Liver glucokinase can be activated by peroxisome proliferator-activated receptor-gamma.
Thiazolidinediones (TZDs), synthetic ligands of peroxisome proliferator-activated receptor (PPAR)-gamma, are known to decrease hepatic glucose production and increase glycogen synthesis in diabetic animals. Recently it was reported that glucokinase (GK) expression was increased by TZDs in the liver of diabetic ZDF rats. However, the mechanism whereby TZDs increase GK expression is not yet studied. We have assumed that liver type glucokinase (LGK) induction by TZDs could be achieved by direct transcriptional activation. Thus, we have dissected the LGK promoter to explore the presence of a PPAR response element (PPRE) in the promoter. From this study, we were able to localize a PPRE in the -116/-104 region of the rat LGK gene. The PPAR-gamma/retinoid X receptor-alpha heterodimer was bound to the element and activated the LGK promoter. The LGK promoter lacking the PPRE or having mutations in the PPRE could not be activated by PPAR-gamma. Furthermore, troglitazone increased endogenous GK mRNA in primary hepatocytes. These results indicate that PPAR-gamma can directly activate GK expression in liver and may contribute to improving glucose homeostasis in type 2 diabetes.
Kim
So-Youn
SY
Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Yonsei University College of Medicine, Seoul, Korea.
Kim
Ha-Il
HI
Park
Sang-Kyu
SK
Im
Seung-Soon
SS
Li
Tianzhu
T
Cheon
Hyae Gyeong
HG
Ahn
Yong-Ho
YH
D000818:Animals; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D014176:Protein Biosynthesis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; C000607073:Rara protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D000072482:Retinoic Acid Receptor alpha; D045162:Thiazolidinediones; D014157:Transcription Factors; D005941:Glucokinase; D000077288:Troglitazone; D005947:Glucose