Associate Professor Peter Meikle
Head, Metabolomics Laboratory
NHMRC Senior Research Fellow
Phone: +61 3 8532 1770
Metabolomics is the systematic study of the unique metabolite (small-molecule) fingerprints of biological systems. The Metabolomics Laboratory uses "state of the art" tandem mass spectrometry to obtain metabolic profiles (primarily lipids and fats) from cell and animal models in addition to clinically relevant human samples to better characterise the dyslipidemia associated with obesity, diabetes and cardiovascular disease and its relationship to the pathogenesis of these disease states. These studies are leading to new approaches to early diagnosis, risk assessment and therapeutic monitoring of these most prevalent diseases in our society.
One of the main goals of the Laboratory is to better understand the difference between stable and unstable coronary disease. At present there is no way of knowing which people among a group with what we know as "stable" coronary disease will develop "unstable" disease. This is a critical area of investigation as stable disease can become unstable - leading to sudden heart attack and stroke - at any time. For many people the first sign that their disease is unstable is death, yet others live long lives with stable disease - partial blockages in the coronary arteries that do not undergo significant change.
Recent funding from the National Institutes of Health (NIH), NHMRC and other funding bodies has enabled studies to characterise the changes in blood plasma lipids and fats associated with obesity, diabetes and cardiovascular disease. These studies will not only improve our understanding of the reasons why people develop disease but will help to develop new tests to identify those at greatest risk of developing these diseases.
Our studies into lipid metabolism associated with chronic disease have identified a specific class of lipid (plasmalogens) as a potential therapeutic target for the prevention and treatment of chronic disease, including cardiovascular disease and type 2 diabetes. Recent animal studies to increase the levels of circulating and tissue plasmalogens have shown promising results and we expect to move into clinical trials in the near future.
Atherosclerosis (AS) is the single most common cause of cardiovascular disease and is the major contributor to the development of angina, heart attacks, coronary heart disease and stroke. Despite the introduction of statin based therapy to reduce levels of plasma LDL cholesterol, the epidemic of cardiovascular disease claimed over 47,000 Australian lives in 2004 and costs the health system over $5 billion per year.
We have developed: Lipid profiling technology that can quantify over 350 lipid species from 10 uL of plasma using a targeted lipidomic approach (analysis of known lipids).
We have demonstrated that: Individuals with AS have altered lipid metabolism that correlates with different stages of disease (healthy, stable CAD, unstable CAD) and that this is reflected in their plasma lipid profile.
We have used the plasma lipid profiles to create multivariate models that can:
The risk of a CVE is directly related to a) coronary plaque severity (plaque burden) and b) coronary plaque stability. We are working to refine our plasma lipid profiles to better reflect these characteristics, to combine these profiles into a model to predict CVE and finally to validate the new model through a series of prospective studies on clinically defined populations.
The Australian population and indeed most of the developed world are facing an obesity epidemic; associated with this is a dramatic increase in the incidence of type 2 diabetes and its precursor, impaired glucose tolerance (IGT). If the current rates of mortality and diabetes incidence continue, the prevalence of diabetes is projected to rise from 7.6% in 2000 to 11.4% by 2025. More than a third of individuals will develop diabetes within their lifetime and there will an additional 1 million cases of diabetes by the year 2025.
This project applies a novel lipidomic approach to characterise the dyslipidemia associated with the different stages of IGT and diabetes. We will determine which aspects of the dyslipidemia precede the onset of disease and develop predictive models for the early identification of those individuals at increased risk of developing diabetes. We will validate this tool using existing plasma samples collected from longitudinal studies of well-characterised populations. We will also use the same lipidomic tools, combined with existing genetic data, to define the molecular mechanisms that perturb lipid homeostasis contributing to disease onset and progression.
Patients with type 2 diabetes are at increased risk of cardiovascular disease, in part due to the associated dyslipidemia which can be ameliorated by fenofibrate treatment. Fibrates are peroxisome proliferator activated receptor α (PPARα) agonists and are reported to lower triglycerides, improve the distribution of LDL subpopulations and raise HDL cholesterol. However, the effects of fenofibrate on lipid fractions (LDL, HDL, triglycerides) can vary with the population under study. We have performed preliminary studies on a subset of the FIELD Trial and have shown that:
The goals of this project are to define the influence of fenofibrate on the plasma/lipoprotein lipidome, determine which aspects of the effect are associated with CVD risk reduction and to identify those individuals who respond to, and benefit from, fenofibrate treatment.
The outcomes of this project will provide mechanistic insight into the mode of action of fenofibrate and quantify the reduction in risk in those individuals who best respond to fenofibrate treatment. Importantly, we will develop a test to identify those individuals who respond to treatment which will allow the targeted application of fenofibrate to reduce risk of CVD events in type 2 diabetes.
Atherosclerosis is one of the leading causes of death in Australia and worldwide. The current primary intervention for atherosclerosis is to reduce the level of low-density lipoprotein cholesterol (LDL-C). However, this only reduces up to 30% of the disease risk.
