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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3566-3578
Number of pages13
JournalJournal of Clinical Investigation
Volume124
Issue number8
DOIs
StatePublished - Aug 1 2014
Externally publishedYes

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Autophagy
Carcinogenesis
Phosphotransferases
Fatty Acids
AMP-Activated Protein Kinases
Hepatocytes
Peroxisome Proliferator-Activated Receptors
Liver
Lipid Metabolism
MAP Kinase Kinase Kinases
Metformin
High Fat Diet
Fatty Liver
Starvation
Interleukin-1
Liver Cirrhosis
Cell Survival
Up-Regulation
mechanistic target of rapamycin complex 1
Lipids

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Inokuchi-Shimizu, S., Park, E. J., Roh, Y. S., Yang, L., Zhang, B., Song, J., ... Seki, E. (2014). TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. Journal of Clinical Investigation, 124(8), 3566-3578. https://doi.org/10.1172/JCI74068

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

In: Journal of Clinical Investigation, Vol. 124, No. 8, 01.08.2014, p. 3566-3578.

Research output: Contribution to journalArticle

Inokuchi-Shimizu, S, Park, EJ, Roh, YS, Yang, L, Zhang, B, Song, J, Liang, S, Pimienta, M, Taniguchi, K, Wu, X, Asahina, K, Lagakos, W, Mackey, MR, Akira, S, Ellisman, MH, Sears, DD, Olefsky, JM, Karin, M, Brenner, DA & Seki, E 2014, 'TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis', Journal of Clinical Investigation, vol. 124, no. 8, pp. 3566-3578. https://doi.org/10.1172/JCI74068
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. / TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 8. pp. 3566-3578.
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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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AU - Inokuchi-Shimizu, Sayaka

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AU - Roh, Yoon Seok

AU - Yang, Ling

AU - Zhang, Bi

AU - Song, Jingyi

AU - Liang, Shuang

AU - Pimienta, Michael

AU - Taniguchi, Koji

AU - Wu, Xuefeng

AU - Asahina, Kinji

AU - Lagakos, William

AU - Mackey, Mason R.

AU - Akira, Shizuo

AU - Ellisman, Mark H.

AU - Sears, Dorothy D.

AU - Olefsky, Jerrold M.

AU - Karin, Michael

AU - Brenner, David A.

AU - Seki, Ekihiro

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