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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK039512-06A2
Application #
2140928
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1989-01-01
Project End
1998-08-31
Budget Start
1994-09-30
Budget End
1995-08-31
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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