The Effect Of Erythropoietin On Hepatic Glucose And Lipid Metabolism And The Related Mechanism

Chapter 1 Erythropoietin improves hepatic insulin resistance via its receptor-mediated PI3K/AKT pathwayAims/hypothesis:Erythropoietin(EPO)has been recently shown to have beneficial effects on glucose metabolism and insulin resistance(IR)in murine adipocytes and skeletal muscles.However,the precise mechanisms by which EPO improves hepatic IR remain unclear.Methods and results:Here,we reported that EPO administration promoted the activation of phosphatidylinositol 3-kinase(PI3K)/AKT pathway and increased cellular glycogen levels,which were blocked by EPO receptor(EPOR)knockdown in palmitic acid-treated HepG2 cells.Moreover,EPO treatment significantly decreased fasting blood glucose and increased glucose and insulin tolerance and hepatic phosphorylation of AKT,GSK3? and FOXO1 in high-fat fed C57BL/6 mice.Conclusions:Therefore,our study suggested that EPO/EPOR signaling improve hepatic insulin resistance in a PI3K/AKT dependent way.Chapter 2 PPARy mediates the effect of erythropoietin on improving hepatic insulin resistanceAims/hypothesis:Erythropoietin(EPO)has been recently shown to have beneficial effects on glucose metabolism and insulin resistance.Peroxisome proliferator-activated receptor y(PPARy)is a nuclear receptor which plays important roles in the regulation of glucose and lipid metabolism in the liver.This study was aimed to investigate whether PPARy mediated the effect of EPO on regulating glucose metabolism and alleviating insulin resistance in hepatocytes.Methods and results:Here,we reported that EPO administration increased gene and protein levels and deacetylation of PPARy,which were blocked by EPO receptor(EPOR)knockdown in palmitic acid-treated HepG2 cells.Importantly,PPARy antagonist and PPAR? siRNA largely attenuated the ability of EPO to increase cellular glycogen levels and to restore AKT phosphorylation.Moreover,lentivirus-vector-mediated silencing of hepatic PPARy in high-fat fed C57BL/6 mice impaired EPO-mediated increase in glucose tolerance and activation of hepatic PI3K/AKT pathway.Simultaneously,we found that EPO elevated SIRT1 expression as well as its activation through increasing the NAD+/NADH ratio,and SIRT1 depletion attenuated both expression and deacetylation of PPARy and PPARy-dependent activation of PI3K/AKT upon EPO intervention in HepG2 cells.Conclusions:these findings suggest for the first time that PPARy functions as a novel downstream mediator in EPO/EPOR signaling and targeting SIRT1/PPAR?/PI3K/AKT pathway by EPO may have potential therapeutic implications for insulin resistance and type 2 diabetes.Chapter 3 the effect of erythropoietin on improving hepatic lipid metabolismAims/hypothesis:Erythropoietin(EPO)has been recently shown to have beneficial effects on weight loss and fat mass reduction in obese and type 2 diabetes mice.However,the effect of EPO on lipid metabolism in liver remains unclear.This study was aimed to investigate the effect of EPO on hepatic fatty acid synthesis and oxidation.Methods and results:We found that EPO sharply reduced fat accumulation in palmitic acid-treated HepG2 cells as assessed by oil red O staining.Meanwhile,EPO significantly decreased gene and protein levels of sterol regulatory element-binding protein lc(SREBPlc)and its target gene acetyl-CoA carboxylase(ACC),but had no effect on Peroxisome proliferator-activated receptor a and its target gene carnitine palmitoyltranferanse-1 A(CPTIA).Conclusions:These results indicated that EPO reduced fat accumulation through inhibiting hepatic fatty acid synthesis but not fatty acid oxidation.Our study suggested that EPO had a beneficial effect on hepatic fat accumulation.