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Endocrine Reviews 23 (4): 443-463
Copyright © 2002 by The Endocrine Society

Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors

John Y. L. Chiang

Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272

Correspondence: Address all correspondence and requests for reprints to: John Y. L. Chiang, Ph.D., Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, 4209 SR 44, P.O. Box 95, Rootstown, Ohio 44272. E-mail: jchiang{at}neoucom.edu

Bile acids derived from cholesterol and oxysterols derived from cholesterol and bile acid synthesis pathways are signaling molecules that regulate cholesterol homeostasis in mammals. Many nuclear receptors play pivotal roles in the regulation of bile acid and cholesterol metabolism. Bile acids activate the farnesoid X receptor (FXR) to inhibit transcription of the gene for cholesterol 7{alpha}-hydroxylase, and stimulate excretion and transport of bile acids. Therefore, FXR is a bile acid sensor that protects liver from accumulation of toxic bile acids and xenobiotics. Oxysterols activate the liver orphan receptors (LXR) to induce cholesterol 7{alpha}-hydroxylase and ATP-binding cassette family of transporters and thus promote reverse cholesterol transport from the peripheral tissues to the liver for degradation to bile acids. LXR also induces the sterol response element binding protein-1c that regulates lipogenesis. Therefore, FXR and LXR play critical roles in coordinate control of bile acid, cholesterol, and triglyceride metabolism to maintain lipid homeostasis. Nuclear receptors and bile acid/oxysterol-regulated genes are potential targets for developing drug therapies for lowering serum cholesterol and triglycerides and treating cardiovascular and liver diseases.




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