Cirrhosis resulting from viral infection, alcohol abuse, hepatotoxicity, or genetic metabolic disorders is a major health problem in the United Sates. In liver fibrogenesis, hepatic stellate cells (HSC) undergo phenotypic changes called activation, by which the vitamin-A storing cells are trans-differentiated into myofibroblast-like cells. Upon HSC activation, the normal basement membrane-like ECM in the perisinusoidal space is replaced by collagenous fibers. Plausible evidence exists for the role of IL-1 in fibrogenesis in liver, kidney, and lung. Despite the known importance of the normal ECM milieu in maintaining HSC in the """"""""quiescent"""""""" state, how HSC respond to fibrogenic stimulation in different three-dimensional (3D) ECM still remains unknown. To this end, we have obtained a novel finding that 3D type I collagen exerts the most powerful synergistic effect on IL-1alpha-induced expression and activation of pro-MMP- 9 and MMP-13 by HSC, proteolytic degradation of ECM, and HSC activation. In support the role of MMP-9 in HSC activation and fibrogenesis, bile duct ligation in MMP-9 null mice results in attenuated liver fibrosis despite comparable hepatocellular damage. Once fully activated, HSC lose the responsiveness to the dual signals for production of MMP-9 and MMP-13, the defect that we believe mirrors the suppressed fibrolytic activity known to accompany advanced liver fibrosis. In human fibrotic livers, MMP-9 is localized in a subpopulation of alpha-smooth muscle actin-positive cells in the leading edge of fibrogenesis. Based on these findings, we propose a hypothesis that type I collagen and IL-1alpha serve as potent dual signals to provoke and perpetuate early HSC activation via induction and activation of pro-MMP9 and MMP-13 while the loss of this MMP inducibility in fully-activated HSC underlie progressive fibrogenesis. Toward this hypothesis, we will address the following four specific aims: 1) To determine the mechanism by which dual signals from 3D type I collagen and IL-1alpha induce proMMP-9; 2) To identify a proMMP-9 activator(s) that is induced by IL-1alpha and type I collagen; 3) To elucidate why fully-activated HSC switch off the responsiveness to the dual signals; 4) To test the contribution of IL-1 and MMP-9 to liver fibrosis in animal models. For the aim 1 and 3, the loss or gain of function approach will be used to test the requirements of key signaling molecules. For the aim 2, we will test whether a chymotrypsin-like proMMP-9 activator recently identified in human skin, is expressed in HSC stimulated by the dual signals while pursuing a systematic molecular search for new activators. Lastly, knock-out and knock-in methods will be used to test the roles of IL-1 signaling and MMP-9 expression in early and late liver fibrogenesis in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069418-02
Application #
6952815
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2004-09-30
Project End
2009-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$305,657
Indirect Cost
Name
University of Southern California
Department
Surgery
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Yang, Zemin; Liu, Yu; Qin, Lan et al. (2017) Cathepsin H-Mediated Degradation of HDAC4 for Matrix Metalloproteinase Expression in Hepatic Stellate Cells: Implications of Epigenetic Suppression of Matrix Metalloproteinases in Fibrosis through Stabilization of Class IIa Histone Deacetylases. Am J Pathol 187:781-797
Zhu, Longdong; Kong, Ming; Han, Yuan-Ping et al. (2015) Spontaneous liver fibrosis induced by long term dietary vitamin D deficiency in adult mice is related to chronic inflammation and enhanced apoptosis. Can J Physiol Pharmacol 93:385-94
Kong, Ming; Zhu, Longdong; Bai, Li et al. (2014) Vitamin D deficiency promotes nonalcoholic steatohepatitis through impaired enterohepatic circulation in animal model. Am J Physiol Gastrointest Liver Physiol 307:G883-93
Han, Yuan-Ping; Kong, Ming; Zheng, Sujun et al. (2013) Vitamin D in liver diseases: from mechanisms to clinical trials. J Gastroenterol Hepatol 28 Suppl 1:49-55
Lu, Ling; Feng, Min; Gu, Jia et al. (2013) Restoration of intrahepatic regulatory T cells through MMP-9/13-dependent activation of TGF-? is critical for immune homeostasis following acute liver injury. J Mol Cell Biol 5:369-79
Kida, Yujiro; Xia, Zanxian; Zheng, Sujun et al. (2011) Interleukin-1 as an injury signal mobilizes retinyl esters in hepatic stellate cells through down regulation of lecithin retinol acyltransferase. PLoS One 6:e26644
Li, Shengwen Calvin; Han, Yuan-Ping; Dethlefs, Brent A et al. (2010) Therapeutic window, a critical developmental stage for stem cell therapies. Curr Stem Cell Res Ther 5:297-3
Qin, Lan; Han, Yuan-Ping (2010) Epigenetic repression of matrix metalloproteinases in myofibroblastic hepatic stellate cells through histone deacetylases 4: implication in tissue fibrosis. Am J Pathol 177:1915-28
Yan, Chunli; Grimm, Wesley A; Garner, Warren L et al. (2010) Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-alpha through bone morphogenic protein-2. Am J Pathol 176:2247-58
Gieling, Roben G; Wallace, Karen; Han, Yuan-Ping (2009) Interleukin-1 participates in the progression from liver injury to fibrosis. Am J Physiol Gastrointest Liver Physiol 296:G1324-31

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