Liver fibrosis is the consequence of chronic liver diseases, such as hepatitis B and C infection, and alcoholic and non-alcoholic steatohepatitis (NASH). Currently there is no effective anti-fibrotic agent for liver cirrhosis. Therefore, the unmet medical needs for liver fibrosis/cirrhosis are significant. Liver inflammation is a crucial mechanism for activation of hepatic stellate cell (HSCs) and liver fibrosis. Activated HSCs produce extracellular matrix (ECM) including collagen, fibronectin, and hyaluronic acids (HA). Endogenous HA have been implicated in the disease progression of lungs, kidneys, joints, heart, and brain. In the liver, patients with liver cirrhosis show elevated HA levels in the blood. However, the biological functions of endogenous HA produced in liver fibrosis have not been determined. HA are produced in high molecular weight forms (HMW; MW>1000kDa) by hyaluronan synthase (HAS) 1-3. In the setting of inflammation, HA are degraded into low molecular weight (LMW) forms (MW~100-300kDa). LMW-HA exacerbates tissue injury and inflammation through binding to its receptors, CD44 and TLR4. The objective of this study is to determine the biological functions of endogenous HA and its downstream effector pathway in HSC activation and in liver fibrosis. Based on previous publications and our preliminary studies, we hypothesize that HAS2-mediated HSC-derived HA and HA's downstream effector pathways promote HSC activation and liver fibrosis. Moreover, we further hypothesize that by targeting HA a new interventional strategy for treating liver fibrosis can be developed. To test our hypotheses, we will investigate if HAS2-mediated HA production in HSCs promotes liver fibrosis through loss- and gain-of-function approaches using HSC-specific Has2 knockout (Has2?HSC) mice and HAS2 transgenic (ASMA-HAS2 Tg) mice. We will also use human tissue samples to examine HSCs as the source of HAS2 and HA in human cirrhotic livers (Aim 1). We will investigate the transcriptional and posttranscriptional regulation of HAS2 expression in HSCs as the molecular mechanisms of dysregulated HAS2 expression in liver fibrosis (Aim 2). We will then investigate the role of Notch1 signaling as the HA's downstream effector pathway for HSC activation and liver fibrosis (Aim 3). Finally, we will examine interventional potential of blocking HA synthesis for treating liver fibrosis (Aim 4).

Public Health Relevance

Liver fibrosis is the consequence of chronic liver diseases, such as hepatitis B and C infection, and alcoholic and non-alcoholic steatohepatitis (NASH). Currently there is no effective anti-fibrotic agent for treating liver cirrhosis and the unmet medical needs for liver fibrosis/cirrhosis are significant. Hyaluronic acids (HA) are major ECM components and patients with liver cirrhosis show an elevation of blood HA levels. Since the biological functions of endogenous HA have not been determined in liver fibrosis, we will investigate the roles of endogenous HA and its downstream effector pathway in HSC activation and liver fibrosis. We will also seek the interventional potential of targeting HA for treating liver fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK085252-08
Application #
9753207
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Burgess-Beusse, Bonnie L
Project Start
2011-02-15
Project End
2021-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Roh, Yoon-Seok; Seki, Ekihiro (2018) Chemokines and Chemokine Receptors in the Development of NAFLD. Adv Exp Med Biol 1061:45-53
Czech, Torrey Y; Wang, Qinglan; Seki, Ekihiro (2018) A new mechanism of action of glucagon-like peptide-1 agonist in hepatic steatosis: Promotion of hepatic insulin clearance through induction of carcinoembryonic antigen-related cell adhesion molecule 1. Hepatol Commun 2:9-12
Wang, Qinglan; Seki, Ekihiro (2018) Astrocyte elevated gene-1 (AEG-1): a new potential therapeutic target for the treatment of nonalcoholic steatohepatitis (NASH). Hepatobiliary Surg Nutr 7:44-47
Pimienta, Michael; Seki, Ekihiro (2018) Tumor Suppressor Down-Regulation Promotes Hepatocyte Proliferation: A New GANKster on the Block. Cell Mol Gastroenterol Hepatol 6:345-346
Zhong, Zhenyu; Liang, Shuang; Sanchez-Lopez, Elsa et al. (2018) New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560:198-203
Song, Isabelle Jingyi; Yang, Yoon Mee; Inokuchi-Shimizu, Sayaka et al. (2018) The contribution of toll-like receptor signaling to the development of liver fibrosis and cancer in hepatocyte-specific TAK1-deleted mice. Int J Cancer 142:81-91
Dow, Michelle; Pyke, Rachel M; Tsui, Brian Y et al. (2018) Integrative genomic analysis of mouse and human hepatocellular carcinoma. Proc Natl Acad Sci U S A 115:E9879-E9888
Yang, Yoon Mee; Fukui, Masato; Wang, Zhijun et al. (2018) Interventional Potential of Recombinant Feline Hepatocyte Growth Factor in a Mouse Model of Non-alcoholic Steatohepatitis. Front Endocrinol (Lausanne) 9:378
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

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