In familial hypercholesterolemia, mutations in the LDL receptor protein impair the intracellular transport and catabolism of LDL, resulting in accumulation of LDL cholesterol in the plasma. In addition, the absence of LDL receptors on liver cells impairs the transport of IDL into the liver, so a greater proportion of plasma IDL is converted into LDL. Thus, patients with familial hypercholesterolemia develop excessive levels of serum cholesterol as a result of the combined effects of reduced catabolism and excessive biosynthesis (
Fig. 7.1 ). This leads to a marked increase of cholesterol uptake by the monocyte-macrophages and vascular walls through the scavenger receptor. This accounts for the appearance of skin xanthomas and premature atherosclerosis.
Familial hypercholesterolemia is an autosomal dominant disease. Heterozygotes have a twofold-to threefold elevation of plasma cholesterol levels, whereas homozygotes may have in excess of a fivefold elevation. Although their cholesterol levels are elevated from birth, heterozygotes remain asymptomatic until adult life, when they develop cholesterol deposits (xanthomas) along tendon sheaths and premature atherosclerosis resulting in coronary artery disease. Homozygotes are much more severely affected, developing cutaneous xanthomas in childhood and often dying of myocardial infarction before the age of 20 years.
Analysis of the cloned LDL receptor gene has shown that more than 900 different mutations can give rise to familial hypercholesterolemia. These can be divided into five categories. Class I mutations are uncommon, and they are associated with complete loss of receptor synthesis. With class II mutations, the most prevalent type, the receptor protein is synthesized, but its transport from the endoplasmic reticulum to the Golgi apparatus is impaired because of defects in protein folding. Class III mutations produce receptors that are transported to the cell surface but fail to bind LDL normally. Class IV mutations give rise to receptors that fail to internalize within clathrin pits after binding to LDL, whereas class V mutations encode receptors that can bind LDL and are internalized but are trapped in endosomes because dissociation of receptor and bound LDL does not occur.
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Clathrin Coated vesicle Recycling vesicle Endosome Lysosome Cholesterol HMG-CoA reductaseDNA RNA RibosomeReceptor protein Endoplasmic reticulum Receptor Golgi apparatus Plasma membrane PCSK9 StimulatesInhibitsInhibitsAmino acids Coated pit Cell membrane, steroid hormones, and bile acidsStorage of cholesterol esters Oversupply of cholesterol Synthesis of cholesterol Synthesis of LDL receptors
Fig. 7.2 TheLDLreceptorpathwayandregulationofcholesterolmetabolism.Theyellow arrows showthreeregulatoryfunctionsoffreeintracellularcholesterol:(1)suppressionofcholesterolsynthesisbyinhibitionofHMG-CoAreductase,(2)stimulatingthestorageofexcesscholesterolasesters,and(3)inhibitionofsynthesisofLDLreceptors.PCSK9causesintracellulardegradationofLDLreceptorsinlivercells,reducingthelevelofLDLreceptorsonthecellmembrane.HMG-CoA reductase, 3-Hydroxy-3-methylglutaryl–coenzymeAreductase;LDL, low-densitylipoprotein;PCSK9, proproteinconvertasesubtilisin/kexintype9.