Research Areas

Innate Immune Signaling in Liver Disease

Liver fibrosis (hepatic fibrosis) is a wound-healing response that is a consequence of chronic liver diseases such as hepatitis B and C infections, autoimmune hepatitis, nonalcoholic steatohepatitis (NASH) and alcoholic liver disease (ALD). Liver cirrhosis, the end stage of hepatic fibrosis, is associated with hepatocellular dysfunction, increased intrahepatic resistance to blood flow and hepatocyte dysplasia, which may lead to hepatic failure, portal hypertension and hepatocellular carcinoma. Currently, there is no treatment or cure for liver fibrosis, and liver transplantation is the only effective therapy. However, the number of cirrhotic patients requiring liver transplants is greater than the supply of donor livers. To develop novel effective therapies for liver fibrosis, we must identify the effective molecular targets. The focus of our research is the study of the molecular mechanism underlying liver fibrosis.

In chronic liver disease, activated hepatic stellate cells (HSCs) transdifferentiate into myofibroblasts, which are a principal cell type for producing extracellular matrix (ECM) proteins (collagen type I, III and IV), which cause liver fibrosis. TGF-β and PDGF are the two major mediators for activating HSCs. In the liver, Kupffer cells (liver resident macrophages) are a primary source of inflammatory and fibrogenic cytokines (TNF-α, IL-6, MCP-1, IL-1 and TGF-β). Activated HSCs also express cytokines and chemokines. These inflammatory and fibrogenic mediators participate in the activation and migration of HSCs and Kupffer cells. The activation of inflammatory and fibrogenic pathways and the interaction between Kupffer cells and HSCs are crucial events for HSC activation and liver fibrosis.

Currently, the Seki Laboratory is focusing on three major research topics:

  • Toll-like receptor signaling in chronic liver disease (liver fibrosis, alcoholic and nonalcoholic steatohepatitis, and hepatocellular carcinoma).
  • Chemokine and chemokine receptor interaction in the progression of chronic liver disease.
  • TAK1 mediated signaling in liver fibrosis and hepatocellular carcinoma.

Our study uses experimental animal models of toxin- and cholestasis-induced liver fibrosis, alcoholic and nonalcoholic steatohepatitis and chemical-induced liver cancer on genetically modified animals.

Our laboratory isolates high-quality mouse primary hepatic cells including hepatocytes, Kupffer cells and hepatic stellate cells. We have established a mouse model that develops spontaneous liver cancer with liver fibrosis that highly mimics human liver cancer with cirrhosis.