The ABC of Hepatic and Intestinal Cholesterol Transport

Abstract

The liver and (small) intestine are key organs in maintenance of cholesterol homeostasis: both organs show active de novo cholesterogenesis and are able to transport impressive amounts of newly synthesized and diet-derived cholesterol via a number of distinct pathways. Cholesterol trafficking involves the concerted action of a number of transporter proteins, some of which have been identified only recently. In particular, several ATP-binding cassette (ABC) transporters fulfil critical roles. For instance, the ABCG5/ABCG8 couple is crucial for hepatobiliary and intestinal cholesterol excretion, while ABCA1 is essential for high-density lipoprotein formation and, hence, for inter-organ trafficking of the highly water-insoluble cholesterol molecules. Very recently, the Niemann-Pick C1-like 1 protein has been identified as a key player in cholesterol absorption by the small intestine and may represent a target of the cholesterol absorption inhibitor ezetimibe. Alterations in hepatic and intestinal cholesterol transport affect circulating levels of atherogenic lipoproteins and thus the risk for cardiovascular disease. This review specifically deals with the processes of hepatobiliary cholesterol excretion and intestinal cholesterol absorption as well as the interactions between these important transport routes. During the last few years, insight into the mechanisms of hepatic and intestinal cholesterol transport has greatly increased not in the least by the identification of involved transporter proteins and the (partial) elucidation of their mode of action. In addition, information has become available on (transcription) factors regulating expression of the encoding genes. This knowledge is of great importance for the development of a tailored design of novel plasma cholesterol-lowering strategies.