|
|
|
| Effects of high glucose on the expression and function of glucagon receptor in the liver |
| LIU Mengdan JI Linlin YE Yang ZHU Chaoyu XIAO Yuanyuan GAO Qingge WEI Li |
| Department of Endocrinology and Metabolism, the Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, China |
|
|
|
Abstract Objective To investigate the changes of the expression and function of glucagon receptor (GCGR) in db/db mice liver and hepatocellular carcinoma cell line HepG2 cells treated with high glucose. Methods Intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) were performed in both db/db mice and control mice. The blood of mice in the two groups was collected for biochemical test; the expression of GCGR, protein kinase A (PKA) and phosphorylated protein kinase A (p-PKA) in the liver of the two groups were detected by Western blot or immunohistochemistry. The expression of GCGR in HepG2 cells treated with high glucose (30 mmol/L) in different glucose concentrations or different time gradients was detected by Western blot without stimulation of glucagon (GLN). Under GLN stimulation, the expression of GCGR, PKA and p-PKA proteins in HepG2 cells treated with high glucose at different time gradients was also detected by Western blot. Results Compared with control mice, the expressions of GCGR were markedly elevated in liver of db/db mice, but phosphorylated PKA levels were decreased (P ＜ 0.05 or P ＜ 0.01). GCGR protein expressions were increased following the growth of glucose concentrations in HepG2 cells, meanwhile, the expressions of GCGR protein were decreased at first, then increased with time extended (all P ＜ 0.01). Under GLN stimulation, the GCGR protein levels were upregulated by high glucose in a time-dependent manner (P ＜ 0.01). However, p-PKA/PKA levels were decreased compared with control group (0 h) (P < 0.05 or P ＜ 0.01). Conclusion Chronic hyperglycemia can increase the expression of GCGR in the liver and lead to glucagon resistance in the liver.
|
|
|
|
|
|
[1] Edgerton DS，Cherrington AD. Glucagon as a critical factor in the pathology of diabetes [J]. Diabetes，2011，60（2）：377-380.
[2] Briant LJB，Reinbothe TM，Spiliotis I，et al. δ-cells and β-cells are electrically coupled and regulate α-cell activity via somatostatin [J]. J Physiol，2018，596（2）：197-215.
[3] Müller TD，Finan B，Clemmensen C，et al. The New Biology and Pharmacology of Glucagon [J]. Physiol Rev，2017， 97（2）：721-766.
[4] Gylfe E，Gilon P. Glucose regulation of glucagon secretion [J]. Diabetes Res Clin Pract，2014，103（1）：1-10.
[5] Kim T，Nason S，Holleman C，et al. Glucagon Receptor Signaling Regulates Energy Metabolism via Hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21 [J]. Diabetes，2018，67（9）：1773-1782.
[6] Zhang H，Qiao A，Yang D，et al. Structure of the full-length glucagon class B G-protein-coupled receptor [J]. Nature，2017，546（7657）：259-264.
[7] Li XC，Carretero OA，Shao Y，et al. Glucagon receptor-mediated extracellular signal-regulated kinase 1/2 phosphorylation in rat mesangial cells：role of protein kinase A and phospholipase C [J]. Hypertension，2006，47（3）：580-585.
[8] Kim K，Ryu D，Dongiovanni P，et al. Degradation of PHLPP2 by KCTD17，via a Glucagon-Dependent Pathway，Promotes Hepatic Steatosis [J]. Gastroenterology，2017，153（6）：1568-1580. e10.
[9] Conarello SL，Jiang G，Mu J，et al. Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia [J]. Diabetologia，2007，50（1）：142-150.
[10] Giri B，Dey S，Das T，et al. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction，infection，cancer progression and other pathophysiological consequences：An update on glucose toxicity [J]. Biomed Pharmacother，2018，107：306-328.
[11] Abrahamsen N，Lundgren K，Nishimura E. Regulation of glucagon receptor mRNA in cultured primary rat hepatocytes by glucose and cAMP [J]. J Biol Chem，1995，270（26）：15 853-15 857.
[12] Burcelin R，Mrejen C，Decaux JF，et al. In vivo and in vitro regulation of hepatic glucagon receptor mRNA concentration by glucose metabolism [J]. J Biol Chem，1998， 273（14）：8088-8093.
[13] Unger RH，Orci L. The essential role of glucagon in the pathogenesis of diabetes mellitus [J]. Lancet，1975，1（7897）：14-16.
[14] Girard J. Glucagon，a key factor in the pathophysiology of type 2 diabetes [J]. Biochimie，2017，143：33-36.
[15] Garcia-Compean D，Jaquez-Quintana JO，Gonzalez-Gonzalez JA，et al. Liver cirrhosis and diabetes：risk factors，pathophysiology，clinical implications and management [J]. World J Gastroenterol，2009，15（3）：280-288.
[16] Kim K，Choi S，Park SM. Association of fasting serum glucose level and type 2 diabetes with hepatocellular carcinoma in men with chronic hepatitis B infection：A large cohort study [J]. Eur J Cancer，2018，102：103-113.
[17] 王倩倩，肖元元，祝超瑜，等.肝脏脂肪变对胰高血糖素受体的表达影响[J].医学研究杂志，2016，45（9）：33-38.
[18] Melancon A，Gagnon V，Milot M，et al. Liver glucagon receptors（GluR）：effect of exercise and fasting on binding characteristics，GluR-mRNA，and GluR protein content in rats [J]. Horm Metab Res，2013，45（10）：716-721.
[19] Wang H，Dolezal JM，Kulkarni S，et al. Myc and ChREBP transcription factors cooperatively regulate normal and neoplastic hepatocyte proliferation in mice [J]. J Biol Chem，2018，293（38）：14 740-14 757.
[20] Iizuka K. The transcription factor carbohydrate-response element-binding protein（ChREBP）：A possible link between metabolic disease and cancer [J]. BBA-Mol Basis Dis，2017，1863（2）：474-485.
[21] Iizuka K，Tomita R，Takeda J，et al. Rat glucagon receptor mRNA is directly regulated by glucose through transactivation of the carbohydrate response element binding protein [J]. Biochem Biophys Res Commun，2012，417（4）：1107-1112. doi：10.1016/j.bbrc.2011.12.042 |
|
|
|
