Manufactured from cholesterol in the liver, bile acids emulsify fats, allowing them to be broken down and absorbed. The research team, studying mice, found that the intestine senses the level of bile acid, triggering the secretion of a hormone, called fibroblast growth factor 15 (FGF15). In turn, FGF15 limits further production of bile acid by the liver.
"Bile acids are powerful detergents whose concentrations must be tightly regulated," said study author Steven Kliewer of the University of Texas Southwestern Medical Center. "The body needs enough to absorb fat and other nutrients, but too much can damage tissues and organs. We've found a new mechanism by which a hormone produced in the intestine protects against the over-production of bile acid."
The researchers found that a receptor in the intestine senses bile acid and responds by secreting FGF15. In the liver, the secreted intestinal protein limits the activity of an enzyme called cholesterol 7a-hydroxylase (CYP7A1) critical to bile acid production, they reported. Mice completely lacking FGF15 have increased CYP7A1 activity and excrete greater quantities of bile acid.
The findings define the FGF15 protein as a hormone with an important role in signaling between the gut and liver, Kliewer said.
The results may also have important medical implications. For example, patients who can only receive nutrients intravenously often develop liver damage, he said. The new study suggests this condition may result from an excess of bile acid as the normal intestinal control is interrupted.
The findings raise additional questions about what role the circulating hormone may play in other parts of the body, Kliewer noted. Additional insight into cholesterol-derived bile acids might also yield important insights into cholesterol control, he added.
"The development of an assay to measure circulating FGFs will be crucial in understanding how FGFs may act as intestinal hormones and whether this phenomenon is relevant in humans," wrote Bo Angelin of Karolinska Institutet in an accompanying Preview. "The possible presence of a gut-liver signaling pathway may additionally help in the understanding of how distinct and rapid diurnal variation in bile acid synthesis is controlled."
The researchers include Takeshi Inagaki, Mihwa Choi, Li Peng, Antonio Moschetta, Carolyn L. Cummins, Jeffrey G. McDonald, James A. Richardson, Robert D. Gerard, Joyce J. Repa, David J. Mangelsdorf, and Steven A. Kliewer of the University of Texas Southwestern Medical Center, Dallas, Texas; Guizhen Luo,Stacey A. Jones and Bryan Goodwin of GlaxoSmithKline Research and Development, Research Triangle Park, NC. This work was supported by funding from the National Institutes of Health, the LIPID MAPS Large-Scale Collaborative Grant, the Robert A. Welch Foundation and the Howard Hughes Medical Institute.
Inagaki et al.: "Fibroblast Growth Factor 15 Functions as an Enterohepatic Signal to Regulate Bile Acid Homeostasis" Publishing in Cell Metabolism, Vol. 2; Issue: 4; October 2005, pages 217-225. DOI 10.1016/j.cmet.2005.09.001 www.cellmetabolism.org
Journal
Cell Metabolism