The Effects Of Exercise And Metformin Intervention On Db/db Mice Liver Endoplasmic Reticulum Stress And Apoptosis

Objective: To investigate the effects of exercise and metformin on liver lipid deposition,oxidative stress,endoplasmic reticulum stress and apoptosis in db/db mice,explore the mechanism of Bi P-PERK-ATF4-CHOP signaling pathway in the intervention of exercise and metformin on liver lipid deposition in db/db mice.Methods: 40 db/db mice were randomly divided into 4 groups: control group(CON,n = 10),exercise group(EX,n = 10),metformin treatment group(MET,n = 10),exercise + metformin intervention group(EM,n = 10).The mice in the M and EM groups were gavaged with MET daily,and the mice in the exercise group were trained on the treadmill for 8 weeks,5 days/week.After 8 weeks,the blood and liver tissues of the mice were taken.The blood indexes were used to detect the four items of blood lipid,AST and ALT.The liver samples were used to determine the liver TG,oxidative stress,Bi P-PERK-ATF4-CHOP signaling pathway and apoptosis protein expression.Histological detection of liver HE,Oil Red O Staining,immunohistochemistry,TUNEL staining.Results: 1)After 8 weeks of feeding,compared with the CON group,the body weight of each experimental group decreased significantly after EX and MET intervention(P < 0.05).2)A large number of orange lipid droplets were observed in the CON group.Compared with the CON group,the serum TG and FFA levels in the EX,MET and EM groups were significantly decreased(P <0.05).The percentage of lipid droplet area and liver TG content were significantly decreased after intervention(P < 0.05).3)Exercise combined with metformin can inhibit the expression of BIP and its downstream PERK-e IF2α-ATF4 pathway genes(P < 0.05),up-regulate AMPK-Nrf2-HO-1signaling pathway(P < 0.05),improve antioxidant defense system and endoplasmic reticulum stress,and alleviate liver lipid deposition.4)Exercise combined with metformin treatment down-regulated the expression of cleaved-caspase-3 / caspase-3 in db / db mice,reduced the positive proportion of TUNEL staining(P < 0.05),reduced the level of hepatocyte apoptosis.Conclusion: 1)Exercise combined with metformin up-regulate AMPK-Nrf2-HO-1 signaling pathway,improve the antioxidant capacity,reduce liver lipid deposition;2)Compared with metformin alone or exercise intervention,exercise combined with metformin treatment improves liver steatosis by improving antioxidant defense system and inhibiting PERK-e IF2α-ATF4 signaling pathway,and inhibits oxidative stress and endoplasmic reticulum stress induced hepatocyte apoptosis.