Human liver fat metabolism and metabolic disease: Understanding the underlying causes and mechanistic basis for intrahepatic fat storage to identify ways of preventing and treating fatty liver disease.

Understanding the underlying causes and mechanistic basis for intrahepatic fat storage to identify ways of preventing and treating fatty liver disease.

The liver has a major role in regulating metabolic homeostasis; it is a central cross-road for fatty acid and glucose metabolism. It aids as an intermediary organ between dietary (exogenous) and endogenous energy sources and other extrahepatic organs/tissues that consume energy. Perturbations in liver metabolism have the potential to impact widely on metabolic disease risk. In health, the liver rapidly adapts to alterations in nutritional state and the nutrient fluxes that occur from a fasted to fed state. However, the deposition of fat in non-adipose tissues (known as ectopic fat) such as the liver is an important factor in the development of obesity-related metabolic abnormalities such as type 2 diabetes and cardiovascular disease. Why the liver starts to accumulate fat is not well understood. My research program aims at understanding the underlying causes and mechanistic basis for intrahepatic fat storage to identify ways of preventing and treating fatty liver disease.

There is now evidence demonstrating that what we eat (the nutrient composition of our diet) can influence if fat starts to accumulate within the liver. For example, we have emerging evidence that eating a weight-maintaining diet enriched with saturated fat may lead to liver fat accumulation whilst consuming an isocaloric diet enriched with sugars upregulates the pathway of making ‘new’ fat (known as de novo lipogenesis), but doesn’t lead to liver fat accumulation. The reasons for the differential effects of diet on liver fat accumulation are not well understood. It is postulated, although not demonstrated, that newly made fat can cause fat droplets within the cell to become larger and this can impact on metabolic health.

To answer questions on how diet composition and other factors, such as therapeutic agents (e.g. diabetes medication) affect the regulation of liver fat content we take a multilevel approach where we combine dietary intervention studies, with whole body human physiological studies that use stable isotope tracer methodology, along with imaging, cellular studies, and genetics.

We are particularly interested in exploring the following areas:
• How specific dietary components (saturated fats, fish oils, sugars) influence liver fat metabolism
• How lipid droplet size and location within hepatocytes influence cellular function
• The effect of different dietary fatty acids on the regulation of cellular processes
• Influence of genotype/genetics on liver metabolism


Training Opportunities
• Whole body human and cellular metabolic physiology using tracers
• Hepatocyte biology, cell culture systems, genetic medication of cells to target certain pathway, i.e. knock-down, knock-in and CRISPR.
• RNA work, RNASeq and monitoring transcriptional activation
• Designing and executing small-scale experimental studies in humans. Access to the Oxford Biobank (www.oxfordbiobank.org.uk) ensures high-quality selection of informative individuals.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division’s Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.