title: Ligand-induced expression of peroxisome proliferator-activated receptor alpha and activation of fatty acid oxidation enzymes in fatty liver.
abstract: BACKGROUND
  Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates lipid metabolism upon activation by ligands. Peroxisome proliferator-activated receptor alpha may play a role in the pathogenesis of fatty liver disease. The aim of this study was to assess the PPARalpha expression pattern and mitochondrial/peroxisomal enzyme activities in response to high fat diet (HFD) and clofibrate, a well known PPARalpha ligand.
  
  
  METHODS
  Four groups of Wistar-Albino rats were included: (1) rats fed a control diet (CD) for 6 weeks, (2) rats fed CD (6 weeks) plus clofibrate (last 2 weeks), (3) rats fed HFD for 6 weeks, and (4) rats fed HFD (6 weeks) plus clofibrate (last 2 weeks). Peroxisome proliferator-activated receptor alpha expression was evaluated by immunohistochemistry. Fatty acid beta-oxidation (peroxisomal-acyl-CoA-oxidase and mitochondrial-acyl-CoA-dehydrogenase) and catalase enzyme activities, and malondialdehyde and glutathion levels were measured spectrophotometrically in liver tissues.
  
  
  RESULTS
  All animals were fed HFD but only 2/12 animals were fed HFD plus clofibrate-developed fatty liver. Both HFD and clofibrate induced PPARalpha expression, clofibrate induction being more prominent than HFD. Clofibrate plus HFD did not further increase PPARalpha expression. Activities of peroxisomal-acyl-CoA-oxidase and mitochondrial-acyl-CoA-dehydrogenase enzymes were not induced by HFD alone. Clofibrate increased the activity of these enzymes in both CD- and HFD-fed animals. However, an increase of acyl-CoA-oxidase activity was blunted in rats fed HFD. Catalase activity and malondialdehyde levels were increased but glutathion levels were unchanged in rats fed HFD plus clofibrate.
  
  
  CONCLUSIONS
  Clofibrate was a more potent inducer of PPARalpha expression than HFD in our rat fatty liver model. The finding of blunted peroxisomal enzyme response to clofibrate in fatty livers suggests that alterations in postreceptor events may exist and further contribute to liver steatosis. Clofibrate seems to stabilize glutathion content and this might contribute to the prevention of liver steatosis.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Hacettepe University, Faculty of Medicine, Ankara, Turkey.
authors.forename: F
authors.initials: F
authors.lastname: Akbiyik
authors.forename: K
authors.initials: K
authors.lastname: Cinar
authors.forename: E
authors.initials: E
authors.lastname: Demirpence
authors.forename: T
authors.initials: T
authors.lastname: Ozsullu
authors.forename: R
authors.initials: R
authors.lastname: Tunca
authors.forename: R
authors.initials: R
authors.lastname: Haziroglu
authors.forename: C
authors.initials: C
authors.lastname: Yurdaydin
authors.forename: O
authors.initials: O
authors.lastname: Uzunalimoglu
authors.forename: H
authors.initials: H
authors.lastname: Bozkaya
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D042962:Acyl-CoA Oxidase; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001835:Body Weight; D002994:Clofibrate / Q000494:pharmacology; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D005234:Fatty Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000648:ultrastructure; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008024:Ligands; D015227:Lipid Peroxidation / Q000187:drug effects; D010088:Oxidoreductases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D004041:Dietary Fats; D000960:Hypolipidemic Agents; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D010088:Oxidoreductases; C107176:peroxisomal acyl-CoA oxidase; D042962:Acyl-CoA Oxidase; D042964:Acyl-CoA Dehydrogenase; D002994:Clofibrate