3 years ago

Tumor progression locus 2 in hepatocytes potentiates both liver and systemic metabolic disorders.

Feng Li, Li Zhang, Zan Huang, Zhihua Wang, Xiao-Dong Zhang, Pi-Xiao Wang, Peng Zhang, Xue-Yong Zhu, Zhi-Gang She, Chun Fang, Gong Jun, Aibing Wang, Li-Jun Shen, Song Tian, Yixing Qiu
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 non-alcoholic 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 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. Overexpression of TPL2 in hepatocytes led to the opposite phenotype. Regarding the mechanism, we found that MKK7 was the specific substrate of TPL2 for JNK activation. TPL2-MKK7-JNK signaling in hepatocytes represents a promising drugable target for treating NAFLD and associated metabolic disorders.

Publisher URL: http://doi.org/10.1002/hep.29820

DOI: 10.1002/hep.29820

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