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 HospitalSchool of Chinese Medicine for Post-Baccalaureate, I-Shou University Shih-Che Huang 黃士哲 2010.10.62010.10.6

INTRODUCTIONBile acids Solubilization of dietary lipids and

promotion of their absorption

From Barrett KE: Ganong’s Review of Medical Physiology. Mc-Graw-Hill, 2010

Human bile acids:CA, CDCA, DCA, LCA

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

Bile acids biosynthetic pathwaysSecondary bile acids

Trends in Pharmacological Sciences 2009;30:570-580

Enterohepatic circulation of bile acids

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

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

Bile acid receptor (TGR5) in muscle tissue thyroid hormone T4 --->T3

Trends in Pharmacological Sciences 2009;30:570-580

Bile acid receptor (TGR5) in intestinal, liver and immune cells

Trends in Pharmacological Sciences 2009;30:570-580

GLP-1: glucagon-like peptide-1

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 saltsTDC: taurodeoxycholate; TUDC: tauroursodeoxycholate

Bile salt/acid inhibit guinea pig gallbladder smooth muscle action potential

J Physiol. 2010;588:3295-305.

In Gpbar1 knockout mice, the rhythmic activity of gallbladder smooth muscle is not affected by LCA

J Physiol. 2010;588:3295-305.

Bile salt receptor GPBAR1 is expressed in mouse and guinea pig gallbladder smooth muscle

J Physiol. 2010;588:3295-305.

AIM

To investigate bile acid effects in the human and guinea pig gallbladder muscle

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.

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.)

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.)

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.

DISCUSSION

cAMP Immunohistochemistry

Serum bile acid levels: normal, 5 M Serum bile acid levels in cholestasis:

up to 30 M

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.