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

Abstract

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.

Ht31, a Protein Kinase A Anchoring Inhibitor, Induces Robust Cholesterol Efflux and Reverses Macrophage Foam Cell Formation through ATP-binding Cassette Transporter A1

“…ABCA1 is highly expressed in these macrophages as a consequence of excess cholesterol (18 . Flotillin 2 is preferentially associated microparticles released from ABCA1-expressing cells.…”

Isoform-Specific Regulation of a Steroid Hormone Nuclear Receptor by an E3 Ubiquitin Ligase inDrosophila melanogaster

“…Different 20E levels activate transcription of different sets of genes (Champlin and Truman 1998;Li and White 2003;Schubiger et al 2003). Like their vertebrate cognates (Chen and Evans 1995), unliganded EcR and USP act as repressors of transcription, whereas the liganded receptor stimulates expression of target genes (Tsai et al 1999;Ghbeish et al 2001;Schubiger et al 2003).On the basis of sequence identities, it is considered that the mammalian orthologs of EcR are the group H of nuclear receptor subfamily 1 that include LXR and FXR, while USP is represented by the retinoic X receptor (Robyr et al 2000;Fitzgerald et al 2002). The regulated activity of these receptors has a widespread effect on multiple aspects of development.…”

“…On the basis of sequence identities, it is considered that the mammalian orthologs of EcR are the group H of nuclear receptor subfamily 1 that include LXR and FXR, while USP is represented by the retinoic X receptor (Robyr et al 2000;Fitzgerald et al 2002). The regulated activity of these receptors has a widespread effect on multiple aspects of development.…”

Preface: the concept and consequences of multidrug resistance

“…The cells in one tissue may need protection against normal secretions used elsewhere, so that resisting endogenous compounds may be as critical as secreting them. P-gp may do both in [61] different tissues, being involved in the secretion of steroid hormones from the adrenal glands [66], and may also provide the brain with much-needed hormone independence [16,67]. Drugs that act on the brain will have their bioavailability modulated by MDR systems that are part of the blood-brain barrier [62] and individual variation in the pharmacology of these compounds, particularly their effects on the brain and liver, will depend on individual variation in P-gp expression and function.…”