MEDICAL HYPOTHESES AND RESEARCH
VOL. 3, No. 1, January 2006



S. Khurana, et al. [2006] Med Hypotheses Res 3: 651-663.


Steroid Ring Hydroxylation and Conjugation Modulate
Bile Acid-Mediated Cellular Signaling: Molecular Basis
of Hormone-Like Behavior


Sandeep Khurana, Kunrong Cheng and Jean-Pierre Raufman*


Abstract. Beyond their known functions of facilitating cholesterol excretion and lipid
absorption, recent studies indicate that bile acids play an important role as cell membrane
and nuclear receptor ligands that alter post-receptor signaling and cell function. These
findings support the novel hypothesis that bile acids are important cellular signaling
molecules. Bile acid structure modifications, particularly steroid nucleus hydroxylation and
conjugation, result in conformational changes that alter molecular charge and solubility.
These structural characteristics determine the interaction of bile acids with cellular receptors,
their access to different cellular compartments, and their interaction with subcellular
components. Unconjugated hydrophobic bile acids interact primarily with death receptor
pathways to induce apoptosis in hepatobiliary and colonic epithelial cells. In contrast, more
soluble conjugated bile acids act as cell membrane receptor ligands that initiate post-receptor
intracellular cell signaling and alter cell function. Experimental evidence indicates that
conjugated secondary bile acids activate several plasma membrane receptors, including
G-protein-coupled receptors and receptor tyrosine kinases. These functional interactions with
cell membrane receptors on gastric chief cells, colon cancer cells and vascular endothelial
cells stimulate pepsinogen secretion, colon cancer cell proliferation and vasorelaxation,
respectively. As reviewed here, cellular signaling actions of bile acids depend on at least three
major variables: (i) hydroxylation and conjugation of the steroid nucleus; (ii) cellular
expression of relevant plasma membrane and nuclear receptors; and (iii) target cell exposure
to effective bile acid concentrations. Further elucidation of molecular mechanisms
underlying the cellular signaling actions of bile acids will identify new therapeutic targets for
common disorders.


*Address all correspondence to: Jean-Pierre Raufman, M.D., Division of
Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 South
Greene Street, N3W62, Baltimore, MD 21201. Phone: 410-328-1895. Fax: 410-328-8315.
E-Mail:
jraufman@medicine.umaryland.edu




Full Text PDF