TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis
Sayaka Inokuchi-Shimizu, … , David A. Brenner, Ekihiro Seki
Sayaka Inokuchi-Shimizu, … , David A. Brenner, Ekihiro Seki
Published July 1, 2014
Citation Information: J Clin Invest. 2014;124(8):3566-3578. https://doi.org/10.1172/JCI74068.
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Research Article Hepatology

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

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.

Authors

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

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Figure 3

Gene expression involved in FAO and induction of FAO are suppressed inTak1Δhepmice.

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Gene expression involved in FAO and induction of FAO are suppressed inT...
One-month-old WT and Tak1Δhep mice were fasted for 12 hours (n = 5 each). (A) Hepatic expression of FAO-related genes (Ppara, Hmgcs2, Cpt1a, Acox1, Cyp4a10, and Sirt3) was measured by quantitative real-time PCR. (B) FAO was measured in WT and Tak1Δhep mice in vivo. 5 μCi [14C] palmitate was injected into mice with or without fasting, and hepatic FAO was measured. FAO is shown as the fold change compared with WT fed controls. (C) mRNA expression of ApoB and Mttp was measured by quantitative real-time PCR. (D) VLDL secretion rate was measured. Black bar, WT; gray bar, Tak1Δhep mice. Data are presented as the means ± SEM. *P < 0.05; **P < 0.01.