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Fig. 1: Sites of action of medications taken by the patient. The liver is central to cholesterol metabolism. Hepatic cholesterol can be synthesized from acetyl coenzyme A (CoA) in a multistep enzymatic process, whose rate-limiting enzyme (3-hydroxy-3-methylglutaryl CoA reductase) is inhibited by statins such as atorvastatin. Hepatic cholesterol is used in part to synthesize bile acids that are destined, with sterols, for secretion in bile. The luminal sterol pool in the upper portion of the small intestine comes from both dietary and biliary sterols. Intestinal luminal sterols are transported into enterocytes and repackaged into chylomicrons for secretion into lymph and, ultimately, plasma. Ezetimibe likely inhibits sterol absorption by interfering with the sterol transporter Niemann–Pick C1 Like 1 protein.5 Bile acids advance through the intestinal lumen and facilitate intestinal cholesterol absorption. Unbound bile acids are normally recycled through the terminal ileum into the enterohepatic circulation. Bile acid-binding resins, such as colestipol, prevent this recycling and force more hepatic cholesterol into bile acid synthesis. To compensate for the depletion of hepatic cholesterol stores induced by all of these drugs, the liver increases expression of cell-surface low-density lipoprotein (LDL) receptors to extract more cholesterol from the plasma by receptor-mediated endocytosis. Although both copies of the LDL-receptor gene were defective in this patient — causing very high baseline plasma LDL cholesterol — each had some residual activity, and she was able to respond to treatment. See the animated figure at www.cmaj.ca/cgi/content/full/172/4/495/DC1. Photo: Lianne Friesen and Nicholas Woolridge
