Hepatic bile formation facilitates the digestion and absorption of lipids from the gut, and provides a mechanism for the excretion of a wide variety of potentially toxic compounds, including cholesterol, bile pigments, and xenobiotics. Hepatic secretion of bile plays a major role in maintaining normal physiology, and failure of this function constitutes a life- threatening condition. A primary driving force for bile formation is hepatocellular secretion of bile salts. Under physiologic conditions, canalicular (apical) membrane transport is rate limiting. We hypothesize that the content of bile salt transport protein(s) in the canalicular membrane is regulated by the bile salt load imposed on the liver. thereby constituting a major mechanism for modulation of hepatic secretory capacity.
The Specific Aims of this proposal are: (1) To define the canalicular membrane transport functions regulated by bile salts, and to determine which bile salts are effective regulators. (2) To characterize the up-regulation of canalicular bile salt transport capacity, by determining the time frame for up-regulation of bile salt transport capacity, and testing possible mechanisms for up-regulation. (3) To characterize the down-regulation of canalicular bile salt transport capacity, by determining the time frame for down-regulation of bile salt transport capacity, and testing possible mechanisms for down-regulation. (4) To examine the intracellular sites where bile salts may modulate trafficking of membranes which contain canalicular proteins. This systematic investigation of hepatic regulation of canalicular bile salt secretion at the intracellular and molecular level is essential for a thorough understanding of mechanisms of hepatic bile formation. Only by elucidating these regulatory mechanisms can rational approaches for enhancing hepatic bile salt secretion capacity be designed, with the goal of alleviating, and possibly preventing, the disastrous consequences of bile secretory failure which may occur in clinical settings.
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