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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.

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  • Full or part time
    Prof L Hodson
    Dr K Pinnick
    Dr Sion Parry
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

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:
◾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.

As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as 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.


Funding Notes

Our main deadline for applications for funded places has now passed. Supervisors may still be able to consider applications from students who have alternative means of funding (for example, charitable funding, clinical fellows or applicants with funding from a foreign government or equivalent). Prospective applicants are strongly advised to contact their prospective supervisor in advance of making an application.

Please note that any applications received after the main funding deadline will not be assessed until all applications that were received by the deadline have been processed. This may affect supervisor availability.

References

Luukkonen P, Sädevirta S, Zhou Y, Ali A, Ahonen L, Lallukka S, Pelloux, V, Gaggini M, Jian C, Hakkarainen A, Lundbom N, Gylling H, Salonen A, Orešič M, Hyötyläinen T, Orho-Melander M, Rissanen A, Gastaldelli A, Clément, K, Hodson L, Yki-Järvinen H. Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars. Diabetes Care 2018;41:1732-1739


Gunn PJ, Green CJ, Pramfalk C, Hodson L. In vitro cellular models of human hepatic fatty acid metabolism: differences between Huh7 and HepG2 cell lines in human and fetal bovine culturing serum. Physiol Rep 2017; 5(24):e13532


Pramfalk C, Pavlides M, Banerjee R, McNeil CA, Neubauer S, Karpe F, Hodson L. Fasting plasma insulin concentrations are associated with changes in hepatic fatty acid synthesis and partitioning prior to changes in liver fat content in healthy adults. Diabetes 2016;65:1858-1867


Parry SA and Hodson L. Influence of dietary macronutrients on liver fat accumulation and metabolism. J Investig Med. 2017;65:1102-1115

Related Subjects

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