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Understanding the causes of non-alcoholic fatty liver disease to identify new biomarkers of disease stage as well as trial novel treatments

Tomlinson

 

About the research

Understanding the causes of non-alcoholic fatty liver disease to identify new biomarkers of disease stage as well as trial novel treatments

The global epidemic of obesity and metabolic disease, including its hepatic manifestation, non-alcoholic fatty liver disease (NAFLD) has hastened the need to identify pathogenic mechanisms and novel, innovative and efficacious treatments. Within the next 3 years, NAFLD will become the leading cause for liver transplantation. NAFLD is not only associated with a significant increase in liver and cardiovascular morbidity and mortality, but significantly increases the risk of development of hepatocellular carcinoma (HCC). Research in our groups seeks to understand the causes of NAFLD, to identify new biomarkers of disease stage as well as trial novel treatments.

We have a long-standing interest in the role of steroid hormones and bile acids to regulate metabolic phenotype. Our recent work has identified specific enzyme targets that appear to be crucial in the development of metabolic liver disease and are potentially amenable to drug targeting. In addition, using gas chromatography mass spectrometry, and working alongside computational scientists, we have been able to develop and entirely novel strategy for staging liver disease without the need for a biopsy.

Adopting a translational approach incorporating both basic science and the use of clinical samples from patients with NAFLD and HCC, we aim to explore the ability of specific steroid hormones and bile acids to regulate multiple aspects of cell biology. Student projects will manipulate the availability of these signalling molecules  (genetic and pharmacological) to identify new potential treatment targets.

 Training Opportunities

Within our research group there are specific training opportunities that will include the use of cell culture models of human hepatocytes alongside the use of primary cultures of liver cells. The project will use many state-of-the-art molecular biology techniques including gene expression by real-time PCR, the use of stable isotopes to track the fat of labelled metabolic substrates as well as genetic manipulation and genome editing techniques using CRISPR technology. Students will be embedded within the broader research group (including basic scientists and clinicians) providing exposure to metabolic research across the translational spectrum

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.

Publications

Prevalence and severity of non-alcoholic fatty liver disease are underestimated in clinical practice: impact of a dedicated screening approach at a large university teaching hospital.  Marjot T, Sbardella E, Moolla A, Hazlehurst JM, Tan GD, Ainsworth M, Cobbold JFL, Tomlinson JW. Diabet Med. 2018 Jan;35(1):89-98.
AKR1C3-Mediated Adipose Androgen Generation Drives Lipotoxicity in Women With Polycystic Ovary Syndrome. O'Reilly MW, Kempegowda P, Walsh M, Taylor AE, Manolopoulos KN, Allwood JW, Semple RK, Hebenstreit D, Dunn WB, Tomlinson JW, Arlt W. J Clin Endocrinol Metab. 2017; 102(9):3327-3339  
Optimizing human hepatocyte models for metabolic phenotype and function: effects of treatment with dimethyl sulfoxide (DMSO). Nikolaou N, Green CJ, Gunn PJ, Hodson L, Tomlinson JW. Physiol Rep. 2016 Nov;4(21). pii: e12944  
Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man. Hazlehurst JM, Oprescu AI, Nikolaou N, Di Guida R, Grinbergs AE, Davies NP, Flintham RB, Armstrong MJ, Taylor AE, Hughes BA, Yu J, Hodson L, Dunn WB, Tomlinson JW. J Clin Endocrinol Metab. 2016 Jan;101(1):103-13  
Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. Armstrong MJ, Hull D, Guo K, Barton D, Hazlehurst JM, Gathercole LL, Nasiri M, Yu J, Gough SC, Newsome PN, Tomlinson JW. J Hepatol. 2016 Feb;64(2):399-408  

 

Supervisors