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


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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.

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

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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


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 pathways

Secondary 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

GLP-1: glucagon-like peptide-1

Trends in Pharmacological Sciences 2009;30:570-580


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


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 mM

  • Serum bile acid levels in cholestasis: up to 30 mM


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.


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