Bile formation and secretion control homeostatic mechanisms for eliminating cholesterol and tetrapyrrole molecules form the organism as well as absorption of dietary fat. Bile dysfunction causes several common diseases, including gallstones and cholestasis. This proposal employs biophysical rationale and physical-chemical methodology to further molecular understanding of the physical biochemistry of bile, its formation, secretion and functions. The PI and colleagues will design and study appropriate model systems and correlate the results with pathophysiological phenomena pertaining to the function and dysfunction of native systems. They will use I)novel flurocholesterol methodology, cryoelectron microscopy and electron energy-loss spectroscopy to elucidate physical-chemical pathways whereby cholesterol molecules are transferred from blood to liver cell and bile, ii) characterize interactions of bile salt molecules with sphingomyelin in micellar solutions and at interfaces related to cholesterol secretion, absorption and apoptosis, iii) determine the physical-chemical origin and pathophysiology of lipoprotein X in bile secretory failure, iv) define how phosphatidylcholine, cholesterol and calcium influence the physical- chemical state of natural conjugated bilrubins in model (bilrubin ditaurate) and native biles employing analytical ultracentrifugation and spectrophotometric techniques, v) measure the metastable and equilibrium solubilities of unconjugated bilirubin in modelbiles utilizing potentiometric titration and dissolution and correlate the information pathophysiologically with pigment-stone biles, vi) discover whether humans with ~black~ pigment gallstones have dysfunctional mutations of the ileal bile acid transporter gene. These objectives are designed to advance our understanding of physical chemistry of bile as ell as normal and abnormal movements of cholesterol and billirubin to and from the liver and alimentary tract. The systematic project should lead to new targets and strategies for prevention of pigment and cholesterol gallstone diseases as well as lipid transport abnormalities sin cholestasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK036588-14
Application #
2850500
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Serrano, Jose
Project Start
1985-07-01
Project End
2004-03-31
Budget Start
1999-05-01
Budget End
2000-03-31
Support Year
14
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Neubrand, Michael W; Carey, Martin C; Laue, Thomas M (2015) Influence of Phosphatidylcholine and Calcium on Self-Association and Bile Salt Mixed Micellar Binding of the Natural Bile Pigment, Bilirubin Ditaurate. Biochemistry 54:6783-95
Woods, Stephanie E; Leonard, Monika R; Hayden, Joshua A et al. (2015) Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous ""black"" pigment gallstone formation in germfree Swiss Webster mice. Am J Physiol Gastrointest Liver Physiol 308:G335-49
Neubrand, Michael W; Carey, Martin C; Laue, Thomas M (2015) Self-assembly of aqueous bilirubin ditaurate, a natural conjugated bile pigment, to contraposing enantiomeric dimers and M(-) and P(+) tetramers and their selective hydrophilic disaggregation by monomers and micelles of bile salts. Biochemistry 54:1542-57
Berman, Marvin D; Carey, Martin C (2015) Metastable and equilibrium phase diagrams of unconjugated bilirubin IX? as functions of pH in model bile systems: Implications for pigment gallstone formation. Am J Physiol Gastrointest Liver Physiol 308:G42-55
Wang, David Q-H; Carey, Martin C (2014) Therapeutic uses of animal biles in traditional Chinese medicine: an ethnopharmacological, biophysical chemical and medicinal review. World J Gastroenterol 20:9952-75
Lavoie, B; Nausch, B; Zane, E A et al. (2012) Disruption of gallbladder smooth muscle function is an early feature in the development of cholesterol gallstone disease. Neurogastroenterol Motil 24:e313-24
Zhang, Ji; Handy, Diane E; Wang, Yufang et al. (2011) Hyperhomocysteinemia from trimethylation of hepatic phosphatidylethanolamine during cholesterol cholelithogenesis in inbred mice. Hepatology 54:697-706
Freudenberg, Folke; Leonard, Monika R; Liu, Shou-An et al. (2010) Pathophysiological preconditions promoting mixed ""black"" pigment plus cholesterol gallstones in a DeltaF508 mouse model of cystic fibrosis. Am J Physiol Gastrointest Liver Physiol 299:G205-14
Wang, David Q-H; Cohen, David E; Carey, Martin C (2009) Biliary lipids and cholesterol gallstone disease. J Lipid Res 50 Suppl:S406-11
Biddinger, Sudha B; Haas, Joel T; Yu, Bian B et al. (2008) Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med 14:778-82

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