Role of MMPs and CD147 in non-alcoholic steatohepatitis progression

Abstract

Obesity and diabetes is increasing exponentially and this is accompanied with prevalence of metabolic diseases like non-alcoholic steatohepatitis (NASH), an inflammatory often fibrotic condition of the liver. Fibrotic NASH is characterised by matrix turnover but the regulation of matrix degrading metalloproteinases (MMPs) remains poorly characterised. The aim of this thesis was to explore the role of MMPs and their regulator CD147 in NASH pathogenesis. Using a novel murine model of diet-induced obesity with added diabetes we showed characteristic temporal changes in MMP activity that increases with severity of NASH. Hepatocyte expression and glycosylation of CD147 also increases. By in-vitro studies we determined CD147 in hepatocytes were up-regulated by saturated free fatty acids and glucose via ERK1/2 and PI3K/Akt pathways. CD147 in cell membranes or when released in microparticles induced MMPs in hepatic cells, an effect abrogated by anti-CD147 antibody. We validated the possible role of microparticles in-vivo where microparticle concentration, particularly those expressing hepatocyte CD147 increased in NASH livers. This thesis establishes that MMPs and CD147 are regulated in NASH progression, and shows MMPs activity is induced by CD147 via cell membrane interaction or via microparticles. Blocking MMP activity or CD147 is therefore a logical therapeutic approach in NASH.