Metabolomics

Associate Professor Peter Meikle
Head, Metabolomics
NHMRC Senior Research Fellow
peter.meikle@bakeridi.edu.au

Phone: +61 3 8532 1770 

- Meikle - Laboratory 

 

Research Overview

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.

In collaboration with other research groups at Baker IDI, we are conducting an investigation into the health effects of dairy products in the diet. Specifically, research will look at the difference to health between fermented dairy products, such as cheese and yoghurt, and non-fermented dairy products, such as cream, milk and butter. It is believed that fermented dairy products in the diet result in a lower blood cholesterol level than non-fermented dairy products. The team will seek to uncover why that is the case and what are the consequences, by analysing blood lipids, and so better understand the role of dairy products in a healthy diet.

Research Focus

  • Changes in lipid metabolism associated with coronary artery disease
  • Risk assessment for unstable coronary artery disease: identification of the "vulnerable patient"
  • The relationship between lipid metabolism, obesity and diabetes: why do some obese people get diabetes but not others?
  • Risk assessment for diabetes
  • The use of plasma lipids for therapeutic monitoring
  • The relationship between lipoprotein composition and function
  • The healthy effects of dairy foods
Peter Meikle in the Metabolomics laboratory

Research Projects

Prediction of unstable coronary artery disease

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:

  1. Stratify healthy from CAD patients, 
  2. Determine plaque stability, and 
  3. Stratify those individuals who have had a cardiovascular event (CVE) from those who have not. Importantly, these models perform better than traditional risk factors (Framingham and Reynolds risk equations) to characterise individuals in our cross sectional studies.

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.

Metabolomic studies into the pathogenesis and risk assessment of type 2 diabetes

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.

  • Early detection of diabetes or the identification of those at increased risk provides the opportunity for early treatment to prevent onset or progression of the disease.
  • Obesity is an important risk factor for diabetes; however, not all obese individuals will go on to develop diabetes. Improved predictive markers are required.
  • Altered lipid metabolism plays a key role in the development and progression of diabetes. However, the metabolic and signalling pathways involved are poorly defined.

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.

Lipidomic analysis of the FIELD Trial: mechanism of action and prediction of response to fenofibrate treatment in type 2 diabetes

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 ╬▒ (PPAR╬▒) 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:

  • Fenofibrate results in specific changes in multiple lipid classes, some of which are associated with coronary artery disease
  • Plasma lipids from lipidomic analyses are better able to classify fenofibrate treatment and placebo than traditional lipoprotein cholesterol and plasma triglyceride measures
  • Lipid responses to fenofibrate treatment differ markedly between individuals

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.

A/Prof Peter Meikle

Lab Head Profile

Associate Professor Meikle completed his PhD in 1986 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, while still maintaining his research program within the LDRU.

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 techniques to obtain metabolic profiles from cell and animal models in addition to clinically relevant human samples. This approach is combined with cell biology studies to improve our understanding of disease mechanisms and develop new diagnostic, prognostic and monitoring strategies in the areas of obesity, diabetes and cardiovascular disease.

Associate Professor Meikle holds affiliate positions at Bio21, University of Melbourne, the Department of Medicine, Monash Medical School, Monash University, and the NHMRC Clinical Trials Centre, University of Sydney.

Publication Highlights

Rasmiena AA, Ng TW, Meikle PJ. Metabolomics and ischaemic heart disease. Clin Sci 2013;124:289-306.

Kulkarni H, Meikle PJ, Mamtani M, Weir JM, Barlow CK, Jowett JB, Bellis C, Dyer TD, Johnson MP, Rainwater DL, Almasy L, Mahaney MC, Comuzzie AG, Blangero J, Curran JE. Variability in associations of phosphatidylcholine molecular species with metabolic syndrome in Mexican-American families. Lipids 2013;48:497-503.

Nestel PJ, Pally S, MacIntosh GL, Greeve MA, Middleton S, Jowett J, Meikle PJ. Circulating inflammatory and atherogenic biomarkers are not increased following single meals of dairy foods. Eur J Clin Nutr 2012;66:25-31.

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;31:2723-32.

Boslem E, MacIntosh G, Preston AM, Bartley C, Busch AK, Fuller M, Laybutt DR, Meikle PJ, Biden TJ. A lipidomic screen of palmitate-treated min6 beta-cells links sphingolipid metabolites with endoplasmic reticulum (ER) stress and impaired protein trafficking. Biochem J 2011;435:267-76.

Staff

Scientific Staff
Dr Chris Barlow
Dr Youping Zhou
Dr Piyushkumar A Mundra
Dr Gerard Wong
Dr Husna Begum
Jacqui Weir
Natalie Mellett
Kevin Huynh
Ricardo Tan
Michelle Cinel

Students
Michael Christopher
Zahir Alshehry
Anmar Anwar
Aliki Rasmiena
Ashlea Murphy
Kang-Yu Peng

 

Download a 2 page lab profile here

Download a publications list here