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Examining the damage caused by excess cholesterol and triglycerides to prevent the onset of diabetes and cardiovascular disease

Elevated lipid levels are highly prevalent in todays’ society, putting individuals at increased risk of diabetes and cardiovascular disease. In particular, 1 in 3 individuals exhibit elevated levels of cholesterol and a similar incidence has been observed for elevated triglyceride levels. These excess lipids can be deposited in tissues where they mediate a variety of pathological effects. In the liver and skeletal muscle they can promote the onset of insulin resistance; in the heart they can lead to cardiomyopathy and in the vasculature they can precipitate atherosclerotic lesion formation. Whilst drugs are available for the treatment of dyslipidaemia, many individuals experience side effects with current therapies. Furthermore, others require additional therapies to further lower lipid levels. Thus, we need to identify novel regulators of lipid metabolism that have the potential to be targeted for therapeutic intervention.

The research program of the Lipid Metabolism and Cardiometabolic Disease Laboratory focuses on preventing the onset of cardiometabolic disease driven by excess lipids. As outlined in the figure below, our research program spans across a number of different disease states in various metabolic tissues with the common underlying theme of preventing lipid-induced disease. These studies combine a wide range of in vitro approaches with a particular focus on molecular and cellular biology together with unique genetically modified mouse models to study in vivo pathophysiology.

Diagram of Lipid Metabolism and Cardiometabolic Disease Research Program

Figure 1: Lipid Metabolism and Cardiometabolic Disease Research Program

Our group also aims to identify novel regulators of lipid metabolism with therapeutic potential. In collaboration with the Molecular Metabolism and Aging Laboratory at the Baker Institute, we have utilised our ties with collaborators at the University of California, Los Angeles (UCLA) to access a specialised discovery platform called the Hybrid Mouse Diversity Panel (HMDP). The HMDP is designed to associate genetic variability with phenotypes of interest across 100+ strains of mice. Previous studies using this approach have focussed on the DNA level to identify novel regulators. However, given that the proteins perform the majority of biological functions in the cell, we have taken the unique approach to perform discovery studies at the protein level in collaboration with one of Australia’s leading proteomics experts. We have combined state-of-the-art analyses of HMDP liver proteins with cutting-edge measurement of liver and blood lipids here at the Baker Institute. To our knowledge, by using this combined approach we have generated the largest discovery platform of its kind in the world, maximising our opportunity to identify novel regulators of lipid metabolism. Subsequent studies include in vitro validation of novel targets followed by in vivo testing in an acute and chronic setting to assess effects on lipid metabolism as well as disease outcomes. Findings are also validated in human samples and cohorts.

Ultimately, these studies have the potential to identify novel therapeutics targeted to the modulation of lipid metabolism for the prevention of cardiometabolic diseases including hepatosteatosis, cardiovascular disease and insulin resistance.

Research focus

  • Identification of novel regulators of cholesterol metabolism and its implications for cardiovascular disease.
  • Identification of novel regulators of DAG/TAG metabolism and its implications for steatosis and diabetes.
  • Identification of novel biomarkers of hepatic steatosis and inflammation.
  • Examining IDOL as a novel therapeutic target to attenuate lipotoxicity with implications for cardiomyopathy, ischaemic heart disease and skeletal muscle insulin resistance.
  • Understanding the importance of cholesterol in the regulation of hepatic glucose metabolism.

One is three Australians have elevated cholesterol levels and there is a similar incidence of individuals with high triglyceride levels. These excess cholesterol and triglycerides can be deposited in tissues such as the heart, liver and skeletal muscle where they have detrimental effects, promoting atherosclerosis, cardiac dysfunction, steatosis and insulin resistance. Despite current therapies to lower lipid levels, these conditions are still major health issues for Australians. Thus, studies are required to identify novel regulators of lipid metabolism as potential targets for therapeutic intervention. We provide a novel approach to identify new pathways associated with lipid regulation. This approach is based on associating the genetic variability across 100 strains of mice with a given phenotype in these mice. Specifically, we have linked differences in hepatic protein expression in 100 strains of mice to changes in plasma and liver lipid levels. Excitingly, this approach has identified many new candidates, never before linked to lipid metabolism.

This project involves validation of these identified candidates in liver cells and translation of these findings to mouse models. It will assess the mechanism of action of these novel candidates and their effect in cardiovascular disease, insulin resistance or fatty liver where relevant.

Staff

Group leader
Dr Brian Drew

Scientific staff
Dr Eser Zerenturk – Post Doctoral Scholar
Yingying Liu – Research Assistant
TieQiao Wu – Research Assistant
Christine Yang – Research Assistant

Students
Emily King – PhD Student
Michael Keating – Honours Student

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With the rising number of Australians affected by diabetes, heart disease and stroke, the need for research is more critical than ever.

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