Liver injury caused by alcohol consumption, hepatitis virus infection, obesity, or drug abuse induces hepatitis and steatohepatitis. Chronic liver injury leads to liver fibrosis and cirrhosis. Although liver cirrhosis is irreversible, recent studies sugest that liver fibrosis is reversible. However, no drugs are currently available for patients with live fibrosis. Thus, understanding the pathogenesis of fibrosis and finding therapeutic targets are important for the prevention of cirrhosis progressed from fibrosis and for reducing medical costs. The long-term goals of our study are to determine the contribution of different types of mesenchymal cells in liver fibrosis and to identify therapeutic targets for suppression of liver fibrosis. Hepatic stellate cells (HSCs) differentiate into myofibroblasts that synthesize collagen and proinflammatory cytokines and participate in fibrogenesis. In addition to HSCs, capsular fibroblasts (CFs) beneath the mesothelium and portal fibroblasts (PFs) around the bile duct can also suggested to differentiate into myofibroblasts. However, their contribution to liver fibrosis remains elusive due to insufficient availability of markers and isolation methods for studying different mesenchymal cell types in liver. In patients with alcoholic liver fibrosis, Glisson's capsule beneath the mesothelium becomes thick and massive deposition of collagen is frequently observed. Although CFs in Glisson's capsule are morphologically characterized, little is known about their markers and roles in fibrosis. This application will use a new humanized Glisson's capsule model induced by chlorhexidine gluconate in mouse livers that provides a unique opportunity to study the effect of alcohol on capsular fibrosis. Using our unique mouse model, we will trace CFs in alcohol-induced liver injury in Aim 1.
In Aim 2, we will isolate CFs from normal Col1a1GFP mouse livers by FACS and identify genes expressed in CFs by comparing expression profiles of CFs to those of HSCs and PFs. We will also establish PF-specific CreERT2 mouse lines for tracing PFs in mouse liver fibrosis. This application will present novel approaches to the study of CF- and PF-mediated liver injury in Glisson's capsule.
Alcohol abuse results in liver fibrosis and cirrhosis. The proposed study will determine roles of different liver mesenchymal cells in alcohol-induced liver injury. The knowledge obtained from this study will help target particular cell types in the liver aimed at suppressing conversion to myofibroblasts and fibrogenesis.