Regulation of the pro-fibrotic connective tissue growth factor in alcoholic liver disease: mechanisms and targeting approaches

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Project Summary / Abstract: Alcoholic liver disease is a major health and financial concern worldwide. Liver fibrosis and its advanced form, cirrhosis, can occur in virtually all types of chronic liver disease (CLD) including alcohol-induced liver injury. According to the American Liver Foundation, 5.5 million Americans are currently afflicted with CLD or cirrhosis, and the National Institutes of Health (NIH) reports cirrhosis as the 12th leading cause of death due to disease in America. Hepatic progenitor cells (HPCs) are the source of an alternative regenerative mechanism when hepatocyte proliferation is inhibited due to severe liver damage. HPC are closely associated with activated myofibroblast cells (MF) and correlate with severity of liver fibrosis in many CLD. No FDA approved treatment is currently available for any fibrotic disorder. There is an urgent need for the development of anti-fibrotic drugs to control progression of fibrosis while in reversible stages. Connective tissue growth factor (Ctgf) is a profibrotic mediator and modulates cell-cell and cell-matrix signaling through binding to a variety of growth factors, matrix protein, and cell surface proteins including integrins. It is a target gene of the transcriptional coactivator Yes-associated protein (Yap) and acts as an enhancer of transforming growth factor (Tgf)-β, promoting liver fibrosis and HPC activation in chronic liver disease. Our studies demonstrated fine-tuned regulation of Ctgf via hepatocyte nuclear factor (Hnf)4α antagonism of Yap and TGF-β1 signaling in regenerating hepatocytes whereas Ctgf deficiency reduces hepatic inflammation, hepatocyte proliferation and collagen synthesis. Adamts7 (a disintegrin and metalloproteinase with thrombospondin type I repeat 7) was identified as a novel enzyme for Ctgf turnover during liver injury. The Ctgf binding protein-extracellular matrix protein (ECM)1- was identified to inhibit Tgf-β activation and exhibited anti-fibrotic potential. The multifaceted regulations of Ctgf during fibrosis offers important translational opportunities for diagnosis and follow-up of hepatic fibrogenesis as well as intriguing targets for therapeutic interventions. Utilizing a noninvasive imaging technique we recently developed, in Aim 1, the function of Adamts7 in regulating fibrotic responses during alcohol-induced liver injury will be examined. In Aim 2, the anti-fibrotic effects of ECM1 on alcoholic liver injury and HPC activation will be assessed. This study will provide new mechanistic insights during alcoholic liver disease. The knowledge we obtain will help identify molecular targets to enhance liver regeneration and reduce liver fibrosis.