The role of 5-alpha reductase in the modulation of non-alcoholic steatohepatitis

Background and Aims: Glucocorticoids (GC) have been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Tissue GC levels are regulated by the enzyme 5α-reductase (5αR), which mediates GC breakdown, as well as converting testosterone to dihydrotestosterone (DHT). The aim of this study was to investigate the role of 5αR in the modulation of NAFLD. Methods: i) Human liver tissues from patients with NAFLD were used for immunohistochemical/qPCR and microarray analysis; ii) a cellular model of steatosis was developed to assess the effect of 5αR manipulation in-vitro; and iii) the effect of genetic 5αR knockdown on development of NAFLD, hepatic lipid metabolism and other metabolic parameters was assessed in a murine model of NAFLD. Results: In human liver, 5αR1 and 5αR3 expression correlate with histological severity of NASH. In a murine model of NAFLD, 5αR1-/- mice demonstrate increased steatosis but no significant difference in inflammation or fibrosis, suggesting that the deleterious effect of increased hepatic GCs on fat accumulation may be subsequently counteracted by their anti-inflammatory effect in NASH. 5αR1-/- also appears to protect against the development of hepatocellular dysplasia/carcinoma, which may result from the effect of reduced DHT levels on hepatic progenitor cell proliferation.EThOS - Electronic Theses Online ServiceGBUnited Kingdo