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

Autor: Gong J; Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.; Institute of Model Animals of Wuhan University, Wuhan, China., Fang C; School of Basic Medical Sciences, Wuhan University, Wuhan, China.; Institute of Model Animals of Wuhan University, Wuhan, China.; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China., Zhang P; School of Basic Medical Sciences, Wuhan University, Wuhan, China.; Institute of Model Animals of Wuhan University, Wuhan, China.; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China., Wang PX; School of Basic Medical Sciences, Wuhan University, Wuhan, China.; Institute of Model Animals of Wuhan University, Wuhan, China.; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China., Qiu Y; Lab of Animal Models and Functional Genomics (LAMFG), College of Veterinary Medicine, Hunan Agricultural University, Changsha, China.; TCM and Ethnomedicine Innovation & Development Laboratory, Sino-Pakistan TCM Research Center, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China., Shen LJ; School of Basic Medical Sciences, Wuhan University, Wuhan, China.; Institute of Model Animals of Wuhan University, Wuhan, China.; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China., Zhang L; School of Basic Medical Sciences, Wuhan University, Wuhan, China.; Institute of Model Animals of Wuhan University, Wuhan, China.; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China., Zhu XY; School of Basic Medical Sciences, Wuhan University, Wuhan, China.; Institute of Model Animals of Wuhan University, Wuhan, China.; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China., Tian S; School of Basic Medical Sciences, Wuhan University, Wuhan, China.; Institute of Model Animals of Wuhan University, Wuhan, China.; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China., Li F; School of Basic Medical Sciences, Wuhan University, Wuhan, China.; Institute of Model Animals of Wuhan University, Wuhan, China., Wang Z; School of Basic Medical Sciences, Wuhan University, Wuhan, China.; Institute of Model Animals of Wuhan University, Wuhan, China.; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China., Huang Z; Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China., Wang A; Lab of Animal Models and Functional Genomics (LAMFG), College of Veterinary Medicine, Hunan Agricultural University, Changsha, China., Zhang XD; Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China., She ZG; School of Basic Medical Sciences, Wuhan University, Wuhan, China.; Institute of Model Animals of Wuhan University, Wuhan, China.; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Jazyk: angličtina
Zdroj: Hepatology (Baltimore, Md.) [Hepatology] 2019 Feb; Vol. 69 (2), pp. 524-544. Date of Electronic Publication: 2018 May 15.
DOI: 10.1002/hep.29820
Abstrakt: 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.
(© 2018 by the American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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