Cholesterol to bile acids via 7-alpha-hydroxylase, the rate-limiting step
Expansion
- Primary bile acids: cholic and chenodeoxycholic acid, made in the liver from cholesterol
- Rate-limiting enzyme: cholesterol 7-alpha-hydroxylase
- Conjugated with glycine or taurine to form bile salts, which are more soluble and better detergents at intestinal pH
- Secondary bile acids: deoxycholic and lithocholic, produced by colonic bacterial dehydroxylation
Regulation: bile acids returning to the liver activate the nuclear receptor FXR, which suppresses 7-alpha-hydroxylase, a negative feedback loop.
Pharmacological exploitation: bile acid sequestrants such as colestyramine bind bile acids in the gut and prevent their reabsorption. The liver responds by increasing 7-alpha-hydroxylase, consuming cholesterol to replace them, and upregulating LDL receptors. Hence they lower LDL.
Side effects follow the mechanism: they interfere with absorption of fat-soluble vitamins and of other drugs, and can raise triglycerides.
Because bile acid excretion is the only major route of cholesterol elimination, interrupting the enterohepatic circulation is a powerful lever on cholesterol balance.