Page 153 - Human Bile Acid Metabolism: a Postprandial Perspective

Review: clinical relevance of TGR5
95% of bile acids are returned to the liver via the portal vein
A small proportion of bile acids escapes hepatic uptake and reaches the systemic circulation
Bile acids are synthesised in the liver and stored in the gallbladder
A small proportion of conjugated bile acids enter the portal vein through passive diffusion along the small intestine
The majority of conjugated bile acids are actively reabsorbed more distally along the ileum
Colonic bacteria dehydroxylate bile acids to form secondary bile acids, which are passively reabsorbed
Figure 1: The enterohepatic circulation of bile acids
After a meal, bile fl ows into the intestine. After reabsorption, the liver extracts most but not all bile acids from the portal vein, leading to postprandial peaks in systemic plasma concentration.
8
A
B
HO
O H3C
R3 CH3 X Conjugation site
CH3 H
HH R R2
Site of dehydroxylation by intestinal bacteria
H 1
Muricholic acid (rodent) Hyodeoxycholic acid (porcine) Ursodeoxycholic acid
Cholic acid
Chenodeoxycholic acid Deoxycholic acid Lithocholic acid
R1 R2 R3
β-OH H H α-OH H H
H β-OH H
H α-OH α-OH H α-OH H
H H α-OH H H H
Affinity to TGR5
+
–
– –/+ + ++ +++
Figure 2: Biochemical properties of the bile acid pool
The basic chemical structure of bile acids (A), and the specific hydroxyl groups that characterise each specific bile acid and their affinity to TGR5 (B). An OH group at R1, R2, or R3, and its spatial orientation determine the type of bile acid. R2 marks the site of dehydroxylation. X marks the site of conjugation.21 +=weak affinity. ++=moderate affinity. +++=strong affi nity. –=no affinity. –/+= weak or no affinity.
151
Hydrophobicity