Role of Inflammation in Control of Hepatic Lipid Metabolism—New Insights to the Pathogenesis of NASH

Abstract

Non‐alcoholic fatty liver disease (NAFLD) is a common metabolic disorder whose incidence among US adults exceeds 30%. While NAFLD manifests as benign hepatic steatosis in most patients, in about 20% of patients it assumes a much more aggressive form – non‐alcoholic steatohepatitis (NASH). The mechanisms that control 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 for studying the disease, we fed high‐fat diet (HFD) to MUP‐uPA mice, which are prone to liver ER stress due to hepatocyte‐specific urokinase plasminogen activator (uPA) expression. Placing these mice on HFD triggered full‐blown NASH within 3–4 months and most of the NASH‐afflicted mice progressed to develop hepatocellular carcinoma (HCC), the most common form of liver cancer whose incidence and development rates greatly increase with steatohepatitis. Both 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 cells. DNL and cholesterol synthesis are also chronically elevated in NASH patients and the hepatic accumulation of free cholesterol was suggested to be a key switch from simple steatosis to NASH. While investigating the mechanism by which 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. Of note, genetic ablation or pharmacological inhibition of Casp2 in MUP‐uPA mice blocks NASH development by preventing hepatic steatosis. Casp2 ablation in both MUP‐uPA and BL6 mice also prevents HFD‐induced adipocyte hypertrophy and increases energy consumption. None of the effects of Casp2 on liver lipid metabolism are related to cell death. The NAFLD/NASH epidemic was also suggested to be associated with increased consumption of fructose, which is a major constituent of high‐fructose corn syrup (HFCS), the main sweetener and a general food additive in the US. Increased consumption of HFCS has been linked to elevated risk of developing HCC, pancreatic and colon cancer. Indeed, feeding MUP‐uPA mice a high‐fructose diet (HFrD) results in NASH and HCC development even without the peripheral obesity that accompanies HFD consumption. Although fructose was believed to give rise to hepatic steatosis through preferential uptake and direct incorporation into the glycolytic pathway in hepatocytes, recent results indicate that the first site of fructose metabolism is 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 both NASH and HCC development.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.