression

Yan Zhang1 , Meilin Xie1 , Jie Xue1 , Zhenlun Gu1
  • 1Department of Pharmacology, Medical School of Soochow University, Suzhou, P.R. China
Further Information

Publication History

Received: November 7, 2006 Revised: May 15, 2007

Accepted: May 23, 2007

Publication Date:
05 July 2007 (online)

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Abstract

The objectives of this study were to determine the therapeutic effect of osthole, an active constituent isolated from Cnidium monnieri (L.) Cusson (Apiaceae), in hyperlipidemic fatty liver (HFL) rats and investigate the possible mechanism of the osthole treatment. The HFL rat model was established by feeding Sprague-Dawley rats with fat milk for 6 weeks. The experimental rats were then treated with a dose of osthole of 5 - 20 mg/kg for 6 weeks. After the treatment, total cholesterol (TC) and triglycerides (TG) in serum and hepatic tissue, as well as the coefficient of hepatic weight were measured. The results showed that the TC and TG in both serum and hepatic tissue and the coefficient of hepatic weight in the osthole-treated rats were lower as compared to those in the experimental group, respectively (P < 0.05 or P < 0.01). Moreover, as compared to the control group, the osthole treatment increased the PPARα/γ mRNA expression by 58.0 - 84.0 % and 20.4 - 77.4 %, respectively. The related target genes for mRNA expression were also increased by osthole-treatment, e. g., 53.4 - 93.2 % for CYP7A, 21.1 - 63.2 % for L-FABP and 34.1 - 57.3 % for FATP4, while the DGAT mRNA expression was decreased by 26.0 - 44.4 %. The therapeutic effect of osthole was further confirmed by histological evaluation of the liver showing a dramatically decreased lipid accumulation and improved ultrastructure of hepatocytes. In conclusion, osthole exerts therapeutic effects on fat milk-induced fatty liver in rats, by regulating mRNA expression of the target genes of CYP7A, DGAT, L-FABP and FATP4 via increasing the PPARα/γ mRNA expression.

Key words

Cnidium monnieri (L.) Cusson - Apiaceae - osthole - fatty liver - PPARα/γ - lipid metabolism

