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.
Figure 1: Lipid Metabolism and Cardiometabolic Disease Research Program
Our group also aims to identify novel regulators of lipid metabolism. We have combined our expertise with that of collaborators at UCLA, Charles Perkins Centre and the Baker Institute to establish a state-of-the-art discovery platform. This approach allows us to associate cutting edge proteomic and lipidomic analyses with phenotypes of 100+ strains of genetically diverse inbred mouse lines. To our knowledge, this combined approach has generated the largest discovery platform of its kind in the world, maximising our opportunity to identify novel regulators of lipid metabolism.
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.
- 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 cardiac lipotoxicity with implications for cardiomyopathy, ischaemia reperfusion injury.
- Investigating the role of IDOL in mediating protection against lipid-induced insulin resistance in skeletal muscle.
- Understanding the importance of cholesterol in the regulation of hepatic glucose metabolism.
Current techniques and technologies
Mouse GWAS: access to Hybrid Mouse Diversity Panel (HMDP) genetic screens and tissue samples from Lusis Laboratory at UCLA.
Ongoing collaborations with the Charles Perkins Centre Proteomics Facility (David James).
Transcription and Bioinformatics
Access to technology and platforms including RNA-sequencing, microarray and bioinformatics pipelines at UCLA.
Cell lines and novel primary cell isolations including hepatocytes, brown and white adipose cells, skeletal muscle myoblasts and fibroblasts.
Significant expertise in cloning, generation of expression constructs including shRNAs, AAV, adenovirus, retrovirus and lentivirus. Perform mutagenesis and generate in-house transgenic mouse constructs.
Utilisation of CRISPR technology to generate gene deletions in cell lines and mouse models.
Measurement of substrate utilisation in cell systems (in vitro), excised tissues (ex vivo) and in whole animals (in vivo). Techniques include oroboros, seahorse flux analyser, oxidation and uptake of substrates, glucose tolerance tests (GTT) and hyperinsulinemic euglycemic clamps.
Mouse models of metabolic disease
Unique tissue-specific transgenic and knockout models and tissue-specific knockout models (skeletal muscle, heart, adipose).
Adeno-Associated Virus (AAV) delivery to mice
Tissue (heart, muscle, adipose) and systemic expression of genes delivered by AAV in collaboration with the Muscle Research and Therapeutics Laboratory.
Blood, human atherosclerotic plaques, liver, skeletal muscle and adipose biopsies.