Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 124, Issue 8, Pages 3566-3578Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI74068
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Funding
- NIH [R01AA02172, R01DK085252, R01CA155120, P42 ES010337, R01AA020753]
- UCSD Digestive Diseases Research Development Center [DK080506]
- National Natural Science Foundation of China [30500658, 81370550]
- American Liver Foundation
- postdoctoral fellowship from Susan G. Komen for the Cure [KG111506]
- Postdoctoral Fellowship for Research Abroad
- Japan Society for the Promotion of Science
- Uehara Memorial Foundation Fellowship
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The MAP kinase kinase kinase TGF beta-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGF beta and in turn activates IKK-NF-kappa beta 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 a (PPAR alpha) target genes and beta-oxidation, which regulate hepatic lipid degradation, were also suppressed in hepatocytes lacking TAK1. Due to suppression of autophagy and beta-oxidation, a high-fat diet challenge aggravated steatohepatitis in mice with hepatocyte-specific deletion of Tak1. Notably, inhibition of mTORC1 restored autophagy and PPAR alpha 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 PPAR alpha activity.
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