References

  • 1 Festi D, Colecchia A, Sacco T, Bondi M, Roda E, Marchesini G. Hepatic steatosis in obese patients: clinical aspects and prognostic significance.  Obes Rev. 2004;  5 27-42.
    CrossrefPubMedGoogle Scholar
  • 2 McCullough A J. Pathophysiology of nonalcoholic steatohepatitis.  J Clin Gastroenterol. 2006;  40 (Suppl 1) S17-29.
    PubMedGoogle Scholar
  • 3 Berger J, Moller D E. The mechanisms of action of PPARs.  Annu Rev Med. 2002;  53 409-35.
    CrossrefPubMedGoogle Scholar
  • 4 Moller D E. New drug targets for type 2 diabetes and the metabolic syndrome.  Nature. 2001;  414 821-7.
    CrossrefPubMedGoogle Scholar
  • 5 Jones P S, Savory R, Barratt P, Bell A R, Gray T J, Jenkins N A. et al . Chromosomal localisation, inducibility, tissue-specific expression and strain differences in three murine peroxisome-proliferator-activated-receptor genes.  Eur J Biochem. 1995;  233 219-26.
    CrossrefPubMedGoogle Scholar
  • 6 Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism.  Endocr Rev. 1999;  20 649-88.
    CrossrefPubMedGoogle Scholar
  • 7 Lian Q S. Progress in study of chemical constituents and pharmacological effects of the fruit of Cnidium monnieri.  Chin Med Mater. 2003;  26 141-4.
    PubMedGoogle Scholar
  • 8 Song F, Xie M L, Zhu L J, Zhang K P, Xue J, Gu Z L. Experimental study of osthole on treatment of hyperlipidemic and alcoholic fatty liver in animals.  World J Gastroenterol. 2006;  12 4359-63.
    PubMedGoogle Scholar
  • 9 Koteish A, Diehl A M. Animal models of steatosis.  Semin Liver Dis. 2001;  21 89-104.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Folch J, Lees M, Sloane Stanley G H. A simple method for the isolation and purification of total lipids from animal tissues.  J Biol Chem. 1957;  226 497-509.
    PubMedGoogle Scholar
  • 11 Adams L A, Angulo P. Recent concepts in non-alcoholic fatty liver disease.  Diabet Med. 2005;  22 1129-33.
    CrossrefPubMedGoogle Scholar
  • 12 Marchesini G, Marzocchi R, Agostini F, Bugianesi E. Nonalcoholic fatty liver disease and the metabolic syndrome.  Curr Opin Lipidol. 2005;  16 421-7.
    CrossrefPubMedGoogle Scholar
  • 13 Adams L A, Angulo P, Lindor K D. Nonalcoholic fatty liver disease.  Can Med Assoc J. 2005;  172 899-905.
    CrossrefPubMedGoogle Scholar
  • 14 Reddy J K, Hashimoto T. Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system.  Annu Rev Nutr. 2001;  21 93-230.
    PubMedGoogle Scholar
  • 15 Xu Y, Rito C J, Etgen G J, Ardecky R J, Bean J S, Bensch W R. et al . Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists.  J Med Chem. 2004;  47 2422-5.
    CrossrefPubMedGoogle Scholar
  • 16 Saad M F, Greco S, Osei K, Lewin A J, Edwards C, Nunez M. et al . Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm.  Diabetes Care. 2004;  27 1324-9.
    PubMedGoogle Scholar
  • 17 Farese RV J r, Cases S, Smith S J. Triglyceride synthesis: insights from the cloning of diacylglycerol acyltransferase.  Curr Opin Lipidol. 2000;  11 229-34.
    CrossrefPubMedGoogle Scholar
  • 18 Post S M, Duez H, Gervois P P, Staels B, Kuipers F, Princen H M. Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression.  Arterioscler Thromb Vasc Biol. 2001;  21 1840-5.
    PubMedGoogle Scholar
  • 19 Cheema S K, Agellon L B. The murine and human cholesterol 7alpha-hydroxylase gene promoters are differentially responsive to regulation by fatty acids mediated via peroxisome proliferator-activated receptor alpha.  J Biol Chem. 2000;  275 12 530-6.
    PubMedGoogle Scholar
  • 20 Waterman I J, Zammit V A. Differential effects of fenofibrate or simvastatin treatment of rats on hepatic microsomal overt and latent diacylglycerol acyltransferase activities.  Diabetes. 2002;  51 1708-13.
    CrossrefPubMedGoogle Scholar
  • 21 Landrier J F, Thomas C, Grober J, Duez H, Percevault F, Souidi M. et al . Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent.  J Biol Chm. 2004;  279 45 512-8.
    PubMedGoogle Scholar
  • 22 Nanji A A, Dannenberg A J, Jokelainen K, Bass N M. Alcoholic liver injury in the rat is associated with reduced expression of peroxisome proliferator-alpha (PPARalpha)-regulated genes and is ameliorated by PPARalpha activation.  J Pharmacol Exp Ther. 2004;  310 417-24.
    CrossrefPubMedGoogle Scholar
  • 23 Motojima K, Passilly P, Peters J M, Gonzalez F J, Latruffe N. Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner.  J Biol Chem. 1998;  273 16 710-4.
    PubMedGoogle Scholar
  • 24 Ameen C, Edvardsson U, Ljungberg A, Asp L, Akerblad P, Tuneld A. et al . Activation of peroxisome proliferator-activated receptor alpha increases the expression and activity of microsomal triglyceride transfer protein in the liver.  J Biol Chem. 2005;  280 1224-9.
    PubMedGoogle Scholar

Dr Meilin Xie

Department of Pharmacology

Medical School of Soochow University

Suzhou 215123

People's Republic of China

Phone: +86-512-6588-0320

Email: Xiemeilin@suda.edu.cn

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