Mechanism of action of bile acid sequestrants and other lipid-lowering drugs

Cardiology. 1989;76 Suppl 1:65-71; discussion 71-4. doi: 10.1159/000174548.

Abstract

Although the primary and direct action of the bile acid sequestrants is to bind bile acids in the gut, their interruption of the enterohepatic recirculation of bile acids has important effects on hepatic lipoprotein metabolism. Three key enzyme systems are affected: phosphatidic acid phosphatase, cholesterol 7 alpha-hydroxylase, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Activation of phosphatidic acid phosphatase promotes hepatic triglyceride (TG) synthesis, induces secretion of TG-rich, very low density lipoprotein particles, and consequently, increases plasma TG levels. The activation of hepatic cholesterol 7 alpha-hydroxylase promotes the conversion of intracellular cholesterol to bile acids. The decrease in intracellular cholesterol stores, in turn, increases low-density lipoprotein (LDL) receptor expression on hepatocyte surface membranes and, consequently, receptor-mediated fractional catabolism of LDL. Reduction of intracellular cholesterol may also increase the synthesis of cholesterol through activation of HMG CoA reductase. The potential loss of the sequestrant's cholesterol-lowering efficacy can be overcome by adding a drug to the regimen that inhibits HMG CoA reductase. Finally, bile acid sequestrants promote apoprotein AI synthesis by an unknown mechanism and tend to raise high-density lipoprotein (HDL) cholesterol levels, primarily by increasing plasma HDL-2 concentrations.

MeSH terms

  • Anion Exchange Resins / pharmacology*
  • Cholesterol / metabolism
  • Humans
  • Intestines / drug effects
  • Ion Exchange Resins / pharmacology*
  • Lipid Metabolism
  • Lipoproteins / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Triglycerides / metabolism

Substances

  • Anion Exchange Resins
  • Ion Exchange Resins
  • Lipoproteins
  • Triglycerides
  • Cholesterol