Defining lipidomic biomarkers of the interactions between Western diet and liver health using mass spectrometry imaging

点击翻译按钮获取中文摘要

Lifestyle factors influence healthy ageing. Dietary choices modify susceptibility to many diseases. The low-fat Mediterranean diet is anti-oxidant and believed beneficial for health, whereas high-fat "Western diet" associates with negative health outcomes. Body mass index is increasing worldwide, linked to increased risk of many diseases, including diabetes and non-alcoholic fatty liver disease (NAFLD), but individual risk is variable. When challenged with a fatty diet, the body responds by adjusting adipose depot volume and by storing fat "ectopically" e.g. in liver. This healthy, adaptive response is initially not harmful. However, beyond a certain level and in some individuals, metabolic flexibility is exceeded and too much ectopic fat triggers progressive liver fibrosis, cirrhosis and hepatocellular carcinoma. Biomarkers are needed to differentiate healthy vs unhealthy dietary adaptation to improve the healthspan of at-risk individuals. Metabolomics provides a fingerprint of personal biochemical status; lipidomics is a sub-field, categorising endogenous lipids regulating metabolism and inflammation. Lipidomics is most commonly conducted in blood, easy to sample and useful for health screening. However, the circulating lipidome may not reflect tissues. When liver health declines, zonal changes occur with healthy and at-risk tissue co-existing. Therefore, the hepatic lipidomic signature must be described spatially. This studentship will develop mass spectrometry imaging (MSI) to spatially profile lipids in liver and define their response to diet. In particular, excessive conversion of lysophosphatidyl cholines to their acidic metabolites by the enzyme autotaxin will be studied in detail.HypothesisDiets varying in fat content differentially affect the hepatic lipidome. The lipidomic signature revealed by MSI will identify pathways to assess liver health and disease and identify markers amenable to therapeutic modification either by lifestyle or drugs.Project PlanInitially, the student will establish MSI to sample lipids from liver sections of mouse and human. LC-MS/MS will also be deployed to measure key lipids in plasma. The profile of lipids will be described and species identified through alignment with lipidomic databases e.g. Lipidmaps.Next, we will study the hepatic lipidome of mouse models representative of healthy animals and study the effect of an obesogenic diet by varying the fat/carbohydrate content. Image analysis methods for co-localising histological and lipidomic features will be developed, aiming to develop predictive models to identify regions at risk. The changes in the lipidome with the duration of diet will be compared and correlated with stages of disease (healthy versus fatty/inflamed/fibrotic liver disease) to stratify biomarkers. Findings in mouse models will be translated to human liver samples from the NHS Lothian BioResource and proof of principle of reversibility established using inhibitors of autotaxin in murine modelsResearch TrainingThe student will receive interdisciplinary training in a broad range of methods including: a) in vivo and in vitro studies using liver tissue from animal models and humans; b) lipidomics by bioanalytical MS; c) multivariate statistical analysis of lipidomic datasets, involving interfacing with online databases; (d) co-registration and image analysis of histological features. Studies will be conducted in well-funded laboratories within the Queen's Medical Research Institute which are fully equipped for the proposed experiments.Khan, Andrew (2019) MSI of lipids, Current and emerging technologies in lipidomics, Royal Society of Chemistry, London, In Press.Iredale, Pellicoro, Fallowfield (2017) Liver Fibrosis: Understanding the dynamics of bidirectional wound repair to inform the design of markers and therapies. Dig Dis 2017;35:310-313.Cobice et al (2017) Quantification of 11beta-HSD1 kinetics and pharmacodynamic effects of inhibitors in br...