Chapter 32: Cholesterol: Absorption, Synthesis, Metabolism, and Fate

Cholesterol biosynthesis begins with acetyl-CoA and proceeds through the HMG-CoA reductase pathway, a critical regulatory step that responds dynamically to cellular cholesterol concentrations, hormonal signals including insulin and glucagon, and pharmaceutical interventions such as statins. Statins function as competitive inhibitors of HMG-CoA reductase, effectively reducing circulating low-density lipoprotein cholesterol and mitigating cardiovascular risk. The chapter presents the structural and functional characteristics of lipoproteins organized by density and composition: chylomicrons mediate dietary triglyceride transport from the intestine, very low-density lipoproteins deliver hepatically synthesized triglycerides to peripheral tissues, low-density lipoproteins serve as the primary cholesterol delivery vehicles to cells, and high-density lipoproteins facilitate reverse cholesterol transport back to the liver for excretion. Apolipoprotein variants including apoB-48, apoB-100, apoC-II, apoE, and apoA-I determine lipoprotein assembly, cellular receptor recognition, and enzymatic activation of lipid-metabolizing enzymes. Clinical case presentations illustrate pathophysiological consequences: familial hypercholesterolemia resulting from defective LDL receptors, metabolic syndrome presenting with elevated triglyceride levels, and coronary artery disease managed through statin and niacin therapy. The chapter addresses genetic disorders disrupting lipid homeostasis including Tangier disease characterized by severely diminished HDL, abetalipoproteinemia caused by microsomal triglyceride transfer protein deficiency, and Smith-Lemli-Opitz syndrome affecting cholesterol biosynthesis. Additional metabolic roles of cholesterol encompass conversion to bile acids for lipid digestion, steroid hormone synthesis in the adrenal cortex producing glucocorticoids and mineralocorticoids, androgen and estrogen production in gonads, and vitamin D synthesis through hydroxylation reactions. Collectively, these processes underscore cholesterol's essential functions in cellular structure, signaling, endocrine regulation, and disease prevention.