Baker IDI – Metabolomics

The Metabolomics Laboratory at the Baker IDI uses “state of the art” tandem mass spectrometry to obtain metabolic profiles (primarily lipids and fats) to better characterise the dyslipidemia associated with obesity, diabetes and cardiovascular disease. These lipid profiles are then used to explore the relationship between metabolism and the pathogenesis of these disease states. Thesemetabolomic 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.

In addition, 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.

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
  • Modulation of plasmalogens for prevention and treatment of chronic disease
MeikleLab2

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 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.

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. 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.

  1. 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.
  2. Obesity is an important risk factor for diabetes; however, not all obese individuals will go on to develop diabetes. Improved predictive markers are required.
  3. 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.

Assessment of the role of plasmalogen as cellular and lipoprotein antioxidants in atherosclerosis

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 that the enrichment of plasmalogens in plasma and heart of the mice resulted in up to 70% reduction in aortic plaque formation.  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).

Other projects:

  • Lipidomic analysis of the FIELD Trial: mechanism of action and prediction of response to fenofibrate treatment in type 2 diabetes
  • The role of hepatocyte phospholipid metabolism in non-alcoholic fatty liver disease

Lab Head Profile

Peter Meikle 2Associate 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 disease..

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.

Publication Highlights

  • 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. The American journal of clinical nutrition. 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. Journal of lipid research. 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

 

Lab Facts

Expertise
Lipidomics
Lipid metabolism
Type 2 diabetes
Cardiovascular disease

Established Workflows
High throughput targeted lipidomics
Lipid flux analyses

Hardware
AB Sciex 4000 Q/TRAP with Agilent 1200 LC system
Agilent 6490 QQQ with Agilent 1290 LC system

Contact
Dr Peter Meikle
peter.meikle@bakeridi.edu.au
Baker IDI website

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