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TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis.

  • Author(s): Inokuchi-Shimizu, Sayaka
  • Park, Eek Joong
  • Roh, Yoon Seok
  • Yang, Ling
  • Zhang, Bi
  • Song, Jingyi
  • Liang, Shuang
  • Pimienta, Michael
  • Taniguchi, Koji
  • Wu, Xuefeng
  • Asahina, Kinji
  • Lagakos, William
  • Mackey, Mason R
  • Akira, Shizuo
  • Ellisman, Mark H
  • Sears, Dorothy D
  • Olefsky, Jerrold M
  • Karin, Michael
  • Brenner, David A
  • Seki, Ekihiro
  • et al.

Published Web Location

https://doi.org/10.1172/JCI74068
Abstract

The MAP kinase kinase kinase TGFβ-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGFβ and in turn activates IKK-NF-κB and JNK, which regulate cell survival, growth, tumorigenesis, and metabolism. TAK1 signaling also upregulates AMPK activity and autophagy. Here, we investigated TAK1-dependent regulation of autophagy, lipid metabolism, and tumorigenesis in the liver. Fasted mice with hepatocyte-specific deletion of Tak1 exhibited severe hepatosteatosis with increased mTORC1 activity and suppression of autophagy compared with their WT counterparts. TAK1-deficient hepatocytes exhibited suppressed AMPK activity and autophagy in response to starvation or metformin treatment; however, ectopic activation of AMPK restored autophagy in these cells. Peroxisome proliferator-activated receptor α (PPARα) target genes and β-oxidation, which regulate hepatic lipid degradation, were also suppressed in hepatocytes lacking TAK1. Due to suppression of autophagy and β-oxidation, a high-fat diet challenge aggravated steatohepatitis in mice with hepatocyte-specific deletion of Tak1. Notably, inhibition of mTORC1 restored autophagy and PPARα target gene expression in TAK1-deficient livers, indicating that TAK1 acts upstream of mTORC1. mTORC1 inhibition also suppressed spontaneous liver fibrosis and hepatocarcinogenesis in animals with hepatocyte-specific deletion of Tak1. These data indicate that TAK1 regulates hepatic lipid metabolism and tumorigenesis via the AMPK/mTORC1 axis, affecting both autophagy and PPARα activity.

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