The Effects Of JAZF1Gene Overexpression On Glucose And Lipids Metabolism, Insulin Sensitivity And Atherosclerosis

PART â… THE EFFECTS OF JAZF1GENE OVEREXPRESSION ONGLUCOSE AND LIPIDS METABOLISM AND INSULINSENSITIVITY IN C57BL/6J MICEObjective To explore the effect of juxtaposed with another zinc fingergene1(JAZF1) gene overexpression on glucose and lipids metabolism andinsulin sensitivity in insulin resistance C57BL/6J mice induced by high fatdiet (HFD).Methods43male C57BL/6J mice were randomly divided into twogroups include normal fat diet group (NFD group, n=10) and high fat dietgroup (HFD group, n=33), and were fed NFD and HFD respectively.After12weeks,26successful insulin resistance (IR) models in HFD group wereselected and randomly divided into HFD fed+saline water group (HF group,n=10), HFD fed+empty vector group (pIRES2-EGFP,GF group, n=6) andHFD fed+JAZF1plasmid group (pIRES2-EGFP-JAZF1,JAZF1group,n=10).Three groups were injected with saline water, pIRES2-EGFP andrecombinant plasmid pIRES2-EGFP-JAZF1by jugular vein.Levels ofblood glucose and lipids, fasting insulin (Fins), glycogen and lipid in liver and muscle were measured in each group.Glucose and lipids metabolismand insulin sensitivity were also assessed by thehyperinsulinemic-euglycemic clamp technique using3-[3H] glucose as atracer.Results Body weight in HFD group was higher than that in NFDgroup(P<0.01).Compared with NF group, body weight, levels of fastingblood glucose (FBG), Fins, triglyceride (TG), total cholesterol (TC), highdensity lipoprotein cholesterol (HDL-C), low density lipoproteincholesterol (LDL-C), free fatty acids (FFA) and liver and muscle TC, TGwere significantly incresed, glycogen in liver and muscle were significantlydecresed in HF, GF and JAZF1groups(P<0.05or P<0.01).Liver tissuesexpression of JAZF1mRNA and protein levels were significantly lower inHF and GF groups than that in NF group (all P<0.05). Compared with HFand GF groups, Liver tissues expression of JAZF1mRNA and protein weresignificantly increased in JAZF1group (all P<0.05).FBG, TC, Fins and liverTC in JAZF1group were significantly decreased than that in HF and GFgroups (P<0.01or P<0.05).During steady-state of clamp, FFA, TC, TG,HDL-C and LDL-C were suppressed in all groups. Fins and TC levels werelower in JAZF1group than that in HF and GF groups (P<0.05or P<0.01).The glucose infusion rate (GIR) in JAZF1group was significantly lowerthan that in NF group (P<0.01) and were significantly higher than that inHF and GF groups (P<0.05or P<0.01).At the end of clamping, glucose disappearance rate (GRd) was significantly lower in JAZF1group than thatin NF group (P<0.01) and higher than that in HF and GF groups (allP<0.05).Moreover, Hepatic glucose production (HGP) was significantlyhigher in JAZF1group compared with that in NF group (P<0.01) and wassignificantly lower in JAZF1group than that in HF and GF groups (allP<0.05).Conclusion obesity and insulin resistance were induced by long-termHFD feeding in C57BL/6J mice.JAZF1gene overexpression caneffectively improve disorder of glucose and lipid metabolism and insulinresistance. PART â…¡THE EFFECTS OF JAZF1GENE OVEREXPRESSION ONLIPIDS METABOLISM AND ATHEROSCLEROSIS IN APOE-/-MICEObjective To investigate the effects of JAZF1gene overexpression onlipid metabolism and atherosclerosis in ApoE-/-mice.Methods48normal8-week old male ApoE-/-mice were divided intothree groups including HFD fed+pIRES2-EGFP group (GF group, n=16)and HFD fed+pIRES2-EGFP-JAZF1group (JAZF1group,n=16)(pIRES2-EGFP or pIRES2-EGFP-JAZF1injection through the tail vein twice per week, respectively) and HFD fed+saline water group (HFgroup, n=16, equal volume of normal saline injection) for4weeks.Plasmalipid, plasma lipid related index, tissue lipid content, fecal bile acids,atherosclerotic lesion, and pathological changes of liver and fat tissue in allgroups were detected and observed. Liver cholesterol syntheses byintraperitoneal injection of14C-acetate and macrophage CD68influx inatherosclerotic plaque by fluorescence were observed.Results Liver tissues expression of JAZF1protein and HDL-C/TCin JAZF1group were significantly higher than that in HF and GF group (allP<0.05). Levels of fasting blood glucose (FBG), fasting plasma insulin(Fins), total cholesterol (TC), HOMA-insulin resistance index (HOMA-IR),arteriosclerotic index (AI), lipid comprehensive index (LCI) and liver TCwere significantly lower in JAZF1groups than that in the other two groups(all P<0.05). Compared with HF and GF groups, red-stained lipidaccumulation of intima,accumulation of foam cells in thoracic aortic plaque,total area of thoracic aortic plaque, ratios of total area of thoracic aorticplaque and lumen area, AOD of macrophage CD68in atheroscleroticplaque of aortic root,14C-labeled cholesterol in liver and total14C-labeledcholesterol in liver and small intestine were markedly reduced (P<0.05orP<0.01) in JAZF1group.Moreover,hepatocyte steatosis were alleviated inJAZF1group.Conclusion JAZF1gene overexpression can reduce liver cholesterol syntheses and content, plasma TC and plasma lipid related index. JAZF1gene overexpression can relieve and delay early atherosclerotic lesion ofaortic intima by improving disorder of lipid metabolism and inhibitingaccumulation of macrophages in atherosclerotic plaques.