The Unfolded Protein Response in Fatty Liver

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver function tests in the United States. NAFLD is a major cause of cirrhosis, hepatocellular carcinoma, need-for-liver transplantation and death. Although fatty liver disease is associated with the metabolic syndrome, the pathogenesis remains poorly understood. In the liver, the fidelity for protein folding is imperfect, and therefore excess misfolded or unfolded proteins may accumulate, a condition termed ER stress. The Unfolded Protein Response (UPR) is a protective signaling response present in all eukaryotic cells, and animal and human studies indicate that the UPR is important in NAFLD, and its progressive sub-type termed non-alcoholic steatohepatitis (NASH). However, the role and mechanisms of UPR signaling in the pathogenesis of NASH remains poorly understood.We now propose three Specific Aims to further investigate the role of the IRE1 alphasignaling in the pathogenesis of steatohepatitis. We will: determine the role of hepatic IRE1alpha/Xbp1 signaling in the pathogenesis of non-alcoholic steatohepatitis usingmice fed high fat diets (Aim 1); determine the interactive role of hepatic IRE1alphasignaling and the PERK/p-eIF2a/ATF4 pathway in the pathogenesis of steatohepatitis (Aim 2); and utilize liver-specific cell cultures and isolated hepatocytes to determine the role of IRE1alpha/Xbp1 signaling in cell fate determination during hepatocyte lipotoxicity. These investigations combine complimentary molecular and cellular biology, physiology and genetics approaches to enhance our understanding of the role of the hepatic UPR pathways in steatohepatitis.