Mechanisms Of Tumor Progression Locus 2(TPL2)in The Development Of Nonalcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease(NAFLD)has become the most common chronic liver disease worldwide according to the development of human society and economy,improvement of living standards and the changes in dietary structure.Non-alcoholic steatohepatitis(NASH),a pathological form of NAFLD,is the important step from simple steatosis to cirrhosis and hepatocellular carcinoma.As the common pathological basis and core mechanism of many metabolic diseases and severe liver injury,NASH is characterized by lipid accumulation,chronic inflammation,insulin resistance,and liver dysfunction.The causes of NASH include genetic,metabolic,environmental and lifestyle factors.The well supported "second hit theory" thought that,hepatocyte lipid accumulation,insulin resistance,and inflammatory response promote each other and form a vicious circle in the development of NAFLD.Therefore,finding a key target to comprehensively control insulin resistance,lipid accumulation,and inflammatory response may be shortcut to prevent and control NASH.Tumor progression locus 2(TPL2),an important kinase of the MAPK signaling promotes inflammatory responses and promotes disease progression though ERK,JNK,and other signals in variety of diseases.Prior studies have provided evidence for the role of TPL2 in obesity-induced insulin resistance,inflammation and metabolic dysfunction.However,the function of TPL2 in regulating hepatocyte metabolism and liver inflammation during the development of NAFLD remains unclear.Here,we report the function and mechanism of TPL2 in the development of NAFLD.Firstly,we find the expression of TPL2 was significantly increased in fatty liver from human patients and nonhuman primates with NAFLD,and expression profile tends to be positively correlated with the development of NAFLD.This finds were further validated in a variety of mouse NAFLD and primary hepatocyte models.Then,hepatocyte-specific TPL2 knockout(TPL2 HKO)and o-verexpression(TPL2 HTG)mice were constructed and fellowed by high-fat diet fed for 12 continuous weeks,respectively.We found that compared to wild-type littermates,hepatocyte-specific TPL2 knockout mice exhibited improved lipid and glucose imbalance,reserved insulin sensitivity and alleviated inflammation in response to high-fat diet(HFD)feeding.While,overexpression of TPL2 in hepatocytes led to the opposite phenotype.Regarding the mechanism,we focused on MAPK signaling,which is an important signaling event during the development of NAFLD,and found that changes in TPL2 directly affect the activation of JNK signaling.Additionally,TPL2 TPL2 directly-induced and specifically interacts with MKK7 and sustains JNK 1/2 activation.To confirm whether the TPL2-MKK7-JNK axis is required for NAFLD associated pathologies,TPL2 HTG mice and its control WT mice were infected with AdshMKK7 or AdshRNA through tail vein injection,respectively.We found that the inhibition of MKK7 activation strongly suppressed HFD-induced IR in TPL2-HTG/AdshMKK7 mice.Furthermore,insulin resistance,dysglycemia,and lipid accumulation were all improved in mice with genetically obese mice injected with AdshTPL2.Our results clearly indicated that TPL2 activates the JNK signaling in hepatocytes upon HFD feeding to promote NAFLD progression by directly binding and phosphorylating MKK7.In conclusion,the data presented here suggest that in hepatocytes,TPL2 plays a pathologically important role in regulating liver and systemic metabolic disorders stemming from chronic low-grade inflammation,and this role is largely dependent on specific activation of downstream MKK7-JNK1/2 signaling.The TPL2-MKK7-JNK axis in hepatocytes is a promising drug target for the treatment of NAFLD and metabolic disorders.Our study further improved the pathogenesis of non-alcoholic fatty liver disease and provided a new feasible solution for drug development of the prevention/treatment of NAFLD and metabolic diseases.