Scientists at the University of British Columbia’s Centre for Molecular Medicine and Therapeutics have provided the first definitive proof that the intestine, together with the liver, produce nearly all of the body’s “good cholesterol.” This discovery could lead to new therapeutic opportunities in patients with cardiovascular disease.
Published today and featured on the cover of the Journal of Clinical Investigation (JCI), Dr. Michael Hayden and collaborators used a gene-deletion approach in mice to demonstrate that the ABCA1 gene in the intestine plays a key role in the production of high-density lipoprotein (HDL) or “good” cholesterol. This unexpected finding establishes the intestine as an important source of HDL.
“These results alter our understanding of how HDL is produced in the body and demonstrate the importance of the intestine in developing new therapeutic approaches for raising HDL levels in the body,” says Dr. Michael Hayden, Director and Senior Scientist of the Centre for Molecular Medicine and Therapeutics at the Child and Family Research Institute.
“This discovery could have significant implications for the treatment of cardiovascular disease such as coronary heart disease and atherosclerosis,” adds UBC graduate student Liam Brunham, lead author on the study.
Cardiovascular disease accounts for the death of more Canadians than any other disease, with more than 74,000 people dying of the disease in 2002. More than half of all cardiovascular deaths are due to coronary heart disease (CHD), which is the leading cause of death in the U.S. A low level of HDL is a common abnormality in individuals with CHD, yet there are no approved treatments that significantly raise HDL levels.
The ABCA1 gene and protein counterpart is known to be involved in the production of HDL. However, until now, scientists have been unsure which specific tissues produce HDL because ABCA1 is found in many parts of the body. In 2005, Dr. Hayden and colleagues demonstrated that the liver plays an important role in the production of “good cholesterol.”
Dr. Hayden and colleagues have created animal models in which ABCA1 is specifically deleted in the intestine, or the intestine and liver, to investigate the hypothesis.
“We generated mice that lacked the ABCA1 gene in the intestinal cells and unexpectedly found that the HDL concentrations were 30 per cent lower than in normal mice,” said Dr. Hayden. “When ABCA1 was deleted in both the liver and intestine, HDL concentrations were reduced by over 90 per cent, indicating that these two tissues produce nearly all of the HDL in the body.”
Dr. Hayden and collaborators will now be investigating compounds to increase ABCA1 levels in the intestine to raise the quantity of “good” cholesterol in the body. The researchers will also explore effects of different diets on ABCA1 levels in the intestine.
Collaborators on this project include Groningen University, the Netherlands, Wake Forest University, State University of New York and the Pasteur Institute, France.
To view the journal article, visit www.jci.org.
The Centre for Molecular Medicine and Therapeutics (CMMT)
The Centre for Molecular Medicine and Therapeutics (CMMT) at the Child and Family Research Institute is a research centre supported collaboratively by the Department of Medical Genetics of UBC, the British Columbia Research Institute, Merck Frosst Canada Inc., and the Government of British Columbia. Built on a 10-year history of research excellence, the CMMT is dedicated to advancing the fundamental understanding of the molecular function and structure of genes as the key to improved diagnosis, treatment and prevention of health problems in children and adults. The Centre now has 140 personnel including six nationally funded principal investigators and trainees, students and administrative staff.
For more information, please refer to the website at www.cmmt.ubc.ca.
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