Plasmalogen is a subclass of phospholipids and previous studies have suggested that plasmalogens have anti-oxidative properties. We had previously observed that the level of plasmalogen was negatively associated with coronary artery disease, suggesting an elevated oxidative stress levels in these patients. We subsequently demonstrated with mouse models of atherosclerosis (ApoE-/- and ApoE-/-GpX1-/-) that the enrichment of plasmalogens in plasma and heart of the mice resulted in up to 70% reduction in aortic plaque formation (see figure below). The modulation of plasmalogen level also had pleiotropic effects including reduced body weight gain, lowering of cholesterol levels, and inflammation and oxidative stress levels at an atherosclerosis prone site (aortic sinus).
Figure 1. Plasmalogen modulation attenuates atherosclerosis in the ApoE KO and ApoE/GPX DKO mice. C57/BL6, ApoE KO and ApoE/GPX DKO mice (n=10 per group) were treated with a high fat diet (+/- 2% w/w batyl alcohol) for 12 weeks. C57/BL6 mice were also fed a low fat diet (+/- 2% w/w batyl alcohol). Plasma PC-plasmalogens were measured by mass spectrometry. Aortic lesions were assessed by the en-face method. Bars/whiskers show median/IQR for the PC plasmalogen and mean/std error for the % plaque area, * indicates p<0.001 relative to 0% batyl alcohol).
The ongoing goals of the project are to:
Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic ailment in developed countries. Excessive amounts of fatty acids have been shown to trigger lipid accumulation, activate inflammatory and ER stress signals, and promote hepatocyte apoptosis, all of which contribute to the pathological changes observed in NAFLD.
In this project we are using both lipidomic profiling and stable-isotopic tracer techniques to study the effects of fatty acid on the hepatocyte phospholipidome. Lipidomic profiling will provide detailed characterisation of the fatty acid composition of the phospholipid pools while stable-isotope tracers will be used to determine the flux of lipid metabolites through the biosynthetic pathways.
The underlying changes in lipid biosynthetic and signalling pathways, in response to excessive fatty acid treatment, will be studied using genetic overexpression/knockdown techniques and/or pharmacological inhibitors of specific pathways. The goal is to define the contributions of these pathways to the disease states resulting from fatty acid overload.
Associate Professor Meikle completed his PhD at James Cook University of North Queensland. Following postdoctoral positions at the National Research Council in Ottawa, Canada, and La Trobe University, Melbourne, he joined the Lysosomal Diseases Research Unit (LDRU) at the Women's and Children's Hospital in Adelaide and established a metabolomics research group focused on the screening diagnosis and pathogenesis of lysosomal storage diseases. In 2000, he was appointed Head of the Metabolic and Therapeutics Program, within the Department of Genetic Medicine.
In 2007, Associate Professor Meikle moved to the Baker IDI Heart and Diabetes Institute where he established the Metabolomics Laboratory. In 2008 he was awarded a NHMRC Senior Research Fellowship. The Metabolomics Laboratory uses state of the art tandem mass spectrometry to obtain metabolic profiles from cell and animal models in addition to clinically relevant human samples. This approach is providing an improved understanding of disease mechanisms leading to new therapeutic strategies in the areas of obesity, diabetes and cardiovascular disease chronic disease. The measurement of plasma lipids is currently being translated into new diagnostic, prognostic and monitoring approaches for chronic diseas.
Associate Professor Meikle holds affiliate positions at the Department of Biochemistry and Molecular Biology, University of Melbourne, the Department of Medicine, Monash Medical School, Monash University, and the NHMRC Clinical Trials Centre, University of Sydney.
Wong G, Trevillyan JM, Fatou B, Cinel M, Weir JM, Hoy JF, Meikle PJ. Plasma lipidomic profiling of treated hiv-positive individuals and the implications for cardiovascular risk prediction. PLOS One 2014;9:e94810.
Wong G, Chan J, Kingwell BA, Leckie C, Meikle PJ. Licre: Unsupervised feature correlation reduction for lipidomics. Bioinformatics 2014;19:2832-3.
Nestel PJ, Straznicky N, Mellett NA, Wong G, De Souza DP, Tull DL, Barlow CK, Grima MT, Meikle PJ. Specific plasma lipid classes and phospholipid fatty acids indicative of dairy food consumption associate with insulin sensitivity. Am J Clin Nutr 2014;99:46-53.
Meikle PJ, Wong G, Barlow CK, Kingwell BA. Lipidomics: Potential role in risk prediction and therapeutic monitoring for diabetes and cardiovascular disease. Pharmacology & therapeutics 2014;143:12-23
Weir JM, Wong G, Barlow CK, Greeve MA, Kowalczyk A, Almasy L, Comuzzie AG, Mahaney MC, Jowett JB, Shaw J, Curran JE, Blangero J, Meikle PJ. Plasma lipid profiling in a large population-based cohort. J Lipid Res 2013;54:2898-2908.
Meikle PJ, Wong G, Tsorotes D, Barlow CK, Weir JM, Christopher MJ, MacIntosh GL, Goudey B, Stern L, Kowalczyk A, Haviv I, White AJ, Dart AM, Duffy SJ, Jennings GL, Kingwell BA. Plasma lipidomic analysis of stable and unstable coronary artery disease. Arterioscler Thromb Vasc Biol 2011;31:2723-2732.