| First Author | Inokuchi-Shimizu S | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 8 | Pages | 3566-78 |
| PubMed ID | 24983318 | Mgi Jnum | J:213859 |
| Mgi Id | MGI:5586755 | Doi | 10.1172/JCI74068 |
| Citation | Inokuchi-Shimizu S, et al. (2014) TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. J Clin Invest 124(8):3566-78 |
| abstractText | The MAP kinase kinase kinase TGFbeta-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGFbeta and in turn activates IKK-NF-kappaB 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 alpha (PPARalpha) 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 PPARalpha 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 PPARalpha activity. |
