Atherosclerosis is the leading cause of death amongst Canadians, and a leading cause or death and disability throughout the world. One major risk factor for the development of this disease is alterations of cholesterol levels in the blood.
Cholesterol is transported through blood in two major types of fat-and-protein-based molecular complexes: low density lipoprotein (LDL), known as the "bad cholesterol" which increases risk for atherosclerosis, and high density lipoprotein (HDL), known as the “good cholesterol” which protects against the development of atherosclerosis, even in the presence of other risk factors.
All of our current therapies for the treatment of abnormal cholesterol levels and prevention of atherosclerosis are aimed at lowering LDL cholesterol. However, low levels of HDL cholesterol are the most common abnormality amongst patients with atherosclerosis, and if we had a way to raise HDL levels we could conceivably protect the vast majority of the population against this devastating illness.
We have identified a gene, called ABCA1, which is absolutely critical for the production of HDL. Dr. Hayden is now using a novel technology, termed conditional gene targeting, to understand the major sites of HDL production in the body, and how ABCA1 in these tissues affects the development of atherosclerosis. This information is absolutely crucial for the design of novel therapies that would raise the levels of ABCA1 activity is specific parts of the body to protect against atherosclerosis.
This work will generate important new knowledge about HDL production, risk for atherosclerosis and ABCA1 function in specific cell types. By understanding how ABCA1 functions in different parts of the body, and how it responds to various environmental and genetic stimuli we will be in a position to design lifestyle and pharmacological therapeutic options for the prevention and treatment of the leading cause of death of Canadians.
Brunham LR, Kastelein JJ, Hayden MR. ABCA1 gene mutations, HDL cholesterol levels, and risk of ischemic heart disease. JAMA 300(17):1997-8; author reply 1998. (2008) PMID 18984885
Brunham LR, Kruit JK, Pape TD, Parks JS, Kuipers F, Hayden MR. Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels. Circ. Res. 99(7):672-4. (2006) PMID 16946132
Singaraja RR, Van Eck M, Bissada N, Zimetti F, Collins HL, Hildebrand RB, Hayden A, Brunham LR, Kang MH, Fruchart JC, Van Berkel TJ, Parks JS, Staels B, Rothblat GH, Fiévet C, Hayden MR. Both hepatic and extrahepatic ABCA1 have discrete and essential functions in the maintenance of plasma high-density lipoprotein cholesterol levels in vivo. Circulation 114(12):1301-9. (2006) PMID 16940190