Final Report Summary - OBECAN (Role of obesity in the development of hepatocellular carcinoma) Our group, funded by the Starting Grant ERC program (OBECAN-260464), has been studying for the last years the molecular mechanisms that control obesity-driven HCC development. Our main goal was to establish which factors associated with obesity could predispose to the development of HCC. We focused on inflammation, steatosis and hyperinsulinemia, evaluating the signalling pathways that might control these processes. As a result of our work, we have demonstrated that p38γ/δ control inflammation in liver. These kinases in macrophages induce TNFα expression through eEF2 activation. In fact, mice lacking p38γ/δ are protected against LPS-induced hepatitis(Gonzalez-Teran et al., 2013). These results suggest that inhibition of these kinases might be a good therapy for inflammatory diseases. Based on these data, we decided to study whether p38γ/δ were also involved in the development of obesity-induced steatosis and diabetes. We found that the expression of p38γ/δ increases in liver from obese humans and in mouse models of diet-induced steatosis. We found that mice lacking p38γ/δ protein kinases are protected against steatosis development in three different models of diet-induced steatosis (high fat diet, methionine-choline deficient diet and high fat high fructose diet)(Gonzalez-Teran et al., 2016b). We have found the importance of p38γ/δ in neutrophils in the development of steatosis. Using animals lacking p38γ/δ in myeloid cells or only in neutrophils we have described that these kinases in neutrophils control the recruitment to liver during inflammation. Moreover, the lack of neutrophils infiltration in mice lacking p38gamma and delta was enough to protect the mice against high fat diet induced steatosis and diabetes in several animal models. As it is established that steatosis and obesity are linked to the HCC development(Dyal et al., 2016), we next evaluated whether these kinases play an important role in the development of liver cancer. Moreover, we have been studying the role of this pathway in adipose tissue and how adipose tissue could be responsible of the higher incidence of HCC in obese patients. In this regard, we have found that there is a cross talk between the adipose tissue and the liver that could control HCC development. In this crosstalk JNK play an important role.Finally, we have found that increased lipid oxidation in liver during obesity could be more deleterious that accumulation of triglycerides in liver.
