Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the zucker diabetic fatty rat

• Published in: Metabolism, clinical and experimental clinical and experimental, 2001-08, Vol.50 (8), p.963-971
• Main Authors: Dana, Sharon L., Hoener, Patricia A., Bilakovics, James M., Crombie, Diane L., Ogilvie, Kathleen M., Kauffman, Raymond F., Mukherjee, Ranjan, Paterniti, James R.
• Format: Article
• Language: English
• Subjects: Animals; Apolipoprotein C-III; Apolipoproteins C - genetics; Base Sequence; Biological and medical sciences; Butyrates - pharmacology; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; DNA Primers; Fenofibrate - pharmacology; Gene Expression Regulation - physiology; General and cellular metabolism. Vitamins; Liver - metabolism; Male; Medical sciences; Pharmacology. Drug treatments; Phenylurea Compounds - pharmacology; Phosphoenolpyruvate Carboxykinase (ATP) - genetics; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - physiology; RNA, Messenger - genetics; Transcription Factors - agonists; Transcription Factors - chemistry; Transcription Factors - physiology; Triglycerides - blood
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1053/meta.2001.24870

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 ][ndash ]specific compound, fenofibrate, a PPAR-[gamma ][ndash ]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.