Cholesterol homoeostasis is the result of the fine tuning between intake and disposal of this molecule. High levels of cholesterol in the blood are detrimental as they may lead to excessive accumulation in vessel walls, a condition predisposing to the development of atherosclerotic lesions. Cholesterol is removed from the vessel wall and transported to the liver through a process called reverse cholesterol transport. Nuclear receptors are among the most important transcription factors regulating genes involved in different steps of reverse cholesterol transport. Here, we discuss the role of the nuclear receptors LXR (liver X receptor) and HNF-4α (hepatocyte nuclear factor-4α) in different steps of reverse cholesterol transport. LXR controls the transcription of crucial genes in cholesterol efflux from macrophages and its transport to the liver, such as ABCA1 (ATP binding cassette A1), CYP27A1 (sterol 27-hydroxylase), CLA-1 (scavenger receptor type B1) and apolipoprotein E. Some oxysterols present in oxidized low-density lipoproteins and proinflammatory cytokines modulate the activity of LXR by antagonizing the effect of activators of this receptor, thus contributing to cholesterol accumulation in macrophages. Bile acid synthesis, which represents the final step of reverse cholesterol transport, is transcriptionally regulated by several nuclear receptors at the level of the liver-specific cytochrome P450 cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme of this metabolic pathway. Bile acids returning to the liver through the enterohepatic circulation down-regulate CYP7A1 transcription via the bile acid sensors farnesoid X receptor and HNF-4α. Based on this evidence, these nuclear receptors are candidate targets of new drugs for the treatment and prevention of atherosclerotic disease.
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Conference Article|
February 01 2004
LXR (liver X receptor) and HNF-4 (hepatocyte nuclear factor-4): key regulators in reverse cholesterol transport
M. Crestani;
M. Crestani
1
Dipartimento di Scienze Farmacologiche, Facoltà di Farmacia, Università degli Studi di Milano, via Balzaretti, 9, 20133 Milano, Italia
1To whom correspondence should be addressed (e-mail Maurizio.Crestani@unimi.it).
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E. De Fabiani;
E. De Fabiani
Dipartimento di Scienze Farmacologiche, Facoltà di Farmacia, Università degli Studi di Milano, via Balzaretti, 9, 20133 Milano, Italia
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D. Caruso;
D. Caruso
Dipartimento di Scienze Farmacologiche, Facoltà di Farmacia, Università degli Studi di Milano, via Balzaretti, 9, 20133 Milano, Italia
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N. Mitro;
N. Mitro
Dipartimento di Scienze Farmacologiche, Facoltà di Farmacia, Università degli Studi di Milano, via Balzaretti, 9, 20133 Milano, Italia
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F. Gilardi;
F. Gilardi
Dipartimento di Scienze Farmacologiche, Facoltà di Farmacia, Università degli Studi di Milano, via Balzaretti, 9, 20133 Milano, Italia
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A.B. Vigil Chacon;
A.B. Vigil Chacon
Dipartimento di Scienze Farmacologiche, Facoltà di Farmacia, Università degli Studi di Milano, via Balzaretti, 9, 20133 Milano, Italia
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R. Patelli;
R. Patelli
Dipartimento di Scienze Farmacologiche, Facoltà di Farmacia, Università degli Studi di Milano, via Balzaretti, 9, 20133 Milano, Italia
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C. Godio;
C. Godio
Dipartimento di Scienze Farmacologiche, Facoltà di Farmacia, Università degli Studi di Milano, via Balzaretti, 9, 20133 Milano, Italia
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G. Galli
G. Galli
Dipartimento di Scienze Farmacologiche, Facoltà di Farmacia, Università degli Studi di Milano, via Balzaretti, 9, 20133 Milano, Italia
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Publisher: Portland Press Ltd
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2004 Biochemical Society
2004
Biochem Soc Trans (2004) 32 (1): 92–96.
Citation
M. Crestani, E. De Fabiani, D. Caruso, N. Mitro, F. Gilardi, A.B. Vigil Chacon, R. Patelli, C. Godio, G. Galli; LXR (liver X receptor) and HNF-4 (hepatocyte nuclear factor-4): key regulators in reverse cholesterol transport. Biochem Soc Trans 1 February 2004; 32 (1): 92–96. doi: https://doi.org/10.1042/bst0320092
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