title: Rosuvastatin ameliorates high-fat and high-cholesterol diet-induced nonalcoholic steatohepatitis in rats.
abstract: OBJECTIVE
  Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibit endogenous cholesterol synthesis, possess pleiotropic activities, such as anti-inflammatory, anti-oxidative and antifibrotic effects. Here, we investigated whether statins ameliorate steatohepatitis using a high-fat and high-cholesterol (HFHC) diet-induced rat model.
  
  
  METHODS
  Eight-week-old male Sprague-Dawley rats were fed control chow or HFHC diet. Half of the HFHC diet-fed rats were orally administered 2 mg/kg/day rosuvastatin for 12 weeks. Hepatic injury, steatosis, fibrosis and markers of lipid peroxidation/oxidant stress were evaluated.
  
  
  RESULTS
  As previously reported, HFHC diet induced steatohepatitis in rat livers with hypercholesterolaemia. Rosuvastatin decreased Oil Red O stained-positive areas, liver/body weight ratio, serum total cholesterol levels and hepatic free fatty acid contents in HFHC diet-fed rats. Further study revealed that rosuvastatin significantly decreased hepatic mRNA expression of tumour necrosis factor-α and interleukin-6, serum alanine aminotransferase levels and hepatic lobular inflammation grade. Hepatic fibrosis was also ameliorated by rosuvastatin with decreases in hepatic mRNA expression of transforming growth factor-β, connective tissue growth factor and type-1 procollagen. Similarly, hepatic Sirius red stained or α-smooth muscle actin stained-positive areas and expression of markers of lipid peroxidation/oxidant stress [hepatic 8-hydroxy-oxyguanosine and hepatic 4-hydroxy-2-nonenal] were decreased. Interestingly, whereas the expression of carnitine palmitoyltransferase-1 and long-chain acyl-CoA dehydrogenase was not affected, that of catalase and acyl-coA oxidase was restored.
  
  
  CONCLUSIONS
  These data suggest that rosuvastatin improved not only hepatic steatosis but also hepatic injury and fibrosis via improved peroxisomal β-oxidation in this rat HFHC model.
authors.affiliation: Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Okada
authors.forename: Kanji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakajima
authors.forename: Taichiroh
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Masayasu
authors.initials: M
authors.lastname: Jo
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Mitsumoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishimura
authors.forename: Nozomi
authors.initials: N
authors.lastname: Tochiki
authors.forename: Kohichiroh
authors.initials: K
authors.lastname: Yasui
authors.forename: Hironori
authors.initials: H
authors.lastname: Mitsuyoshi
authors.forename: Masahito
authors.initials: M
authors.lastname: Minami
authors.forename: Keizo
authors.initials: K
authors.lastname: Kagawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Okanoue
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Itoh
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000378:metabolism; D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001391:Azo Compounds; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D017931:DNA Primers / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology*; D005464:Fluorobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001391:Azo Compounds; D002791:Cholesterol, Dietary; D017931:DNA Primers; D005230:Fatty Acids, Nonesterified; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; D002374:Catalase; D042962:Acyl-CoA Oxidase; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002334:Carnitine O-Palmitoyltransferase; D000410:Alanine Transaminase; C011049:oil red O