Liver fibrosis caused by excessive alcohol consumption, viral hepatitis, autoimmune diseases, and non- alcoholic steatohepatitis (NASH), can progress to cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. Hepatic fibrosis is characterized by the excessive deposition of extracellular matrix, mainly produced by activated hepatic stellate cells (HSCs), and is highly associated with chronic liver inflammation. However, the precise link between inflammation and hepatic fibrosis is still unknown. Thus, understanding the molecular mechanisms of hepatic fibrosis may help to design strategies for the prevention and treatment of liver injury and fibrosis. Patients with cirrhosis show increased systemic levels of endotoxin (lipopolysaccharide, LPS). We have previously shown that Toll-like receptor 4 (TLR4), a pattern recognition receptor for LPS, plays a critical role in hepatic fibrosis. Gut microflora-derived LPS entering into the portal circulation directly activates HSCs through TLR4, but not Kupffer cells. Activation of the LPS/TLR4 pathway enhances signaling by TGF-2, the most potent fibrogenic agonist, by downregulating bone morphogenetic protein and Activin membrane bound inhibitor (Bambi), a transmembrane suppressor of TGF-2 signaling. Based on our findings, we propose to further characterize the role of TLR4 in the activation of HSCs and in hepatic fibrosis. We hypothesize that gut intestinal microflora-derived LPS binds to the TLR4 receptor in HSCs. Activated TLR4 signaling results in the formation and the release of an intracellular signaling complex. The resulting intracellular signaling activates genes including chemokines and leads to hepatic inflammation and hepatic fibrosis. The TGF-2 signaling modulator Bambi is regulated by TLR4 signaling at the promoter level in HSCs. Based on these hypotheses, we will determine the distinct roles of MyD88 and TRIF between HSCs and Kupffer cells, and TLR4-dependent receptor-associated signaling complex in HSCs (Aim 1). We will determine the regulation of Bambi at the signaling and promoter levels by LPS in HSCs (Aim 2). Moreover, we will address the role of TLR4-induced chemokines in hepatic fibrosis (Aim 3). The pursuit of these three aims will elucidate the crucial role of TLR4 signaling in HSC activation and hepatic fibrosis. The long-term goal of this project is to provide a novel therapeutic approach targeting TLR4 signaling in the prevention and therapy of liver fibrosis.

Public Health Relevance

Hepatic fibrosis and its end stage, cirrhosis, represent a massive health care burden worldwide. The goal of this study is to investigate whether lipopolysaccharide and its receptor TLR4 affect hepatic fibrosis through TLR4 intracellular signaling, TGF-2 signaling, and chemokine/receptor systems. The results from this study might establish TLR4 and its related functions as targets for the therapy of hepatic fibrosis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
Zip Code
Yang, Ling; Miura, Kouichi; Zhang, Bi et al. (2017) TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in Mice. Cell Mol Gastroenterol Hepatol 3:469-483
Matsushita, Hiroshi; Yang, Yoon Mee; Pandol, Stephen J et al. (2016) Exosome Migration Inhibitory Factor as a Marker and Therapeutic Target for Pancreatic Cancer. Gastroenterology 150:1033-5
Zhong, Zhenyu; Umemura, Atsushi; Sanchez-Lopez, Elsa et al. (2016) NF-?B Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell 164:896-910
Hsin, I-Fang; Montano, Erica; Seki, Ekihiro (2016) Finding a new role for NEMO: A key player in preventing hepatocyte apoptosis and liver tumorigenesis by inhibiting RIPK1. Hepatology 64:295-7
Odena, Gemma; Chen, Jiegen; Lozano, Juan Jose et al. (2016) LPS-TLR4 Pathway Mediates Ductular Cell Expansion in Alcoholic Hepatitis. Sci Rep 6:35610
Seki, Ekihiro (2016) HEDGEHOG Signal in hepatocytes mediates macrophage recruitment: A new mechanism and potential therapeutic target for fatty liver disease. Hepatology 63:1071-3
Seki, Ekihiro (2016) Acrolein, a New Villain in the Development of Alcoholic Liver Disease. Cell Mol Gastroenterol Hepatol 2:544-545
Patel, Niraj S; Doycheva, Iliana; Peterson, Michael R et al. (2015) Effect of weight loss on magnetic resonance imaging estimation of liver fat and volume in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 13:561-568.e1
Seki, Ekihiro; Schwabe, Robert F (2015) Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 61:1066-79
Roh, Yoon-Seok; Loomba, Rohit; Seki, Ekihiro (2015) The TM6SF2 variants, novel genetic predictors for nonalcoholic steatohepatitis. Gastroenterology 148:252-4

Showing the most recent 10 out of 45 publications