Bile Acids as Hormones

Bile acids have long been known to facilitate digestion and absorption of lipids in the small intestine. Recently, it has been demonstrated that bile acids also function as hormones that bind to nuclear receptors and, through that mechanism, modulate expression of proteins involved in cholesterol homeostasis. More generally, there is considerable evidence that bile acids act in conjunction with insulin to promote the metabolism of nutrients in the liver.

Several orphan nuclear receptors have been shown to bind bile acids (cholic and chenodeoxycholic acids), including the farsenoid X receptor (FRX), the LXRalpha receptor and the CPA receptor. Further, the resulting bile acid-receptor complexes have been shown capable of binding to promoter regions of specific genes and either stimulating or suppressing their transcription. In essence, bile salts can function as steroid hormones.

Studies on the binding of bile acids to the FRX receptor has provided two examples of how bile salts affect cholesterol homeostasis by altering gene expression:

• Bile acids are synthesized in hepatocytes from cholesterol. The rate-limiting enzyme in this pathway is cholesterol 7-alpha hydroxylase (7AH). The FRX-bile acid complex binds the promoter region of the 7AH gene, which suppresses its transcription. Thus, bile acids feed back negatively to block their own synthesis.
• A majority of bile acids delivered into the intestine are recycled by absorption in the ileum (enterohepatic recirculation). Absorption of bile acids into ileal epithelial cells is dependent on expression of a plasma membrane protein called the ileal bile acid transporter, which is encoded by the IBAT gene. The promoter of the IBAT gene also binds the FRX-bile acid complex, which activates transcription, leading to synthesis of additional transporters. In this case, bile salts feed forward positively to enhance their reabsorption from the gut.

These two actions suggest that in the whole animal, elevated blood levels of bile acids leads both to diminished synthesis of new bile acids and enhanced recycling of those that exist. Undoubtedly, additional endocrine actions of bile salts will be delineated through current and future studies of this newly discovered system.

References and Reviews

• Chiang JY: Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocrine Reviews 23:443-463, 2001.
• Parks DJ, Blanchard SG, Bledsoe RK, etc: Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365, 1999.
• Russell DW: Nuclear orphan receptors control choesterol catabolism. Cell 97:539, 1999.
• Zhou H, Hylemon PB. Bile acids are nutrient signaling hormones. Steroids 2014; 82:62-68.

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