Bile Acid Synthesis

1. 1

   Cholesterol + O2 + NADPH -> 7-alpha-hydroxycholesterol

   Cholesterol 7-alpha-hydroxylase (CYP7A1) 1.14.14.23 ST-0320 Irreversible rate-limiting O2 NADPH heme
   In Cholesterol O2 NADPH

   Out 7-Alpha-hydroxycholesterol
   › Notes

   Rate-limiting and committed step of the classic (neutral) pathway; feedback-inhibited by bile acids returning via FXR/FGF19, and induced when bile acids are sequestered by resins.

2. 2

   7-alpha-hydroxycholesterol -> cholic acid or chenodeoxycholic acid

   CYP8B1, CYP27A1 and side-chain oxidation enzymes ST-0321 Irreversible/directional NADPH O2
   In 7-Alpha-hydroxycholesterol

   Out Cholic acid or chenodeoxycholic acid
   › Notes

   CYP8B1 activity determines the ratio of cholic to chenodeoxycholic acid (the primary bile acids).

3. 3

   Bile acid + glycine or taurine -> glyco- or tauro-conjugated bile salt

   Bile acid-CoA synthetase + bile acid-CoA:amino acid N-acyltransferase (BAAT) ST-0322 Irreversible/directional ATP CoA-SH
   In Bile acid Glycine or taurine

   Out Glyco- or tauro-conjugated bile salt
   › Notes

   Conjugation lowers the pKa so the bile salts stay ionised and act as detergents at intestinal pH.

4. 4

   Primary bile salts -> deoxycholate and lithocholate (gut bacteria) -> enterohepatic recycling

   Bacterial 7-alpha-dehydroxylase (colonic microbiota) ST-0323 Irreversible/directional
   Out Deoxycholate
   › Notes

   About 95% of bile salts are reabsorbed in the terminal ileum by ASBT and returned to liver; loss of ileum or resin binding forces cholesterol into new bile acid synthesis.

Showing all 4 steps.