The mechanisms of active inorganic and organic solute transport and passive water movement that underlie bile formation and other critical hepatocellular functions are not clearly understood. Until recently, methods of study that have been responsible for the exponential increase in our understanding of transport phenomena in other epithelia had not been fully adapted to studies of hepatic transport. The proposed work seeks to identify and characterize membrane transport processes present in hepatocytes with an aim towards a better understanding of the mechanisms of bile formation and the pathophysiologic events that lead to cholestasis. Moreover, the relationship of specific transport mechanisms to other hepatocellular functions will be examined. Ion permeability and transport characteristics of rat liver plasma membrane vesicles derived from sinusoidal and canalicular domains will be studied, with particular emphasis on electrogenic Na:HCO3 transport, the sinusoidal Na:H antiport and canalicular C1:HCO3 exchange, transport processes proposed to be critically involved in a variety of hepatocellular functions, including bile formation and cell growth. With respect to bile formation, in vivo and in vitro models will be used to study specific effects of choleretic and cholestatic agents, including bile acids glucocorticoids, ethinyl estradiol, and thyroid hormone, on ion transport and permeability as well as the time course of these effects. The physiologic relevance of certain results will be further evaluated by comparison with studies on bile formation in the isolated perfused rat liver, using agents known to inhibit of stimulate specific transport processes. With respect to cell growth, the role of specific transport processes in hepatic regeneration following partial hepatectomy will be addressed using a recently described membrane vesicle preparation derived from partially hepatectomized rats and isolated perfused livers as experimental models. Vesicle transport in all sections of the proposal will be studied by radioactive tracer uptake measurements using a rapid-filtration technique. Ion permeability will be monitored with a calibrated, potential-sensitive carbocyanine dye. Isolated livers will be perfused with and erythrocyte-free solution in a previously validated recirculating system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK039167-03
Application #
3463063
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Moseley, R H; Jarose, S M; Permoad, P (1992) Organic cation transport by rat liver plasma membrane vesicles: studies with tetraethylammonium. Am J Physiol 263:G775-85
Moseley, R H; Jarose, S; Permoad, P (1992) Hepatic Na(+)-dicarboxylate cotransport: identification, characterization, and acinar localization. Am J Physiol 263:G871-9
Moseley, R H; Vashi, P G; Jarose, S M et al. (1992) Thiamine transport by basolateral rat liver plasma membrane vesicles. Gastroenterology 103:1056-65
Moseley, R H; Jarose, S; Permoad, P (1991) Adenosine transport in rat liver plasma membrane vesicles. Am J Physiol 261:G716-22
Moseley, R H; Morrissette, J; Johnson, T R (1990) Transport of N1-methylnicotinamide by organic cation-proton exchange in rat liver membrane vesicles. Am J Physiol 259:G973-82
Moseley, R H; Johnson, T R; Morrissette, J M (1990) Inhibition of bile acid transport by cyclosporine A in rat liver plasma membrane vesicles. J Pharmacol Exp Ther 253:974-80