20-HETE induces hyperglycemia through the cAMP/PKA-PhK-GP pathway.
We previously generated cytochrome P450 4F2 (CYP4F2) transgenic mice and showed high 20-hydroxyeicosatetraenoic acid (20-HETE) production, which resulted in an elevation of blood pressure. However, it was unclear whether 20-HETE affected glucose metabolism. We measured fasting plasma glucose, insulin, hepatic CYP4F2 expression, and 20-HETE production by hepatic microsomes, and hepatic 20-HETE levels in transgenic mice. We also assessed glycogen phosphorylase (GP) activity and the cAMP/protein kinase A (PKA)-phosphorylase kinase (PhK)-GP pathway, as well as expressions of insulin receptor substrate 1 and glucose transporters in vivo and in vitro. The transgenic mice had overexpressed hepatic CYP4F2, high hepatic 20-HETE and fasting plasma glucose levels but normal insulin level. The GP activity was increased and the cAMP/PKA-PhK-GP pathway was activated in the transgenic mice compared with wild-type mice. Moreover, these alterations were eliminated with the addition of N-hydroxy-N'-(4-butyl-2 methylphenyl) formamidine, which is a selective 20-HETE inhibitor. The results were further validated in Bel7402 cells. In addition, the transgenic mice had functional insulin signaling, and 20-HETE had no effect on insulin signaling in Bel7402 cells, excluding that the observed hyperglycemia in CYP4F2 transgenic mice resulted from insulin dysfunction, because the target tissues were sensitive to insulin. Our study suggested that 20-HETE can induce hyperglycemia, at least in part, through the cAMP/PKA-PhK-GP pathway but not through the insulin-signaling pathway.
Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, Peoples Republic of China.
Guangrui
G
Lai
Jingjing
J
Wu
Xiaoliang
X
Liu
Yanyan
Y
Zhao
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D006943:Hyperglycemia / Q000150:complications / Q000201:enzymology*; D006973:Hypertension / Q000150:complications / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010764:Phosphorylase Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology
D000578:Amidines; D001786:Blood Glucose; D051272:Glucose Transporter Type 1; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D007546:Isoquinolines; C495678:Slc2a1 protein, mouse; D013449:Sulfonamides; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; D024981:Glycogen Phosphorylase; D010764:Phosphorylase Kinase; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide