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

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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 黃黃黃 2010.10.6 2010.10.6

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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. - PowerPoint PPT Presentation

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

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

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INTRODUCTIONBile acids Solubilization of dietary lipids and

promotion of their absorption

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

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Human bile acids:CA, CDCA, DCA, LCA

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

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Bile acids biosynthetic pathwaysSecondary bile acids

Trends in Pharmacological Sciences 2009;30:570-580

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Enterohepatic circulation of bile acids

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

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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

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

Trends in Pharmacological Sciences 2009;30:570-580

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

Trends in Pharmacological Sciences 2009;30:570-580

GLP-1: glucagon-like peptide-1

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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

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

J Physiol. 2010;588:3295-305.

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

J Physiol. 2010;588:3295-305.

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

J Physiol. 2010;588:3295-305.

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AIM

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

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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.

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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.)

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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.)

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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.

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DISCUSSION

cAMP Immunohistochemistry

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

up to 30 M

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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.