ACTION OF BILE ACID ON GALLBLADDER MUSCLE 膽汁 酸於膽囊肌肉之作用

1. ACTION OF BILE ACID ON GALLBLADDER MUSCLE 膽汁酸於膽囊肌肉之作用 Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital School of Chinese Medicine for Post-Baccalaureate, I-Shou University Shih-Che Huang 黃士哲 2010.10.6

2. INTRODUCTIONBile acids • Solubilization of dietary lipids and promotion of their absorption From Barrett KE:Ganong’s Review of Medical Physiology.Mc-Graw-Hill, 2010

3. Human bile acids:CA, CDCA, DCA, LCA From Barrett KE:Ganong’s Review of Medical Physiology.Mc-Graw-Hill,2010；23：439

4. Bile acids biosynthetic pathways Secondary bile acids Trends in Pharmacological Sciences 2009;30:570-580

5. Enterohepatic circulation of bile acids From Barrett KE: Ganong’s Review of Medical Physiology. Mc-Graw-Hill, 2010；23：439

6. Bile acids • Bile acids act as signaling molecules • activate the bile acid receptor, a cell-surface G protein-coupled receptor (TGR5) • LCA > DCA > CDCA > CA; cAMP pathway • energy expenditure • activate the farnesoid-X-receptor (FXR), a nuclear hormone receptor • CDCA > LCA = DCA; transcription • bile acid homeostasis

7. Bile acid receptor (TGR5) in muscle tissue thyroid hormone T4 --->T3 Trends in Pharmacological Sciences 2009;30:570-580

8. Bile acid receptor (TGR5) in intestinal, liver and immune cells GLP-1: glucagon-like peptide-1 Trends in Pharmacological Sciences 2009;30:570-580

9. Bile salt TDC inhibits gallbladder contraction Dose-response curves of the gallbladder to CCK alone and in the presence of bile salts TDC: taurodeoxycholate; TUDC: tauroursodeoxycholate GASTROENTEROLOGY 1997;112 :1699-1706

10. Bile salt/acid inhibit guinea pig gallbladder smooth muscle action potential J Physiol. 2010;588:3295-305.

11. In Gpbar1 knockout mice, the rhythmic activity of gallbladder smooth muscle is not affected by LCA J Physiol. 2010;588:3295-305.

12. Bile salt receptor GPBAR1 is expressed in mouse and guinea pig gallbladder smooth muscle J Physiol. 2010;588:3295-305.

13. AIM • To investigate bile acid effects in the human and guinea pig gallbladder muscle

14. METHODS • We measured relaxation of muscle strips from the human and guinea pig gallbladder muscle caused by bile acids, CA, CDCA, DCA and LCA, in vitro.

15. RESULTS • Bile Acid DCA Causes Relaxation of Human Gallbladder Muscle Strip • Bile Acids Cause Relaxation of Carbachol-contracted Guinea Pig Gallbladder • Bile Acids Cause Relaxation of Endothelin-contracted Guinea Pig Gallbladder • (Figures are presented in the meeting place.)

16. RESULTS-continued • Bile Acids Cause Relaxation of Carbachol-contracted Human Gallbladder • Bile Acids Cause Relaxation of Endothelin-contracted Human Gallbladder • Bile Acid Caused TTX and Atropine-insensitive Relaxation of Endothelin-contracted Human Gallbladder • Reverse transcription-polymerase chain reaction analyses of the expression of bile acid receptor (TGR5) mRNA • (Figures are presented in the meeting place.)

17. SUMMARY • In carbachol-contracted gallbladder muscle strips, LCA, DCA, CDCA and CA caused relaxation. • The relative potency for bile acids to cause relaxation were LCA > DCA > CDCA > CA. • These indicate the existence of G protein-coupled bile acid receptors mediating bile acid-induced relaxation.

18. DISCUSSION • cAMP • Immunohistochemistry • Serum bile acid levels: normal, 5 mM • Serum bile acid levels in cholestasis: up to 30 mM

19. Take home message • Bile acids activate cell-surface G-protein bile acid receptors, TGR5, and nuclear receptors, FXR. • Bile acids cause relaxation of human and guinea pig gallbladder muscle through bile acid receptors, TGR5.