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 2010.10.6 Shih-Che Huang 黃士哲 2010.10.6

2. INTRODUCTION Bile 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 Trends in Pharmacological Sciences 2009;30:570-580 GLP-1: glucagon-like peptide-1

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

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  M  Serum bile acid levels in cholestasis: up to 30  M

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.