Mouralidarane, AC; (2012) The Role of Developmental Programming in the Pathogenesis of Non-Alcoholic Fatty Liver Disease (NAFLD). Doctoral thesis , UCL (University College London).

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Abstract

Obesity induced, non-alcoholic fatty liver disease (NAFLD), describes the spectrum from steatosis-to-cirrhosis. NAFLD is now the commonest cause of chronic liver disease in affluent populations. Its prevalence is increasing in tandem with rising obesity rates. However, given the exponential rise in obesity and NAFLD disease prevalence, availability of cheap energy dense foods may not alone be the sole determinant of these rising rates: maternal obesity – through developmental programming - may also be involved. A growing body of epidemiological evidence suggests that perinatal factors may contribute to chronic disease in adulthood via programming. Programming is the process whereby an insult/stimulus during a critical period of development induces permanent structural and/or physiological changes. The role of developmental programming in NAFLD is unknown. The aims, therefore were to determine if maternal obesity during gestation and/or lactation transmits a predisposition to NAFLD in offspring, to evaluate the natural progression of such programmed disease, to examine the relative contributions of maternal obesity and the post-natal environment on offspring NAFLD and to investigate the mechanisms therein. Using a rodent diet induced obesity-programming model, our initial studies confirmed that maternal obesity, through developmental programming, was indeed involved in the pathogenesis of NAFLD with the lactation period most susceptible to these programming effects. Moreover, there was an interaction between in utero exposure to an obesogenic environment and a post-weaning obesogenic environment to cause exacerbated offspring NAFLD. Mechanistically, perturbed hepatic innate immune function and disrupted peripheral circadian rhythms were observed in offspring with NAFLD programmed by maternal obesity. Finally, these results also provide a novel and uniquely pathophysiologically relevant model of NAFLD.

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