MRC Precision Medicine DTP: Modelling Sex Dependent Differences in Human Liver Disease using Stem Cell Derived Models and Organ on a Chip Devices

Background

Metabolic syndrome is a cluster of conditions, which include increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels. This increases the individual’s risk of developing liver and heart disease, stroke and diabetes. Our interest lies in human liver disease and more specifically, liver steatosis. Liver steatosis is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion, which are risk factors for developing non-alcoholic fatty liver disease (NAFLD). While the liver can be steatotic, without disturbing normal function, NAFLD does progress to non-alcoholic steatohepatitis (NASH) in many patients. In NASH steatosis is combined with inflammation and results tissue fibrosis, with up to 20% of patients with NASH going onto develop cirrhosis of the liver.

NAFLD susceptibility varies across the population, however, both obesity and insulin resistance play a strong role in the disease process. Epidemiological studies show sex and age differences are important factors in developing fatty liver disease and metabolic syndrome, suggesting that sex hormones play important roles. Sex steroid hormone deficiency in post-menopausal women and in ageing men, predispose the older population to the metabolic syndrome and NAFLD (1-2). Notably, NAFLD is twice as common in post-menopausal women as in pre-menopausal women that could be consistent with a protective role of oestrogens in NAFLD although this remains under-explored (3).

Androgens and oestrogens regulate lipid, glucose and cholesterol homeostasis differently in men and women. For example, testosterone in men favours liver glucose metabolism, whereas in females it impairs it. Additionally, androgens reduce lipid accumulation in male livers, but increase lipid storage in females. In the context of cholesterol metabolism, both oestrogen and androgens decrease serum cholesterol and circulating LDL levels, promoting bile formation in females and liver accumulation in men. Oestrogens have an impact on inflammatory processes. In summary, sex hormones are important drivers for the fundamental differences observed in human metabolism and disease outcomes. There is an urgent need to better understand these differences at the molecular level as a platform for developing new and novel ways to therapeutically intervene in the context of human NAFLD.

Aim
To define the molecular basis for sex dependent differences in the development of non-alcoholic fatty liver disease as the basis for developing novel therapies to correct the aberrant phenotype.

Methods
We will use our novel NAFLD model which employs pluripotent stem cell derived hepatocyte like cells (HLCs) (4). During hepatocyte specification, male and female HLCs will be exposed to physiologic relevant levels of androgen, oestrogen and growth hormone signaling. Following hormone treatment, stem cell derived HLCs will be exposed to ‘normal’ and fatty diets. The interaction of hormone signaling and the development of steatosis will be studied ‘in the dish’ using our semi-automated platform, with a focus on key changes in liver cell biology, including hepatic metabolism and function, cell viability, gene transcription and factor secretion. Following in-depth analysis using bioinformatics coupled with target identification, the sex specific models developed from these studies will be further sophisticated using organ on a chip systems. The gene regulatory datasets derived in static and perfused culture will be used as a basis to restore hepatocyte homeostasis by reversing steatosis and/or reducing inflammatory gene expression. Studies will benefit from a close collaboration with an industrial partner and an opportunity to work in different laboratories to gain experience in a broad range of methods and different working environments.
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------
This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location:

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you should contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.

For more information about Precision Medicine visit:

http://www.ed.ac.uk/usher/precision-medicine