Ursolic Acid Improves Glycolipid Metabolism Disorder,Mitochondrial Dysfunction And Autophagy In Aged Rats

Purpose To investigate the effect of ursolic acid(UA)on glycolipid metabolism disorder,mitochondrial dysfunction and hepatic and skeletal muscle's autophagy in naturally ageing rats and explore the underlying mechanisms.Materials and Methods Twenty-five male aging rats were divided randomly into three groups: the natural aging rat group(Aging,n=9),the aging rats supplemented with ursolic acid at 10 mg/kg(UA-L,n=8)and 50 mg/kg(UA-H,n=8)for 7 weeks.Eight young rats were randomly selected as the young normal group(Young,n=8).Enzymatical method and ELISA were used for the examination of plasma glucose,triglycerides,insulin concentrations and HOMA-IR index was calculated;Liver triglycerides were measured by enzymatical method;Liver lipid deposition was observed by Oil Red "O" staining;The hepatic and muscle's autophagy-related proteins and mitochondrial quality proteins were analysed by Western blot;Meanwhile,mitochondrial quality and oxidative stress in skeletal muscle were evaluated by enzymatic method.Results Treatment with UA(50 mg/kg,once daily,by oral gavage)could attenuate age-associated high plasma TG and insulin concentration under fasting conditions as well as suppress the increase in the HOMA-IR index,which suggests there is an improvement of systemic insulin sensitivity,and had no effect on chow,weight,liver/body weight,gastrocnemius/body weight,soleus/body weight of rats.Moreover,liver weight and hepatic triglyceride content was also decreased.Attenuation of the increased Oil Red O staining area was evident on histological examination of liver in UA(50 mg/kg)-treated rats.Importantly,UA(50 mg/kg)administration reversed the decreased expressions of autophagy-related proteins LC3B/3A and Beclin1,and mitochondrial quality proteins PGC-1? and Drp1 in aging rats,although P62 and Pink1 remained unchanged.For skeletal muscle,The autophagy-related proteins' results were consistent with liver.In addition,ursoic acid(50mg/kg)not only improved skeletal muscle insulin resistance induced by natural aging rats,but also improved mitochondrial quality(i.e.,NOX,ATP,COX-IV,PGC-1?,Drp1).The results of oxidative stress showed that ursolic acid could reverse the phenomenon of lipid peroxidation(MDA)in skeletal muscle of aging rats,which was consistent with the results of T-SOD.The results of skeletal muscle autophagy related proteins suggested that ursolic acid also enhanced the expression of skeletal muscle autophagy related proteins LC3B/3A,ATG10 and ATG3,while Beclin1,P62 and other proteins showed no significant changes.Conclusions In conclusion,UA may attenuate systematic insulin resistance and hepatic lipid deposition,enhance hepatic and skeletal muscle autophagy,improve mitochondrial quality and reduce oxidative stress in aging rats.