Schistosome Infection Improves Hepatic Insulin Sensitivity Through Downregulating MiR-802 Expression In Obese Mice

Schistosomiasis japonica is a beast of parasitic diseases.The main pathological mechanism is the local chronic inflammation in liver and intestine triggered by eggs and tissue damage caused by over-repair of chronic infection,and development into liver fibrosis.Schistosomes are regarded as detrimental to humans,however,some studies have shown that schistosomes not only cause damage to the body,but also can reduce the rate of some autoimmune diseases and metabolic diseases.Chronic inflammation associated with obesity contributes to some metabolic syndromes,such as insulin resistance and type 2 diabetes.The type 2 immune responses induced by Schistosoma mansoni infection and egg antigens immunization were reported to improve the whole-body glucose tolerance and insulin sensitivity,and tissue-specific insulin sensitivity of adipose tissue in obese mice.As Schistosoma japonicum and Schistosoma mansoni have many similarities in biological characters,pathogenesis and pathophysiology changes etc.We conceived that Schistosoma japonicum infection could improve whole-body and tissue-specific insulin sensitivity in type 2 diabetes.We established Schistosoma japonicum（S.japonicum）infection mice model with BALB/c,C57BL/6 and Lepr^db/db male mice in order to explore the relationship between schistosome infection and energy metabolism.Six experimental groups were designed as the BALB/c control group（BALB/c-con）,BALB/c infected group（BALB/c-inf）,C57BL/6 control group（C57BL/6-con）,C57BL/6 infected group（C57BL/6-inf）,Lepr^db/db control group(Lepr^db/db-con)and Lepr^db/db infected group(Lepr^db/db-inf).Glucose tolerance test and insulin tolerance test were used to evaluate body insulin sensitivities.Next,we used automatic biochemical analyzer to test serum alanine aminotransferase（ALT）,aspartate aminotransferase（AST）,total cholesterol（TC）,triglyceride（TG）,high-density lipoprotein cholesterol（HDL-C）,and low-density lipoprotein cholesterol（LDL-C）.HE staining to evaluate the degree of liver inflammation,oil red staining to determine the fat deposition,enzyme-linked immunosorbent assay（ELISA）to measure serum insulin concentration,real-time fluorescent quantitative PCR to detect the transcription level of miR-802,Hnf1 b and some inflammation related genes.The main results of our studies were as follows:1.miRNA transcriptome in murine liver with S.japonicum infection showed that compared with normal mice,some miRNAs were differentially expressed in S.japonicum infected group,such as miR-155,miR-146 b and miR-802.2.Liver miR-802 expression was reduced and its target gene Hnf1 b m RNA transcription was elevated after schistosome infection.Thus,S.japonicum infection might suppress the expression of miR-802 in host liver and weaken its inhibitory function of Hnf1 b.3.The fasting glucose in S.japonicum infected mice were decreased compared with the controls.After glucose loading,blood glucose concentrations in S.japonicum infected C57BL/6 and Lepr^db/db mice were persistently lower than those in their respective controls,especially in Lepr^db/db mice.These suggested that S.japonicum infection induced glucose intolerance in C57BL/6 and Lepr^db/db mice.4.The results of HE staining and oil red staining in the liver showed that there were little fat in the liver of C57BL/6 mice.Compared with Lepr^db/db control group,the density and area of fat in the liver of Lepr^db/db infected group were significantly decreased.5.ELISA results showed that the serum insulin concentration of infected mice were decreased compared with the respective controls.6.Compared with the respective control group,the levels of serum TC,TG,HDL-L,LDL-L in mice of S.japonicum infected group dropped significantly.7.RT-PCR results showed that hepatic miR-802 expression in infected group was significantly decreased and m RNA level of Hnf1 b was increased.More significant change was observed in Lepr^db/db mice.8.RT-PCR results showed that m RNA levels of some proinflammatory and anti-inflammatory cytokines,including TNF-α,IL-6,IL-22 and IL-4,in 6w infected group were significantly higher than those in the control group.Lepr^db/db mice showed more obvious change.9.In vitro results showed that miR-802 expression in murine hepatocytes line were downregulated with IL-22 stimulation and upregulated with TNF-α treatment.To sum up,we found that Schistosoma japonicum infection could improve hepatic insulin sensitivity possibly through downregulating miR-802 expression in obese mice.These experimental evidences may provide further guide in the prevention and control of type 2 diabetes mellitus.