Research Areas

Liver fibrosis is a consequence of chronic liver diseases, such as hepatitis B and C infections, autoimmune hepatitis, nonalcoholic steatohepatitis (NASH) and alcohol-associated liver disease (ALD). Liver cirrhosis, the end stage of hepatic fibrosis, is associated with hepatocellular dysfunction, hepatic failure, portal hypertension and hepatocellular carcinoma. Currently, there is no curative treatment for liver fibrosis, and liver transplantation is the only effective therapy. However, supply of donor livers is always insufficient for all patients that require liver transplantation. In order to develop novel effective therapies for liver fibrosis, we must identify the effective molecular targets. The mission of our research group is to study the molecular mechanism underlying liver fibrosis.

Currently, Dr. Seki’s Laboratory is focusing on three major research topics:

Dr. Seki has reported Toll-like receptor 4 (TLR4), an innate immune receptor for LPS, expressed on hepatic stellate cells (HSCs) and, for the first time, intestine-derived LPS play a central role in HSC activation and liver fibrosis development. His research team also determined that TLR2 and TLR9 contribute to the development of NASH fibrosis. His recent report further demonstrated that macrophage autophagy controls the activation of TLR4 signaling in the development of ALD. Currently, our team studies to develop new therapies for ALD and NASH by targeting TLR signaling.

The large patient cohort reported fatty liver is associated with colorectal cancer liver metastasis. Our recent study has reported that M2 type tumor-associated macrophages and IL-1 are the promoter of colorectal cancer liver metastasis in NAFLD livers. Our ongoing study investigates whether factors secreted from lipid-stored hepatocytes and cancer-associated fibroblasts contribute to enhanced liver metastasis in NAFLD and ALD.

Kupffer cells, liver resident macrophages, and recruited macrophages respond to intestine-derived LPS through TLR4 and produce inflammatory cytokines and TGF-ß production. TGF-ß then activates hepatic stellate cells (HSCs), a precursor of hepatic myofibroblasts. Activated HSCs produce hyaluronan (HA), through HA synthesis 2 (HAS2), which enhances the production of collagens, promoting liver fibrosis.