Hepatocyte growth factor family negatively regulates hepatic gluconeogenesis via induction of orphan nuclear receptor small heterodimer partner in primary hepatocytes.
Hepatic gluconeogenesis is tightly balanced by opposing stimulatory (glucagon) and inhibitory (insulin) signaling pathways. Hepatocyte growth factor (HGF) is a pleiotropic growth factor that mediates diverse biological processes. In this study, we investigated the effect of HGF and its family member, macrophage-stimulating factor (MSP), on hepatic gluconeogenesis in primary hepatocytes. HGF and MSP significantly repressed expression of the key hepatic gluconeogenic enzyme genes, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (Glc-6-Pase) and reduced glucose production. HGF and MSP activated small heterodimer partner (SHP) gene promoter and induced SHP mRNA and protein levels, and the effect of HGF and MSP on SHP gene expression was demonstrated to be mediated via activation of the AMP-activated protein kinase (AMPK) signaling pathway. We demonstrated that upstream stimulatory factor-1 (USF-1) specifically mediated HGF effect on SHP gene expression, and inhibition of USF-1 by dominant negative USF-1 significantly abrogated HGF-mediated activation of the SHP promoter. Elucidation of the mechanism showed that USF-1 bound to E-box-1 in the SHP promoter, and HGF increased USF-1 DNA binding on the SHP promoter via AMPK and DNA-dependent protein kinase-mediated pathways. Adenoviral overexpression of USF-1 significantly repressed PEPCK and Glc-6-Pase gene expression and reduced glucose production. Knockdown of endogenous SHP expression significantly reversed this effect. Finally, knockdown of SHP or inhibition of AMPK signaling reversed the ability of HGF to suppress hepatocyte nuclear factor 4alpha-mediated up-regulation of PEPCK and Glc-6-Pase gene expression along with the HGF- and MSP-mediated suppression of gluconeogenesis. Overall, our results suggest a novel signaling pathway through HGF/AMPK/USF-1/SHP to inhibit hepatic gluconeogenesis.
Chanda
Dipanjan
D
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
Li
Tiangang
T
Song
Kwang-Hoon
KH
Kim
Yong-Hoon
YH
Sim
Jeonggu
J
Lee
Chul Ho
CH
Chiang
John Y L
JY
Choi
Hueng-Sik
HS
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005943:Gluconeogenesis / Q000235:genetics*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D051720:Upstream Stimulatory Factors / Q000378:metabolism*
D001786:Blood Glucose; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D051720:Upstream Stimulatory Factors; C497182:Usf1 protein, rat; C082332:macrophage stimulating protein; C099713:nuclear receptor subfamily 0, group B, member 2; D017228:Hepatocyte Growth Factor; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP)