Regulation of hepatic biliary secretion is poorly understood and has particular relevance to liver transplantation. Previous work from our laboratory has shown that gastrointestinal (GI) hormones may play an important role in the control of biliary secretion and composition at both the canalicular and ductular levels. Insulin and glucagon stimulate bile flow and erythritol clearance markedly inhibited biliary cholesterol secretion during stable bile salt output and had variable effects upon phospholipid output depending on the rate of bile salt secretion. Recent experiments also revealed that somatostatin profoundly inhibited basal bile flow, feeding choleresis, bile salt independent fraction, and release of a number of gastrointestinal hormones. Most studies of bile secretion have been performed with an intact nerve supply to the liver. Since hepatic transplantation severs all extrinsic neural connections to the liver, it is proposed to study the importance of neural influences in the control of biliary secretion using primarily a canine autotransplant model. the proposed studies also use a chronic bile fistula dog model and an in situ rodent liver perfusion model, both of which have already been developed in our laboratory. In addition, healthy liver transplant recipients will be studied closely as experimental subjects for similar studies. Basic animal experiments will be performed for the study of hepatic clearance of bile salts and bile salt influences on flow, electrolytes, lipid, and protein secretion after denervation. In addition, determinations of bile salt independent canalicular and ductular contributions to bile flow will be made, as well as effects of stimulation or inhibition of these fractions. Methods to study the regulation of biliary protein and a model of measuring portal and hepatic arterial blood flow using GI hormone or neural influences on bile are proposed to be developed. These studies should increase our understanding of the basic physiology of bile secretion and possibly could have direct application to the study of liver transplantation. There also may be important implications related to the pathophysiology of gallbladder disease, fatty liver, and arteriosclerosis.
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