ATP-binding cassette transporter A1, fatty acids, and cholesterol absorption.

Abstract

A significant advance in our understanding of the reverse cholesterol transport pathway occurred in 1999 with the identification of defects in the ATP-binding cassette transporter A1 gene as the cause of Tangier disease. Since this discovery, an overwhelming number of experiments have been conducted to further define the function of this gene. Among the concepts emerging from such studies is a possible role for the gene in cholesterol absorption. The present review summarizes the most recent of these studies, as well as the only report to describe the effects of fatty acids on ATP-binding cassette transporter A1 gene activity. From the one study conducted thus far, it appears that unsaturated fatty acids can reduce ATP-binding cassette transporter A1 gene activity by enhancing its degradation. Among the primary modulators of the gene's transcription is the liver X receptor, with liver X receptor-selective agonists significantly increasing expression of the gene. While some studies indicate that upregulation of the gene inhibits cholesterol absorption, the results of other studies suggest that it facilitates cholesterol absorption and the transfer of cholesterol into the bile. Preliminary evidence from studies with transgenic and knockout mice supports the concept that increasing ATP-binding cassette transporter A1 gene expression may be beneficial in the prevention of diet-induced atherosclerosis. Although there is substantial evidence from and studies to suggest that the ATP-binding cassette transporter A1 gene regulates intestinal cholesterol absorption, perhaps by mediating cholesterol efflux from the basolateral surface of enterocytes, it remains unclear whether or not this gene is the primary ATP-binding cassette transporter involved in the process.