title: Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat.
abstract: Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues.
authors.affiliation: Department of Pharmacology, Ligand Pharmaceuticals, Inc, San Diego, CA 92121, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Dana
authors.forename: P A
authors.initials: PA
authors.lastname: Hoener
authors.forename: J M
authors.initials: JM
authors.lastname: Bilakovics
authors.forename: D L
authors.initials: DL
authors.lastname: Crombie
authors.forename: K M
authors.initials: KM
authors.lastname: Ogilvie
authors.forename: R F
authors.initials: RF
authors.lastname: Kauffman
authors.forename: R
authors.initials: R
authors.lastname: Mukherjee
authors.forename: J R
authors.initials: JR
authors.lastname: Paterniti
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000235:genetics; D001483:Base Sequence; D002087:Butyrates / Q000494:pharmacology; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010671:Phenylurea Compounds / Q000494:pharmacology; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000737:chemistry / Q000502:physiology*; D014157:Transcription Factors / Q000819:agonists / Q000737:chemistry / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
chemical_list: D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D002087:Butyrates; D017931:DNA Primers; C105715:GW 2331; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D011345:Fenofibrate