Nod2 regulation of AMP-kinase modulates obesity-associated liver cancer 9086

Description Nod2 is an innate immunity protein in host defense against bacteria. Nod2 deficiency is associated with inflammatory diseases, and diet-induced obesity, metabolic dysfunction, and liver cancer. We have previously shown that Nod2 protects from high fat diet (HFD)-dependent obesity and metabolic syndrome. We have also shown that that Nod2-/- mice treated with the carcinogen dimethylbenz[a]-anthracene (DMBA) and maintained on HFD have increased sensitivity to hepatic tumorigenesis compared with WT mice. Livers of Nod2-/- tumorigenic mice had elevated expression of genes involved in cell proliferation, immune responses, and cholesterol biosynthesis, increased infiltration of neutrophils, inflammatory monocytes, and T cells, and increased activation of STAT3 and ERK. We now show that liver cells in Nod2-/- mice treated with DMBA and maintained on HFD have decreased activation of AMP-dependent kinase (AMPK) compared with similarly treated WT mice. This results in increased activation of mTORC1 and p70S6K and inhibition of 4EBP1 in Nod2-/- liver cells, which likely results in increased translation. In Nod2-/- mice there is increased activation of acetyl CoA carboxylase, which likely results in increased fatty acid synthesis and a fatty liver. In summary, we demonstrate that Nod2 protects from HFD-dependent obesity and liver malignancy and that decreased activation of AMPK and the AMPK-pathway in the absence on Nod2 contributes to the pathology.