title: A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats.
abstract: We investigated the biological activity of a novel thiazolidinedione (TZD) derivative, KRP-297, and the molecular basis of this activity. When administered to obese Zucker fatty rats (obese rats) at 10 mg/kg for 2 weeks, KRP-297, unlike BRL-49,653, restored reduced lipid oxidation, that is, CO2 and ketone body production from [14C]palmitic acid, in the liver by 39% (P < 0.05) and 57% (P < 0.01), respectively. KRP-297 was also significantly more effective than BRL-49,653 in the inhibition of enhanced lipogenesis and triglyceride accumulation in the liver. To understand the molecular basis of the biological effects of KRP-297, we examined the effect on peroxisome proliferator-activated receptor (PPAR) isoforms, which may play key roles in lipid metabolism. Unlike classical TZD derivatives, KRP-297 activated both PPAR-alpha and PPAR-gamma, with median effective concentrations of 1.0 and 0.8 micromol/l, respectively. Moreover, radiolabeled [3H]KRP-297 bound directly to PPAR-alpha and PPAR-gamma with dissociation constants of 228 and 326 nmol/l, respectively. Concomitantly, KRP-297, but not BRL-49,653, increased the mRNA and the activity (1.5-fold [P < 0.01] and 1.8-fold [P < 0.05], respectively) of acyl-CoA oxidase, which has been reported to be regulated by PPAR-alpha, in the liver. By contrast, KRP-297 (P < 0.05) was less potent than BRL-49,653 (P < 0.01) in inducing the PPAR-gamma-regulated aP2 gene mRNA expression in the adipose tissues. These results suggest that PPAR-alpha agonism has a protective effect against abnormal lipid metabolism in liver of obese rats.
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Murakami
authors.forename: K
authors.initials: K
authors.lastname: Tobe
authors.forename: T
authors.initials: T
authors.lastname: Ide
authors.forename: T
authors.initials: T
authors.lastname: Mochizuki
authors.forename: M
authors.initials: M
authors.lastname: Ohashi
authors.forename: Y
authors.initials: Y
authors.lastname: Akanuma
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D042962:Acyl-CoA Oxidase; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008024:Ligands; D050356:Lipid Metabolism; D008099:Liver / Q000033:anatomy & histology / Q000166:cytology / Q000378:metabolism; D008297:Male; D018996:Myelin P2 Protein / Q000235:genetics; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009765:Obesity / Q000097:blood / Q000201:enzymology / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D045162:Thiazolidinediones; D053778:Thiazolidines; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D008024:Ligands; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D053778:Thiazolidines; D014157:Transcription Factors; D014280:Triglycerides; D000077154:Rosiglitazone; C116017:5-((2,4-dioxo-5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase