It TAK(es) 1 to prevent steatohepatitis and tumorigenesis.

Article commented: TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis. Comment: TAK1 (TGF-β activated kinase 1) is activated by TLRs, IL-1, TNF, and TGF-β, and in turn, regulates two main transcription factors, IKK/NF-κB and JNK, which control a plethora of essential cellular functions such as cell proliferation, survival, growth, inflammation, tumorigenesis, insulin sensitivity and lipid metabolism. 1 While sustained JNK signaling has been known to exert pathophysiological effects on the liver by causing inflammation, cell death, reactive oxygen species (ROS) generation, lipid accumulation and hepatocellular carcinoma (HCC), 2 IKK/NF-κB signaling has been shown to prevent TNF-and ROS-mediated cell death, steatosis and HCC. 3 Since TAK1 regulates both IKK/NF-κB and JNK pathways with seemingly contrasting effects, 2,3 its role in liver has been difficult to envisage. These authors previously showed that hepatocyte-specific ablation of TAK1 led to spontaneous liver inflammation, apoptosis, fibrosis and HCC development, mediated through TNF-and TGF-β signaling. 4 In addition to regulating IKK/NF-κB and JNK, TAK1 signaling is also believed to enhance AMPK-mediated autophagy. 5 Since AMPK is a metabolic sensor, it is activated upon nutrient deprivation, and in turn suppresses mTORC1 complex, a regulator of lipid metabolism and autophagy. 6 Under of nutrient excess, conditions, when ATP levels are high, AMPK activity is suppressed leading to activation of mTORC1, and thereby increased lipid biosyn-thesis via upregulation of ppar γ and SREBP1c. 7 In addition, mTORC1 is also known to inhibit ppar alpha , which regulates hepatic fatty acid oxidation (FAO). 8 AMPK activation and mTORC1 inhibition regulate autophagy, to remove and recycle cellular components, during a phase with limited nutrients. Autophagy promotes lipid breakdown and inhibits li-pid storage. 9 In this elegant work, the authors have expanded our understanding of this enigmatic and important regulator by clarifying the metabolic function of TAK1, and the pathophysiological relevance of TAK1 regulating autophagy and lipid metabolism through AMPK/mTORC1, and therefore, its effect on liver metabolism and liver tumorigenesis. 9 To address the physiological role of TAK1 in the liver, the authors first assessed the effect of acute fasting on 1 month old WT (wild type) mice, and mice carrying a hepatocyte-specific deletion of TAK1. After 12 hours of fasting, they found that the livers of Δhep TAK1 mice showed hepatic steatosis and had significantly elevated hepatic triglycerides. Hepato-cytes isolated from such mice showed lipid accumulation , relative to their WT counterparts. Furthermore, liver lysates from fasted Δhep TAK1 …