Structure and Main Functions
Bile acids are amphiphilic molecules, meaning they possess surfactant properties. Their chemical structure features a hydrophobic part—a massive steroid nucleus (cyclopentanoperhydrophenanthrene)—and a hydrophilic part, represented by a side chain with a carboxyl or ionized group, as well as hydroxyl radicals.
They perform three main tasks in the body:
- Digestive. They ensure lipid emulsification in the intestine. Acid molecules surround a fat droplet, immersing their hydrophobic regions inward while their hydrophilic regions face the aqueous phase. This reduces surface tension, prevents droplets from coalescing, and makes fats accessible to enzymes.
- Solubilizing. As part of bile, they keep cholesterol in a dissolved state, preventing stone formation.
- Excretory. The excretion of bile acids in feces (1.0–1.3 g/day) is the final stage of catabolism and the main pathway for eliminating cholesterol from the body (over 90% of all losses).
Biosynthesis and Classification
Acid synthesis takes place in the membranes of the endoplasmic reticulum of hepatocytes. The process is catalyzed by hydroxylase enzymes (including cytochrome $P_{450}$), which require oxygen and the coenzyme NADPH + $H^+$ to function. During chemical transformations, hydroxyl groups are added to the steroid nucleus (at positions $7\alpha$ and $12\alpha$), the side chain is shortened, and its end is oxidized to a carboxyl group.
Depending on their site of formation, acids are divided into two groups:
- Primary. Synthesized directly in the liver from cholesterol. Main representatives: cholic (three hydroxyl groups) and chenodeoxycholic (two hydroxyl groups).
- Secondary. Formed in the intestine from primary acids under the influence of bacterial microflora, which cleaves off the $7\alpha$-hydroxyl group. Cholic acid yields deoxycholic acid, and chenodeoxycholic acid yields lithocholic acid.
Conjugation and Regulatory Mechanisms
Before entering the bile, primary acids undergo conjugation. They are activated by coenzyme A (forming cholyl-CoA and chenodeoxycholyl-CoA), after which they bind to the amino acid glycine or the cysteine derivative taurine. The ratio of glycine to taurine conjugates is approximately 3:1. This step is vital: conjugation makes the molecules more polar, massively enhancing their emulsifying properties.
The synthesis process is strictly controlled at the level of the key enzyme—$7\alpha$-hydroxylase:
- Upregulation of synthesis: the substrate cholesterol induces the enzyme. Thyroid hormones also have a stimulating effect.
- Downregulation of synthesis: bile acids themselves inhibit gene transcription via negative feedback. Estrogens also act as corepressors.
Enterohepatic Circulation
The body maintains a continuous circulation of bile acids between the liver and the intestine. The release of bile stored in the gallbladder is stimulated by the hormone cholecystokinin, which is secreted in response to dietary fat intake.
Having performed their emulsifying function in the small intestine and partially converted into secondary acids by bacteria, about 95% of the bile acid pool is reabsorbed in the ileum. Via the portal vein, they return to the liver, where they are re-conjugated and secreted. Lithocholic acid, being the most hydrophobic, is the least reabsorbed and quickly leaves the body with feces.
Briefly: answers to topical questions
What cofactors and vitamins are required for the activity of 7-alpha-hydroxylase?
The activity of 7$\alpha$-hydroxylase requires oxygen ($O_2$) and NADPH as cofactors; NADPH + $H^+$ and $O_2$ are also listed in the enzymatic system of bile acid synthesis. 7$\alpha$-hydroxylase is a microsomal enzyme belonging to cytochrome $P_{450}$-containing hydroxylases, and it catalyzes the conversion of cholesterol to 7$\alpha$-hydroxycholesterol during the synthesis of primary bile acids. Sources contain no information on vitamins required for this enzyme's function.
What leads to decreased colloidal stability of bile and the formation of cholesterol stones?
Decreased colloidal stability of bile and the formation of cholesterol stones are caused by an altered ratio of bile components: cholesterol : (bile acids + phospholipids) > 1:10 (lithogenic index).
Factors contributing to this:
- absolute increase in cholesterol concentration;
- decreased concentration of solubilizers—bile acids and phospholipids/lecithin;
- decreased phospholipid excretion into bile due to a defect in the ABCB4 gene, which reduces cholesterol solubilization and leads to cholesterol stone formation or microlithiasis.
Dietary factors contributing to cholelithiasis: excess cholesterol and saturated fats, excess refined carbohydrates, lack of dietary fiber, irregular eating habits leading to bile stasis.
To remember primary acids, use the mnemonic "CHOL-ic LIVER": CHOL — CHOLic, LIVER — CHENodeoxycholic (both are formed in the liver).
Class and exam questions
Why do gallstones form when bile composition changes?
Cholesterol is a highly hydrophobic substance. Bile acids and phosphatidylcholine keep it in the form of micelles. If the concentration of acids drops, cholesterol loses its colloidal stability and precipitates.
What is the purpose of bile acid conjugation with glycine and taurine?
Binding to these molecules increases the amphiphilicity (polarity) of the acids. Consequently, their detergent properties increase sharply, allowing them to dissolve fats in the intestine more effectively.
Which bile acid is excreted from the body the fastest?
Lithocholic. Due to having only one hydroxyl group, it is the least soluble and most toxic, so the body barely reabsorbs it in the intestine.
What else to study on this topic
- Biochemical mechanism of HMG-CoA reductase inhibition by cholesterol
- Structure of bile micelles and maintenance of its colloidal stability
- Mechanism of bacterial 7α-dehydroxylation in the intestine
- Hormonal pathway of cholecystokinin action on gallbladder smooth muscle
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