DiMeN Doctoral Training Partnership: Mechanisms of genetic polymorphisms associated with non-alcoholic fatty liver disease (NAFLD) and its role in disease progression

This PhD offers cutting edge multidisciplinary training in cell biology, super resolution microscopy, inflammatory diseases and state of the art analytical techniques to determine associations between a person’s genetics and the predisposition to disease. The project involves researchers from the Leeds Institute of Cardiovascular and Metabolic Medicine, the School of Food Science and the Leeds Institute of Data Analytics. The breadth of specialist training provided will enable the student to become a next generation researcher ready to tackle the major health problems that we face today.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide (1). NAFLD can be relatively harmless with few symptoms but it can progress to advanced liver disease and ultimately liver failure. Patients with NAFLD are also more likely to develop cardiovascular and metabolic diseases. The molecular mechanisms that promote the progression of a fatty liver to a more aggressive form are not fully understood but they involve inflammation and fibrosis. Endothelial cells, cells that line all the blood vessels, are major regulators of inflammation because they control the secretion of pro-inflammatory mediators in response to infection and assault (2). When endothelial cells become dysfunctional, as proposed in patients with NAFLD, secretion becomes inappropriate and untimely, thus contributing to the inflammatory environment that is characteristic of NAFLD progression.
Secretion from cells is regulated by Rab proteins, a family of small GTPases that regulate all aspects of membrane trafficking. Recently a single nucleotide polymorphism (SNP) was described in a gene that encodes for a Rab GTPase (CRACR2A-L or Rab46) that is expressed in endothelial cells (3, 4). In addition, this SNP has been identified in a genome wide association study as being linked to NAFLD and in particularly contributes to inflammation.

Our hypothesis is that the presence of polymorphisms in endothelial cells contributes to inflammation and disease progression in non-alcoholic fatty liver disease and other inflammatory diseases. This study aims to determine mechanisms that underlie the progression of NAFLD so that we can identify novel therapeutic targets.

The project has 3 objectives: (1) Characterisation of Rab46 SNP and other polymorphisms associated with NAFLD in patient endothelial cells. (2) Evaluate the effect of these polymorphisms on endothelial cell function. (3) Analysis of data obtained from the UK Biobank to explore the associations between Rab46 SNP and inflammatory disease.

1. Systems biology approaches for studying the pathogenesis of non-alcoholic fatty liver disease. Fisher CP, Kierzek AM, Plant NJ and Moore JB. World J Gastroenterol. 2014 20(41):15070-8.
2. Liver sinusoidal endothelial cells: physiology and role in liver disease. Poisson J, Lemoinne S, Boulanger C, Durand F, Moreau R, Valla D, Rautou PE. J Hepatol. 2016 Jul 13.
3. Expression of a long variant of CRACR2A that belongs to the Rab GTPase protein family in endothelial cells. Wilson LA1, McKeown L1, Tumova S, Li J, Beech DJ. Biochem Biophys Res Commun. 2015 Jan 2;456(1):398-402.
1. Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Chalasani N et al. Nonalcoholic Steatohepatitis Clinical Research Network. Gastroenterology. 2010 Nov;139(5):1567-76."