Metabolic and Immune Regulation of Non-Viral Hepatocellular Carcinoma: Basic Mechanisms and New Translational Opportunities

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder whose global prevalence is estimated to be ~25%. NAFLD typically manifests as benign hepatic steatosis, but ~20% of patients present non-alcoholic steatohepatitis (NASH), an aggressive form associated with inflammation and liver damage. The mechanisms controlling the switch from benign steatosis to NASH are poorly understood but were suggested to depend on ER stress. To query the role of ER stress in NASH development and establish a proper mouse model, we fed high-fat diet (HFD) to MUP-uPA mice, which are prone to liver ER stress. HFD triggered full-blown NASH in these mice within 3-4 months and most of the NASH-afflicted mice developed hepatocellular carcinoma (HCC), the main form of liver cancer whose incidence greatly increases with steatohepatitis. NASH and HCC development in MUP-uPA mice depend on ER stress and are associated with persistent activation of sterol response element binding proteins (SREBP) 1 and 2. SREBP1 activation drives de novo lipogenesis (DNL) and cholesterol biosynthesis in HFD-fed MUP-uPA mice remains elevated without any sign of feedback inhibition mechanisms that control SREBP2 activation in tissue culture. DNL and cholesterol synthesis are chronically elevated during NASH and the hepatic accumulation of free cholesterol was suggested to be a key switch from simple steatosis to NASH. While investigating how ER stress leads to persistent SREBP activation, we uncovered a previously unknown pathway in which caspase-2 (Casp2) leads to constitutive activation of site 1 protease (S1P), which initiates SREBP cleavage activating protein (SCAP)-independent SREBP activation. Genetic ablation or pharmacological inhibition of Casp2 in MUP-uPA mice blocks NASH development by preventing hepatic steatosis, and Casp2 ablation in both MUP-uPA and BL6 mice prevents HFD-induced adipocyte hypertrophy and increases energy consumption. The NAFLD/NASH epidemic was also suggested to be associated with increased consumption of fructose, a major constituent of the common sweetener high-fructose corn syrup (HFCS). Increased HFCS consumption has been linked to elevated risk of HCC, pancreatic, and colon cancers. MUP-uPA mice fed high-fructose diet (HFrD) develop NASH/HCC without the peripheral obesity that accompanies HFD consumption. Although fructose was believed to cause hepatic steatosis through preferential uptake and direct incorporation into the glycolytic pathway in hepatocytes, recent results indicate that fructose is first metabolized in the small intestine. Correspondingly, we found that fructose gives rise to NASH and HCC by first disrupting the intestinal epithelial barrier, evoking an inflammatory response that drives NASH/HCC development.