Nuclear hormone receptors and cholesterol trafficking: the orphans find a new home

There are many homeostatic mechanisms that contribute to the regulation of cellular and serum cholesterol levels in humans. Much of our understanding of this regulation arose from studies of the cellular pathways controlling cholesterol synthesis and the uptake and degradation of low-density lipoproteins. The physiology governing cholesterol disposition in whole animals, including the molecular mechanisms responsible for dietary uptake of cholesterol and its subsequent catabolism to bile acids, are only now being uncovered. This review summarizes recent studies that have used modern genetic techniques, as well as cell biological methods, to begin to elucidate the pathways responsible for cholesterol trafficking in vivo. This work has led to the realization that networks of nuclear hormone receptors, including the LXR, FXR, PPAR, and RXR proteins, play critical roles in lipid metabolism by virtue of their transcriptional regulation of the genes that control sterol metabolic pathways. Some of the major downstream targets of these regulatory networks involve members of the ABC transporter family, including ABCA1, ABCG1, ABCG5, ABCG8, MDR3/Mdr2, and SPGP/BSEP. These transporters contribute to the movement of sterols and biliary lipids across cellular membranes via mechanisms that have yet to be elucidated. The potential for manipulating these cholesterol trafficking pathways via drugs targeted to the nuclear hormone receptors has generated great interest in their biology and will undoubtedly lead to new therapeutic approaches to human disorders in the coming years.