Protective Effects And The Underlying Mechanisms Of OGA On Liver Metabolism Homeostasis

Background and aim:O-GlcNAcylation plays a role as a metabolic sensor regulating cellular metabolism.Aberrant regulation of O-GlcNAcylation is closely linked to insulin resistance,type 2 diabetes and obesity.Here,we aimed to evaluate the effects of conditional liver knockout of OGA(OGA-LKO),which causes hyper-O-GlcNAcylation on liver glucose and lipid metabolism.Methods:1.OGA-LKO mice model was generated by using the Cre-LoxP recombinase system.OGA-LKO mice genetype were confirmed through standard PCR.2.The effects of OGA loss on glucose tolenrance were and gluconeogenesis evaluated by IPGTT and qRT-PCR.3.Effects of OGA-LKO on HFD-induced insulin resistance were observed by IPITT/IPGTT under HFD condition.After the model was completed,the influence of OGA-LKO on HFD-induced liver steatosis was evaluated by observing various index,including liver morphology,weight,hematoxylin-eosin/ oil red O dyeing,serum biochemistry and blood fat.4.The numbers of macrophage in liver tissue were evaluated by IHC.Intestinal microbiome of OGA-LKO and WT mice were analyzed by using fecal 16 s RNA sequencing.5.Parameters such as FBW,FBG,IPITT and IPGTT in OGA-LKO and WT mice of the IF model were monitored.Results:1.Conditional liver OGA deletion leads to reduction of OGA and OGT expresson levels and causes inceased O-GlcNAcylation levels in mouse liver.OGA-LKO mice model was successfully established.2.OGA-LKO mice exhibited decreased impaired glucose tolerance.OGA stimulates gluconeogenesis by stabilizing FoxO1.3.IPITT showed that,after challenged with HFD,OGA-LKO mice exhibited exacerbated insulin resistance as compared with WT group,however no difference in IPGTT was observed.And the H&E stain and oil O red dying of liver tissues showed that the hepatic steatosis of OGA-LKO mice was heavier than that of the WT mice and with apparrent inflammatory infiltration.Serum ALT,AST,LDL,TG were significantly increased in OGA-LKO mice.OGA liver specific knock out up-regulates SREBP1 protein content and transcriptional activity.4.Increased O-GlcNAcylation levels and reduced OGA expresson levels are observed in liver tissue of NASH,especialy those with apparrent inflammatory infiltration.OGA deletion could enhance liver lipid steatosis and promote liver inflammatory response by altering the abundance of gut microbiome.5.After subjected to IF for 12 weeks,the WT mice showed improved insulin sensitivity and glucose tolerance compared with the al libitum group demonstrated by IPITT and IPGTT.On the contrary,LKO-IF mice showed no difference as compared with the WT-IF group.Moreover,OGA-LKO exhibited exacerbated insulin resistance and impaired glucose tolerance after subjected to 12 weeks IF as compared with WT group.Our observations suggest that IF exerted its metabolic protective effect through OGA,and liver OGA deletion could block IF-induced metabolic benefits.Conclusion:OGA exerts protective function in maintaining liver glucose and lipid metabolism.Deletion of OGA alters O-GlcNAcylation level and impairs liver glucose and lipid metabolic homeostasis.This finding provides a novel therapeutic target for metabolic syndrome.