Role of the pseudokinase tribbles 3 in the development of non-alcoholic steatohepatitis and its progression to hepatocellular carcinoma

Résumé

Liver is one of the largest and most important metabolic organ of human body. It is responsible for vital functions such as digestion, blood detoxification, metabolism and distribution of nutrients and energy to the rest of the body. All these functions make the liver more exposed to harmful substances than other organs and hence, more vulnerable to injury. Liver disease is an important cause of morbidity and mortality worldwide affecting both adults and children.In the last few years non-alcoholic fatty liver disease (NAFLD) have emerged as major contender and is now considered the world’s most common chronic liver disease, with its prevalence increasing parallelly with the rising risk in diabetes and obesity - a fact that is associated to changes in our lifestyle including bad dietary habits, a more sedentary life and excessive drug consumption, among others. Liver damage, depending on the cause and whether it is detected early may be reversible, although in most cases including NAFLD, the disease chronifies and progresses over time non-alcoholic steatosis (NASH) to cirrhosis and finally to hepatocellular carcinoma (HCC), which is an irreversible condition with poor prognosis. Despite the increased incidence of liver disease, the molecular mechanisms involved in its development and progression have not been fully elucidated, which largely limits the availability of more effective therapeutic treatments. Furthermore, in most cases the disease is detected at an advanced stage and lacks an established treatment. For all these reasons, a better understanding of the mechanisms underlying liver disease is crucial for the development of more effective therapeutic and preventive strategies. Tribbles proteins (and specifically TRIB3) have been implicated in the regulation of metabolism and cancer development and progression in various animal models. Likewise, TRIB3 upregulation has been shown to play an important role in the mechanism of action of several anticancer agents. Therefore, in this doctoral thesis, we studied the role of TRIB3 in the development and progression of NAFLD-NASH-HCC. To this aim, we used different experimental approaches to analyze the effect the loss / genetic inactivation has on the disease pathogenesis. We used dietary, cellular and genetic models to better understand the role of TRIB3 in the disease development. Along this line, we have shown that the genetic inhibition of TRIB3 induces steatosis and inflammation in the dietary NAFLD-NASH models. Additonally, we have shown that loss of TRIB3 in hepatocytes alters the morphology of the lipids accumulated which can be due to the altered lipohagy and/or mitochondrial respiration5, while the loss in the immune cells leads to an aggravated disease phenotype with increase in steatosis and inflammation which in part may be explained by the activation of the NF-kb pathway. Spontaneous accumulation of fat and fibrosis was also seen in older Trib3 -/- (TRIB3 KO) animals (8 and 12 months), a phenotype enhanced in Trib3 -/- x Gnmt -/- (double mutants, GNMT KO mice spontaneously develop HCC). Genetic inactivation of TRIB3 enhances the tumorigenic properties in the GNMT KO model, as observed with the increase in the frequency of tumors in the double mutants. This study will be helpful in identifying the role of TRIB3 in NAFLD-NASH and its progression to HCC, establishing its role on the regulation of the interplay between immune system, adipose tissue and transformed epithelial tissue. It would also help in the identification of possible novel anticancer treatments based in the modulation of the levels and function of TRIB3. Taken together, the data obtained in this work support the idea that TRIB3 may be involved in the pathogenesis of liver disease, particularly in the regulation of the interplay between immune system, adipose tissue and transformed epithelial tissue.