title: Amelioration of high fructose-induced metabolic derangements by activation of PPARalpha.
abstract: To elucidate molecular mechanisms of high fructose-induced metabolic derangements and the influence of peroxisome proliferator-activated receptor-alpha (PPARalpha) activation on them, we examined the expression of sterol regulatory element binding protein-1 (SREBP-1) and PPARalpha as well as its nuclear activation and target gene expressions in the liver of high fructose-fed rats with or without treatment of fenofibrate. After 8-wk feeding of a diet high in fructose, the mRNA contents of PPARalpha protein and its activity and gene expressions of fatty acid oxidation enzymes were reduced. In contrast, the gene expressions of SREBP-1 and lipogenic enzymes in the liver were increased by high fructose feeding. Similar high fructose effects were also found in isolated hepatocytes exposed to 20 mM fructose in the media. The treatment of fenofibrate (30 mg.kg(-1).day(-1)) significantly improved high fructose-induced metabolic derangements such as insulin resistance, hypertension, hyperlipidemia, and fat accumulation in the liver. Consistently, the decreased PPARalpha protein content, its activity, and its target gene expressions found in high fructose-fed rats were all improved by fenofibrate treatment. Furthermore, we also found that the copy number of mitochondrial DNA, the expressions of mitochondrial transcription factor A, ATPase-6 subunit, and uncoupling protein-3 were increased by fenofibrate treatment. These findings suggest that the metabolic syndrome in high fructose-fed rats is reversed by fenofibrate treatment, which is associated with the induction of enzyme expression related to beta-oxidation and the enhancement of mitochondrial gene expression.
authors.affiliation: Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Nagai
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nishio
authors.forename: Takaaki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kikkawa
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
mesh_terms: D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D001794:Blood Pressure; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004822:Epididymis; D005227:Fatty Acids / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology; D005632:Fructose / Q000494:pharmacology*; D018628:Gene Dosage; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000201:enzymology; D006949:Hyperlipidemias / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D007473:Ion Channels; D008099:Liver / Q000166:cytology / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000502:physiology; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000502:physiology; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000071247:Uncoupling Protein 3
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D005632:Fructose; D011345:Fenofibrate