Tumor Progression Locus 2 in Hepatocytes Potentiates Both Liver and Systemic Metabolic Disorders in Mice

Tumor progression locus 2 (TPL2), a serine/threonine kinase, has been regarded as a potentially interesting target for the treatment of various diseases with an inflammatory component. However, the function of TPL2 in regulating hepatocyte metabolism and liver inflammation during the progression of nonalcoholic fatty liver disease (NAFLD) is poorly understood. Here, we report that TPL2 protein expression was significantly increased in fatty liver from diverse species, including humans, monkeys, and mice. Further investigations revealed that compared to wild‐type (WT) littermates, hepatocyte‐specific TPL2 knockout (HKO) mice exhibited improved lipid and glucose imbalance, reserved insulin sensitivity, and alleviated inflammation in response to high‐fat diet (HFD) feeding. Overexpression of TPL2 in hepatocytes led to the opposite phenotype. Regarding the mechanism, we found that mitogen‐activated protein kinase kinase 7 (MKK7) was the specific substrate of TPL2 for c‐Jun N‐terminal kinase (JNK) activation. TPL2‐MKK7‐JNK signaling in hepatocytes represents a promising drugable target for treating NAFLD and associated metabolic disorders. Conclusion: In hepatocytes, TPL2 acts as a key mediator that promotes both liver and systemic metabolic disturbances by specifically increasing MKK7‐JNK activation.