Impact of the aberrant cell-matrix interaction in Non-Alcoholic fatty liver diseases progression

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Non-Alcoholic fatty liver diseases (NAFLD) with a 25% worldwide prevalence are leading causes of liver associated morbidity and mortality. No pharmacological treatment is yet available for chronic inflammation/Non-Alcoholic SteatoHepatitis (NASH) and associated fibrosis that are the progressive forms of NAFLD. Although the mechanisms underlying NAFLD progression are not fully understood, chronic inflammation is a key player mediating dysfunction of liver, adipose tissue and the gut. Chronic inflammation modifies the physiological tolerance of the liver and promotes liver injury and fibrogenesis. The extracellular matrix (ECM) and its receptors play a key role in orchestrating chronic inflammation (liver, adipose tissue) and fibrosis leading to NASH. Signaling by CD44 (cell-surface glycoprotein) is initiated by ECM molecules (osteopontin (OPN), hyaluronan (HA), and indirectly tenascin-C (TNC)) that may enhance signal intensity and duration. OPN, HA, TNC and CD44 can form complexes with cell surface receptors (e.g. c-Met, VEGFR, TLR4, EGFR, CXCR4….) that are known to promote inflammation, angiogenesis and fibrogenesis. We propose that CD44 acts as a central integrator and potentiator by transmitting signals from the ECM into the cytoplasm thus triggering proinflammatory signaling that drives NAFLD. Indeed, the consortium already discovered that targeting CD44 strongly alleviates liver injury, steatohepatits and fibrosis by downregulating the recruitment of macrophages and neutrophils into the liver and, by decreasing OPN levels and TNC signaling. In patients, hepatic CD44 and TNC expression strongly correlates with each other and with hepatic macrophage infiltration/abundance suggesting a combined action of both molecules in NAFLD. The aims of MATRIXNASH are: 1.-To decipher the ECM-dependent pathways promoting onset and progression of NAFLD by proteomic and genomic approaches in murine NAFLD models with engineered levels of key candidates (e.g. CD44, OPN, TNC). 2.-To establish novel therapeutic strategies in our fibrotic-NASH models by targeting candidates (CD44, TNC) alone or in combination through general or hepatic cell type specific approaches using novel state of the art AAV delivery systems. 3.-To establish relevance for the human patient in an integrative approach. We will gain comprehensive knowledge about ECM and CD44 complex composition in human NAFLD by proteomic and genomic approaches and tissue analysis for candidates derived from the murine models (cohort of 1006 obese patients). Candidates, relevant in the human disease, will be confirmed in cell culture and our murine NAFLD models. The consortium will employ a common multidisciplinary approach combining unbiased proteomics, transgenic mouse models, novel therapeutic targeting of CD44 and TNC and a large cohort of human tissue samples to acquire comprehensive knowledge about NAFLD onset and progression. This information may provide novel tools for diagnosis and therapy of NAFLD.