Biological role of bile acids
Bile acids are amphiphilic cholesterol derivatives that play a key role in the digestion and absorption of lipids in the small intestine. They emulsify fats, vastly increasing the contact area between lipid droplets and pancreatic lipase, which ensures efficient hydrolysis of triacylglycerols.
In addition to their digestive function, bile acids are the end product of cholesterol catabolism. The synthesis of bile acids is the primary pathway for eliminating cholesterol from the body: a significant amount of cholesterol is used for this purpose daily, making this mechanism the main regulator of cholesterol levels.
Synthesis of primary bile acids
Synthesis occurs in hepatocytes from cholesterol involving hydroxylases, enzymes belonging to the P450 cytochrome system. Hydroxylases introduce hydroxyl groups at the 7α and 12α positions of the steroid nucleus.
The key and regulatory enzyme of the pathway is 7α-hydroxylase. The reaction requires:
- molecular oxygen (O₂);
- two NADPH molecules, derived from the active pentose phosphate pathway.
As a result, two primary bile acids are formed in the liver:
- cholic acid (trihydroxylated);
- chenodeoxycholic acid (dihydroxylated).
Conjugation of bile acids
To increase amphiphilicity and enhance emulsifying properties, bile acids undergo conjugation with glycine or taurine. The reaction is preceded by the activation of the bile acid to form a thioester with coenzyme A (e.g., cholyl-CoA).
This yields conjugated bile acids (bile salts):
- glycocholic and taurocholic acids, which are derivatives of cholic acid;
- glycochenodeoxycholic and taurochenodeoxycholic acids, which are derivatives of chenodeoxycholic acid.
Conjugated forms are stronger detergents and exist as salts at physiological pH.
Regulation of synthesis
The rate of bile acid synthesis is determined by the activity of 7α-hydroxylase and is weakly dependent on the transition between absorptive and postabsorptive states. Regulation occurs primarily via feedback at the transcriptional level:
- Cholic and chenodeoxycholic acids inhibit the transcription of the 7α-hydroxylase gene;
- Cholesterol induces 7α-hydroxylase transcription while suppressing HMG-CoA reductase, the rate-limiting enzyme of its own synthesis;
- Thyroid hormones increase 7α-hydroxylase expression;
- Estrogens decrease its expression.
Thus, cholesterol stimulates its own conversion into bile acids while inhibiting its synthesis, thereby maintaining cholesterol homeostasis. The influence of estrogens explains the greater propensity of women for cholesterol accumulation: they have decreased bile acid synthesis and increased cholesterol synthesis.
Secondary bile acids and enterohepatic circulation
From the liver, bile acids pass into the gallbladder, where they are concentrated. When fatty food enters the duodenum, cholecystokinin is released, causing gallbladder contraction and the discharge of bile into the intestinal lumen.
In the lower parts of the small intestine, the intestinal microflora deconjugates the bile acids and removes the 7α-hydroxyl group, forming secondary bile acids:
- deoxycholic acid from cholic acid;
- lithocholic acid from chenodeoxycholic acid.
In the ileum, about 95% of bile acids are reabsorbed and returned via the portal vein to the liver, where they are re-conjugated with glycine and taurine and re-secreted into bile. This process is called enterohepatic circulation. Thus, bile contains both primary and secondary bile acids.
Bile composition and cholelithiasis
The main components of bile are bile acids, cholesterol, phosphatidylcholine, and bile pigments (heme catabolism products). Bile acids, together with phosphatidylcholine, keep cholesterol in a dissolved (micellar) state.
If the ratio of these components is disrupted—due to a decrease in bile acids or phosphatidylcholine or an excess of cholesterol—the solubility of cholesterol drops, and it precipitates to form stones. This leads to cholelithiasis (gallstone disease).
Stones are classified as:
- pure cholesterol stones (colorless);
- pigment stones (dark, containing bilirubinates);
- mixed stones.
Normally, 1–3 g of bile acids and cholesterol are excreted through the intestine per day, ensuring the elimination of more than 90% of dietary and tissue-synthesized cholesterol, thus maintaining its homeostasis.
Key points
- Bile acids are amphiphilic cholesterol derivatives that emulsify fats and provide the primary pathway for cholesterol elimination.
- Primary bile acids—cholic and chenodeoxycholic—are synthesized in the liver from cholesterol.
- The regulatory enzyme of synthesis is 7α-hydroxylase (cytochrome P450), which requires O₂ and NADPH.
- Bile acids are conjugated with glycine or taurine via an acyl-CoA intermediate.
- Cholesterol activates 7α-hydroxylase and inhibits HMG-CoA reductase; estrogens reduce bile acid synthesis.
- Microbial action produces secondary acids—deoxycholic and lithocholic.
- About 95% of bile acids are reabsorbed in the ileum—the enterohepatic circulation.
- Disruption of the ratio of cholesterol, bile acids, and phosphatidylcholine in bile leads to the development of cholelithiasis.