SLMS Academic Careers Office

Grand Challenges

5. Immune mechanisms in Developmental Programming of Non-Alchoholic Fatty Liver Disease

Supervisor Pair: Dr Jude Oben and Professor Tessa Crompton
Potential Student’s Home Department: Institute for Liver & Digestive Health

Obesity induced liver disease, non-alcoholic fatty liver disease (NAFLD), is now the commonest cause of chronic liver disease in affluent nations, including the UK. The initiating defect in NAFLD is obesity related insulin resistance, with an ensuing spectrum of hepatosteatosis-steatohepatitis-cirrhosis and hepatocellular cancer. There are no proven treatments for NAFLD and understanding its pathogenesis is therefore an imperative. Obesity amongst women of reproductive age follows the general population trend with about 29% of women, aged 20-39 years, in the UK reported to be obese and this proportion continues to rise. The increasing prevalence of obesity and NAFLD may be partially explained by the increasing availability of inexpensive energy-dense foods. Excitingly, murine data from our group suggests that maternal obesity may influence offspring liver phenotype through unknown mechanisms but see: eg Mouralidarane ……., Oben JA (2013), Maternal obesity programs offspring non-alcoholic fatty liver disease via innate immune dysfunction in mice. Hepatology, 2013 Jan 12. [Epub ahead of print] and Oben et al (2010), Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice. J Hepatol. 52:913-20.

Our aim here is to build on our success and further study the role of immune mechanisms in developmentally programmed NAFLD our pathophysiologically relevant murine model in which we will wean offspring of obese dams weaned onto an obesogenic diet, to determine if they develop a more robust dysmetabolic and NAFLD phenotype, compared to offspring of lean dams weaned onto the same obesogenic diet or a standard, control diet. Outcome measures of NAFLD will include plasma concentrations of leptin, alanine transaminase, interleukin-6, 12 and 18 and tumour necrosis factor (TNF)-α, plus hepatic triglycerides and histological evidence of hepatic steatosis. We will further determine evidence of induction of pro-fibrotic pathways in association with histological evidence for hepatic fibrogenesis. Mechanistic studies will assay the functions of key components of the hepatic innate immune system including NK-T cells and Kupffer cells. Alterations in the functions of components of the adaptive immune system in the pathogenesis of developmentally programmed NAFLD will also be investigated.

Recognition of our work is evidenced by the fact that Dr Oben has recently been invited to join the All Party Parliamentary Group on Obesity with an inaugural meeting at the House of Commons in April ’13.

Please direct enquiries to Dr Oben.