p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes.
Free fatty acids (FFA) are considered as a causative link between obesity and diabetes. In various animal models and in humans FFA can stimulate hepatic gluconeogenesis. Although the in vivo role of FFA in hepatic gluconeogenesis has been clearly established, the intracellular role of FFA and related signaling pathway remain unclear in the regulation of hepatic gluconeogenic gene transcription. In this study, we have identified p38 mitogen-activated protein kinase (p38) as a critical signaling component in FFA-induced transcription of key gluconeogenic genes. We show in primary hepatocytes that both mid- and long-chain fatty acids (saturated or unsaturated) could activate p38 and increase levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, and peroxisome proliferator-activated receptor gamma coactivator alpha (PGC-1alpha) gene transcripts. The FFA-induced expression of PEPCK and PGC-1alpha genes and gluconeogenesis in isolated hepatocytes could be blocked by the inhibition of p38. Furthermore, PGC-1alpha phosphorylation by p38 was necessary for FFA-induced activation of the PEPCK promoter. Additionally, FFA stimulated phosphorylation of cAMP-response element-binding protein (CREB) through p38. The overexpression of the dominant-negative CREB prevented FFA-induced activation of the PEPCK promoter. Finally, we show that FFA activation of p38 requires protein kinase Cdelta. Together, our results indicate that p38 plays a critical role in FFA-induced transcription of gluconeogenic genes, and the known gluconeogenic regulators, PGC-1alpha and CREB, are also integral parts of FFA-stimulated transcription of gluconeogenic genes.
Collins
Qu Fan
QF
Division of Biological Sciences, Endocrine Biology Program, CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA.
Xiong
Yan
Y
Lupo
Edgar G
EG
Liu
Hui-Yu
HY
Cao
Wenhong
W
D000818:Animals; D002262:Carboxy-Lyases / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D005952:Glucose-6-Phosphatase; D002262:Carboxy-Lyases