Scientists Identify Unexpected Source of “Good Cholesterol”

Cross-section of the mammal duodenum or small intestine showing villi and the intestinal glands. Magnification of x140

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.

Source / Credit: University of British Columbia