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Journal of Lipid Research, Vol. 50, 1509-1520, August 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Thematic Review

Thematic Review Series: Bile Acids

Bile acids as regulatory molecules

Phillip B. Hylemon^1,*, Huiping Zhou^*, William M. Pandak, Shunlin Ren, Gregorio Gil and Paul Dent

^* Departments of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0678
Department of Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0678
Department of Biochemistry, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298-0678

¹ To whom correspondence should be addressed. e-mail hylemon{at}vcu.edu

In the past, bile acids were considered to be just detergent molecules derived from cholesterol in the liver. They were known to be important for the solubilization of cholesterol in the gallbladder and for stimulating the absorption of cholesterol, fat-soluble vitamins, and lipids from the intestines. However, during the last two decades, it has been discovered that bile acids are regulatory molecules. Bile acids have been discovered to activate specific nuclear receptors (farnesoid X receptor, preganane X receptor, and vitamin D receptor), G protein coupled receptor TGR5 (TGR5), and cell signaling pathways (c-jun N-terminal kinase 1/2, AKT, and ERK 1/2) in cells in the liver and gastrointestinal tract. Activation of nuclear receptors and cell signaling pathways alter the expression of numerous genes encoding enzyme/proteins involved in the regulation of bile acid, glucose, fatty acid, lipoprotein synthesis, metabolism, transport, and energy metabolism. They also play a role in the regulation of serum triglyceride levels in humans and rodents. Bile acids appear to function as nutrient signaling molecules primarily during the feed/fast cycle as there is a flux of these molecules returning from the intestines to the liver following a meal. In this review, we will summarize the current knowledge of how bile acids regulate hepatic lipid and glucose metabolism through the activation of specific nuclear receptors and cell signaling pathways.—Hylemon, P. B., H. Zhou, W. M. Pandak, S. Ren, G. Gil, and P. Dent. Bile acids as regulatory molecules.

Supplementary key words short heterodimer partner • fibroblast growth factor 15/19 • G protein coupled receptor TGR5 • muscarinic receptors • cholesterol 7-hydroxylase • sterol 12-hydroxylase • sterol 27-hydroxylase • steroidogenic acute regulatory protein • secondary bile acids • intestine

Abbreviations: ASM, acidic sphingomyelinase; CYP7A1, cholesterol 7-hydroxylase; D2, type 2 iodothyronine deiodinase; FXR, farnesoid X receptor; HNF4, hepatocyte nuclear factor 4; IL-1, interleukin 1; JNK, c-jun N-terminal kinase; LXR, liver X receptor; PKA, protein kinase A; PKC, protein kinase C; PXR, preganane X receptor; SHP, short heterodimer partner; SREBP, sterol-regulatory element binding protein; TNF-, tumor necrosis factor-; VDR, vitamin D receptor

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