Types of bile acids
1.2 Biosynthesis of Bile Acids
Two pathways, classical (neutral) pathway and alternative pathway, are known for the biosynthesis of bile acids .
Neutral pathway is the major pathway of the biosynthesis of bile acids in adult humans, which starts from 7ɑ-hydroxylation of cholesterol, followed by the oxidative cleavage of the side chain staring from 27-hyrdoxylation (Fig. 1.2). 7ɑ-Hydroxylation of cholesterol (1) is performed in hepatic microsomes, and 7ɑ-hydroxycholesterol (2) is produced. This reaction is catalyzed by cholesterol 7ɑ-hydroxylase (CYP7A1), a rate-limiting step of bile acid biosynthesis. The activity of CYP7A1 is subjected to negative feedback by bile acids returning to the liver via the portal vein. This negative feedback does not occur by external bile drainage, ileal resection, and bile acid absorbent administration, and the activity of CYP7A1 is increased and bile acid biosynthesis increases up to six- to sevenfolds. 7ɑ-Hydroxycholesterol (2) is metabolized to 7ɑ-hydroxycholest-4-en-3-one (3) by the oxidation of 3 ß-hydroxyl residue and the transposition of the double bond from Δ5 to Δ4. A part of 7ɑ-hydroxycholest-4-en-3-one (3) is converted to 7ɑ, 12ɑ-dihydroxycholest-4-en-3-one (8) by microsomal sterol 12ɑ-hydroxylase (CYP8B1). 7ɑ-Hdroxycholest-4-en-3-one (3) and 7ɑ, 12ɑ-dihydroxycholest-4-en-3-one (8) are subjected to the oxidation of the Δ4–3-keo residue and converted to the intermediates of 5ß-cholestane-3ɑ,7ɑ-diol (4) and 5ß-cholestane-3ɑ, 7ɑ, 12ɑ-triol (9) with the mother nucleus of CDCA and CA, respectively, and the side chain of cholesterol, followed by the oxidized cleavage of the side chain. At first, 5ß-cholestane-3ɑ, 7ɑ-diol (4) and 5ß-cholestane-3ɑ, 7ɑ, 12ɑ-triol (9) are converted to 5ß-cholestane-3ɑ, 7ɑ, 27-triol (5) and 5ß-cholestane-3ɑ, 7ɑ, 12ɑ, 27-tetrol (10) by sterol 27-hydroxylase (CYP27A1) of hepatic mitochondria. Next, the hydroxyl residues of 5ß-cholestane-3ɑ,7ɑ, 27-triol (5) and 5ß-cholestane-3ɑ, 7ɑ, 12ɑ, 27-tetrol (10) are oxidized to the carboxyl residue via the aldehyde residue, producing 3ɑ, 7ɑ-dihydoxy-5ß-cholestanoic acid (6) and 3ɑ, 7ɑ, 12ɑ-trihydoxy-5ß-cholestanoic acid (11). Finally, these are subjected to ß-oxidation, similar to the ß-oxidation of fatty acids, and CDCA (7) and CA (12) are produced. In fact, CDCA and CA are produced as the CoA derivatives and secreted as the glycine or taurine conjugates after the conjugation with glycine or taurine.
The biosynthesis pathway of bile acids (2) 7ɑ-hydroxycholesterol, (3) 7ɑ-hydroxycholest-4-en-3-one, (4) 5ß-cholestane-3ɑ,7ɑ-diol, (5) 5ß-cholestane-3ɑ,7ɑ, 26-triol, (6) 3ɑ,7ɑ-dihydoxy-5ß-cholestanoic acid, (8) 7ɑ, 12ɑ-dihydroxycholest-4-en-3-one, (9) 5ß-cholestane-3ɑ,7ɑ, 12ɑ-triol, (10) 5ß-cholestane-3ɑ,7ɑ, 12ɑ, 27-tetrol, (11) 3ɑ,7ɑ, 12 ɑ-trihydoxy-5ß-cholestanoic acid
The acidic pathway of bile acid biosynthesis is started by CYP27A1, which produces 27-hydoxycholesterol, followed by oxysterol 7α-hydroxylase (CYP7B1), which produces 3ß,7ɑ-dihydoxy-5-cholestenoic acid . These two enzymes are expressed in most tissues and are responsible for oxidation of cholesterol. Oxysterols transported to hepatocytes are converted to bile acids. Other alternative pathways have also been reported in humans.
Farnesoid X receptor (FXR) is known to inhibit CYP7A1, CYP8B1, CYP27A1, and CYP7B1 . Two mechanisms have been reported to inhibit bile acid biosynthesis by bile acids. In the liver, FXR induces the negative nuclear receptor, small heterodimer partner (SHP), which inhibits CYP7A1 and CYP8B1 gene transcription. FXR and SHP are activated by bile acids in the liver. In the intestine, FXR agonists induce fibroblast growth factor 15 (FGF15; FGF19 in humans), which activates the liver FGF receptor 4/β-Klotho signaling pathway in the liver to inhibit CYP7A1 and CYP8B1 expression . Schaap et al. reported that hepatic FGF19 levels were increased and inversely correlated to the reduced CYP7A1 expression levels in patients with extrahepatic cholestasis .