eTheses Repository

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

Dowman, J.K. (2012)
Ph.D. thesis, University of Birmingham.

Loading
Dowman12PhD.pdf
PDF (10Mb)Accepted Version

Restricted to Repository staff only until 31 December 2042.

Abstract

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.

Type of Work:Ph.D. thesis.
Supervisor(s):Newsome, Phil and Tomlinson, J.W.
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Centre for Liver Research
Subjects:R Medicine (General)
Institution:University of Birmingham
ID Code:3600
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
Export Reference As : ASCII + BibTeX + Dublin Core + EndNote + HTML + METS + MODS + OpenURL Object + Reference Manager + Refer + RefWorks
Share this item :
QR Code for this page

Repository Staff Only: item control page