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Disruption of neuroendocrine signaling during cholestatic liver disease: pathogenic role of bile acids in the CNS
ABSTRACT: The hypothalamic-pituitary adrenal (HPA) axis is suppressed during cholestasis, a condition in which bile cannot flow properly in the bile ducts leading to an increase in circulating bile acids. A key pathogenic hallmark of cholestatic liver disease is an outgrowth of the biliary tree. The consequences of a suppressed HPA axis on biliary growth has yet to be determined. We show biliary outgrowth is induced when circulating glucocorticoids are diminished. Bile acids are detergent molecules synthesized in the liver, which also possess signaling properties. The blood brain barrier (BBB) is known to become compromised during the course of liver disease, however the mechanism has yet to be fully elucidated. When bile acids are increased to a pathogenic level in the circulation, the BBB becomes compromised. This is due to a disruption of tight junctions in vascular endothelial cells induced by the detergent properties of bile acids. Once bile acids permeabilize the BBB they gain entrance to the brain where they accumulate in the hypothalamus. In the hypothalamus, bile acids act in a neuroendocrine fashion to reduce the activity of the HPA axis. The dampening effects of bile acids on circulating corticosterone is independent of altering GABAergic tone and the bile acid/neurosteroids receptor TGR5 activation. Bile acids can bind to the glucocorticoid receptor and lead to its nuclear translocation in a similar fashion to glucocorticoids. Hence, there is a possibility that bile acids act as decoy glucocorticoids to activate the glucocorticoid receptor and limit the activity of the HPA axis. These data suggests a novel relationship exists between the body's stress axis and biliary tree. Moreover, bile acids are potentially a molecular link between the liver and the CNS, namely the hypothalamus, and should be viewed now as a neuroendocrine hormone and not merely a detergent.
"Submitted to the Office of Research and Graduate Studies of The Texas A&M University System Health Science Center in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2013." - title page.
"Submitted to the Office of Research and Graduate Studies of the Texas A&M Health Science Center Graduate School of Biomedical Science in partial fulfillment of the requirements for the degree of Doctor of Philosophy." - leaf after title page.
Approved as to style and content by: Sharon DeMorrow, Russell Sanchez, Alejandro Arroliga, Cynthia Meininger, Heather Francis.
Ph. D. Texas A&M University System Health Science Center 2013.
Includes bibliographical references (leaves 88-98).