The Regulating Effect Of E3 Ubiquitin Ligase HRD1 To Hepatic Gluconeogenesis

Gluconeogenesis is the organism converts a variety of non sugar substances(such as lactic acid,glycerin,raw sugar,amino acids)into sugar(glucose and glycogen)process,which is the important mechanism of balancing the glucose metabolism in our body.The major gluconeogenetic organs are liver(80%)and kidney(20%).The physiological significance of gluconeogenesis is maintaining the blood glucose level constant when the body is under the fasting situation.It was reported that abnormally activated hepatic gluconeogenesis in the patients with type 2 diabetes.The protein degradation through proteasomal pathways is one of important mechanisms in regulation of physiological functions and pathogenetic processes.HMG-CoA reductase degr adation protein1(HRD1),one of the ubiquitin E3 ligases has been demonstrated playing an important role for proteasomal degradation.HRD1 is invovled in various physiological and pathological processes,such as Alzheimer’s disease,diabetic retinopathy,breast cancer by mediating the degradation of the related proteins.However,there is no definite report about the effect of HRD1 on hepatic gluconeogenesis at present.The purpose of our study is to explore the effect of HRDl on hepatic gluconeogenesis.In the current study,we found the downreguation of HRD1 expression in the liver of the fasting wild type mice.Pathologically,the upregulation of HRD1 expression was exhibited in the liver of db/db mice and high-fat diet fed mice.We next studied the role of HRD1 on hepatic gluconeogenesis.Overexpression of HRD1 in the forskolin stimulated HepG2 cells showed an inhibitary effect on the glucose production in the hepatocytes.The further co-immunoprecipitation(CO-IP)test demonstrated the interaction between HRD1 and eIF2α,which is a key component of endoplasmic reticulum(ER)proteins.Meanwhile,we also performed ubiquitination experiment to demonstrate that overexpression of HRD1 promoted the ubiquitination and degradation of eIF2α.In conclusion,HRD1 plays an inhibitory role in hepatic gluconeogenesis by mediating eIF2α degradation.