Succinate aggravates NAFLD progression to liver cancer on the onset of obesity: An in silico model

Abstract

The incidence and prevalence of nonalcoholic fatty liver disease (NAFLD) have been increasing to epidemic proportions around the world. NAFLD, a chronic liver disease that affects the nondrinkers, is mainly associated with steatohepatitis and cirrhosis. The progression of NAFLD associated with obesity increases the risk of liver cancer, a disease with poor outcomes and limited therapeutic options. In order to investigate the underlying cellular dynamics leading to NAFLD progression towards cancer on the onset of obesity, we have integrated human hepatocyte pathway with hypoxia-inducible factor1-[Formula: see text] (HIF1-[Formula: see text]) signaling pathway using state space model based on classical control theory. Modified Michaelis–Menten equation and mass action law have been used to define flux vectors of the proposed model. We have incorporated feedback inhibition/activation and allosteric effects into the simulink-based model. The values of kinetic constants have been taken from the literature. It is found that on the onset of obesity, HIF1-[Formula: see text]-induced proteins stabilize approximately 62 times that in the case of a normal cell. Consequently, the HIF1-[Formula: see text]-induced proteins enhance the enzymatic activities of hexokinase (HK), phosphofructo kinase (PFK), lactate dehydrogenase (LDH), and pyruvate dehydrogenase (PDH), which induce Warburg effect promoting an environment suitable for cancer cells.