Inhibition of gluconeogenesis in primary hepatocytes by stromal cell-derived factor-1 (SDF-1) through a c-Src/Akt-dependent signaling pathway.
Hepatic gluconeogenesis is elevated in diabetes and a major contributor to hyperglycemia. Stromal cell-derived factor-1 (SDF-1) is a chemokine and an activator of Akt. In this study, we tested the hypothesis that SDF-1 suppresses hepatic gluconeogenesis through Akt. Our results from isolated primary hepatocytes show that SDF-1alpha and SDF-1beta inhibited glucose production via gluconeogenesis and reduced transcript levels of key gluconeogenic genes glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Additionally, SDF-1alpha and SDF-1beta both inhibited activation of the PEPCK promoter. In examining the mechanism by which SDF-1 inhibits gluconeogenesis, we found that SDF-1 promoted phosphorylation of Akt, FoxO1, and c-Src, but did not activate insulin receptor substrate-1-like insulin. Blockade of Akt activation by LY294002, FoxO1 translocation by constitutively nuclear FoxO1 mutant, or c-Src activation by the chemical inhibitor PP2, respectively, blunted SDF-1 suppression of gluconeogenesis. Finally, our results show that knocking down the level of SDF-1 receptor CXCR4 mRNA blocked SDF-1 suppression of gluconeogenesis. Together, our results demonstrate that SDF-1 is capable of inhibiting gluconeogenesis in primary hepatocytes through a signaling pathway distinct from the insulin signaling.
Liu
Hui-Yu
HY
Division of Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA. hliu@thehamner.org
Wen
Ge-Bo
GB
Han
Jianmin
J
Hong
Tao
T
Zhuo
Degen
D
Liu
Zhenqi
Z
Cao
Wenhong
W
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology / Q000235:genetics; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000096:biosynthesis / Q000235:genetics; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D002867:Chromones; C515256:Cxcl12 protein, mouse; D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D009025:Morpholines; D019718:Receptors, CXCR4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose
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