2017 research grant award spotlight: green, “the role of hepatic xbp1 in cholestatic liver injury”

Each year, PSC Partners asks research grant awardees to share a lay summary as part of our grant process.  In order to make this information more digestible and shine a light on each individual study, we will share a summary each week (in alphabetical order of the Principal Investigator’s last names).  We welcome your comments or thoughts for the researchers at the bottom of each of these blog posts, and are excited to share this new PSC-related research with you!

Title: The Role of Hepatic XBP1 In Cholestatic Liver Injury

Principal Investigator:
Richard M. Green, MD, Professor of Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL

Brief Lay Summary:
Primary Sclerosing Cholangitis (PSC) is a disease of the bile ducts that can progress to fibrosis (scarring), cirrhosis, end-stage liver disease and liver cancer. Although the initial damage in PSC typically occurs in the large bile ducts, disease progression is characterized by injury to the hepatocytes (primary liver cells) and other cells in the liver. PSC is a form of cholestatic liver disease. Cholestasis is a term used to describe the impairment of bile secretion, and can damage the liver due to bile acid toxicity. Bile acids are made by the liver and secreted into bile, but they can injure the liver when secretion is impaired and bile acid levels increase. A protein termed X-box binding protein-1 (XBP1) is a protective liver protein that may be impaired in many liver diseases. However, the role of XBP1 in PSC and other cholestatic liver diseases is essentially unexplored. We have developed mice that lack XBP1 in hepatocytes and we will utilize these mice to determine the effect of XBP1 on cholestatic liver injury. Mice will undergo a bile duct ligation (obstruction of the bile duct), which is a widely utilized model of cholestatic diseases such as Primary Sclerosing Cholangitis. We will determine whether diminished XBP1 in liver cells causes the rapid development of liver injury and cirrhosis. In addition, the MDR2-knockout mouse (mice lacking a protein termed MDR2) is a frequently utilized murine model of PSC. We will develop MDR2-knockout mice with diminished XBP1 in the liver. These mice will be studied to determine if they are more susceptible to develop progressive liver disease, liver malignancies and bile duct cancers (cholangiocarcinoma). By determining the role of hepatic XBP1 in Primary Sclerosing Cholangitis, we can develop novel pharmacologic and other therapies targeting XBP1 for the treatment of patients with PSC.