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Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet.
Eur J Pharmacol. 2006 Apr 24; 536(1-2):182-91.EJ

Abstract

We evaluated the effects of bezafibrate, a peroxisome proliferator-activated receptor (PPAR) pan-agonist, and GW501516, a PPARdelta agonist, on mice fed a methionine- and choline-deficient (MCD) diet, a model of non-alcholic steatohepatitis (NASH), to investigate (a) the efficacy of bezafibrate against non-alcholic steatohepatitis and (b) the relation between non-alcholic steatohepatitis and the functional role of PPARdelta. Bezafibrate (50 or 100 mg/kg/day) and GW501516 (10 mg/kg/day) were administered by gavage once a day for 5 weeks. Hepatic lipid contents, plasma triglyceride, high density lipoprotein (HDL)-cholesterol and alanine aminotransferase (ALT) concentrations were evaluated, as were histopathological changes in the liver and hepatic mRNA expression levels. Bezafibrate and GW501516 inhibited the MCD-diet-induced elevations of hepatic triglyceride and thiobarbituric acid-reactants contents and the histopathological increases in fatty droplets within hepatocytes, liver inflammation and number of activated hepatic stellate cells. In this model, bezafibrate and GW501516 increased the levels of hepatic mRNAs associated with fatty acid beta-oxidation [acyl-CoA oxidase (ACO), carnitine palmitoyltransferase-1 (CPT-1), liver-fatty acid binding protein (L-FABP) and peroxisomal ketothiolase], and reduced the levels of those associated with inflammatory cytokines or chemokine [transforming growth factor (TGF)-beta1, interleukin (IL)-6, IL-1beta, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF) alpha and nuclear factor (NF)-kappaB1]. In addition, bezafibrate characteristically reduced the elevation in the level of plasma ALT, but enhanced that in plasma adiponectin and increased the mRNA expression levels of its receptors (adiponectin receptors 1 and 2). These results suggest that (a) bezafibrate (especially) and GW501516 might improve hepatic steatosis via an improvement in fatty acid beta-oxidation and a direct prevention of inflammation, (b) treatment with a PPARdelta agonist might improve non-alcholic steatohepatitis, (c) bezafibrate may improve non-alcholic steatohepatitis via activation not only of PPARalpha but also of PPARdelta, because bezafibrate is a PPAR pan-agonist.

Authors+Show Affiliations

Toxicology Research Laboratory, R&D, Kissei Pharmaceutical Co., Ltd., 2320-1 Maki, Hotaka, Azumino-city, Nagano-Pref., 399-8305, Japan. tatsuya_nagasawa@pharm.kissei.co.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16574099

Citation

Nagasawa, Tatsuya, et al. "Effects of Bezafibrate, PPAR Pan-agonist, and GW501516, PPARdelta Agonist, On Development of Steatohepatitis in Mice Fed a Methionine- and Choline-deficient Diet." European Journal of Pharmacology, vol. 536, no. 1-2, 2006, pp. 182-91.
Nagasawa T, Inada Y, Nakano S, et al. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur J Pharmacol. 2006;536(1-2):182-91.
Nagasawa, T., Inada, Y., Nakano, S., Tamura, T., Takahashi, T., Maruyama, K., Yamazaki, Y., Kuroda, J., & Shibata, N. (2006). Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. European Journal of Pharmacology, 536(1-2), 182-91.
Nagasawa T, et al. Effects of Bezafibrate, PPAR Pan-agonist, and GW501516, PPARdelta Agonist, On Development of Steatohepatitis in Mice Fed a Methionine- and Choline-deficient Diet. Eur J Pharmacol. 2006 Apr 24;536(1-2):182-91. PubMed PMID: 16574099.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. AU - Nagasawa,Tatsuya, AU - Inada,Yoichi, AU - Nakano,Shigeru, AU - Tamura,Toru, AU - Takahashi,Tetsuaki, AU - Maruyama,Kazuyasu, AU - Yamazaki,Yoshinobu, AU - Kuroda,Junji, AU - Shibata,Nobuo, Y1 - 2006/02/28/ PY - 2005/11/24/received PY - 2006/02/15/revised PY - 2006/02/17/accepted PY - 2006/4/1/pubmed PY - 2006/7/26/medline PY - 2006/4/1/entrez SP - 182 EP - 91 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 536 IS - 1-2 N2 - We evaluated the effects of bezafibrate, a peroxisome proliferator-activated receptor (PPAR) pan-agonist, and GW501516, a PPARdelta agonist, on mice fed a methionine- and choline-deficient (MCD) diet, a model of non-alcholic steatohepatitis (NASH), to investigate (a) the efficacy of bezafibrate against non-alcholic steatohepatitis and (b) the relation between non-alcholic steatohepatitis and the functional role of PPARdelta. Bezafibrate (50 or 100 mg/kg/day) and GW501516 (10 mg/kg/day) were administered by gavage once a day for 5 weeks. Hepatic lipid contents, plasma triglyceride, high density lipoprotein (HDL)-cholesterol and alanine aminotransferase (ALT) concentrations were evaluated, as were histopathological changes in the liver and hepatic mRNA expression levels. Bezafibrate and GW501516 inhibited the MCD-diet-induced elevations of hepatic triglyceride and thiobarbituric acid-reactants contents and the histopathological increases in fatty droplets within hepatocytes, liver inflammation and number of activated hepatic stellate cells. In this model, bezafibrate and GW501516 increased the levels of hepatic mRNAs associated with fatty acid beta-oxidation [acyl-CoA oxidase (ACO), carnitine palmitoyltransferase-1 (CPT-1), liver-fatty acid binding protein (L-FABP) and peroxisomal ketothiolase], and reduced the levels of those associated with inflammatory cytokines or chemokine [transforming growth factor (TGF)-beta1, interleukin (IL)-6, IL-1beta, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF) alpha and nuclear factor (NF)-kappaB1]. In addition, bezafibrate characteristically reduced the elevation in the level of plasma ALT, but enhanced that in plasma adiponectin and increased the mRNA expression levels of its receptors (adiponectin receptors 1 and 2). These results suggest that (a) bezafibrate (especially) and GW501516 might improve hepatic steatosis via an improvement in fatty acid beta-oxidation and a direct prevention of inflammation, (b) treatment with a PPARdelta agonist might improve non-alcholic steatohepatitis, (c) bezafibrate may improve non-alcholic steatohepatitis via activation not only of PPARalpha but also of PPARdelta, because bezafibrate is a PPAR pan-agonist. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/16574099/Effects_of_bezafibrate_PPAR_pan_agonist_and_GW501516_PPARdelta_agonist_on_development_of_steatohepatitis_in_mice_fed_a_methionine__and_choline_deficient_diet_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(06)00199-3 DB - PRIME DP - Unbound Medicine ER -