Apolipoprotein defects

Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 1989 86 587-591. 

Marz W, Baumstark M, Scharnagl H, Ruzicka V, Buxbaum S, Herwig J, et al. Accumulation of small dense low density lipoproteins in a homozygous patient with familial defective apolipoprotein B-100 results from heterogenous interaction of LDL subfractions with the LDL receptor. J Clin Invest 1993 92 2922-2933. 

Myant NB. Familial defective apolipoprotein B-100 a review, including some comparisons with familial hypercholesterolaemia [published erratum appears in Atherosclerosis 1994 Feb 105[2] 253[. Atherosclerosis 1993 104 1-18. 

Schaefer JR, Scharnagl H, Baumstark MW, Schweer H, Zech LA, Seyberth H, et al. Homozygous familial defective apolipoprotein B-100. Enhanced removal of apolipoprotein E-containing VLDLs and decreased production of LDLs. Arter-ioscler Thromb Vase Biol 1997 17 348-353. 

H15. Hansen, P. S., Meinertz, H., Jensen, H. K., Fruergaard, P., Launbjerg, J., Klausen, 1. C., Lemming. L., Gerdes, U., Gregersen, N., and Faergeman-, O., Characteristics of 46 heterozygous carriers and 57 unaffected relatives in five Danish families with familial defective apolipoprotein Bin,. Atheroscler. Thromb. 14, 207-213 (1994). 

Lipoprotein(a) in subjects with familial defective apolipoprotein Bl00. Atherosclerosis (Shannon. Irel.) 92, 203-212 (1992). 

D. Reduced hepatic LDL-receptor activity. Familial hypercholesterolemia is most often due to dehcient LDL-receptor activity. A less likely possibility, although not considered in this question, is reduced LDL clearance from the circulation due to defective apolipoprotein Bioo. 

Fojo SS, Brewer HB (1992) Hypertriglyceridaemia due to genetic defects in lipoprotein lipase and apolipoprotein C-II. J Intern Med 231 669-677... 

Francis GA, Knopp RH, Oram JF (1995) Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier disease. J Clin Invest 96 78-87... 

Miserez AR, Laager R, Chiodetti N, Keller U (1994) High prevalence of familial defective apolipoprotein B-100 in Switzerland. J Lipid Res 35 574-583... 

The LDL, rich in cholesterol and its esters, is taken up by receptor-mediated endocytosis, in which the apolipoprotein B-100 of LDL is recognized by receptors in the plasma membrane. HDL removes cholesterol from the blood, carrying it to the liver. Dietary conditions or genetic defects in cholesterol metabolism may lead to atherosclerosis and heart disease. 

Fate of the remaining chylomicron components After most of tt triacylglycerol has been removed, the chylomicron remnan (which contain cholesteryl esters, phospholipids, apolipoprotein and some triacylglycerol) bind to receptors on the liver (seej 228) and are then endocytosed. The remnants are the hydrolyzed to their component parts. Cholesterol and the nitrogf nous bases of phopholipids (for example, choline) can be req cled by the body. [Note If removal of chylomicron remnants by th liver is defective, they accumulate in the plasma. This is seen i type III hyperlipoproteinemia (also called familial dysbetalipopro teinemia, see p. 229). 

Release of VLDLs VLDLs are secreted directly into the blood by the liver as nascent VLDL particles containing apolipoprotein B-100. They must obtain apo C-ll and apo E from circulating HDL (see Figure 18.17). As with chylomicrons, apo C-ll is required for activation of lipoprotein lipase. [Note Abetalipoproteinemia is a rare hypolipoproteinemia caused by a defect in triacylglycerol transfer protein, leading to an inability to load apo B with lipid. As a consequence, no chylomicrons or VLDLs are formed, and tria-cylglycerols accumulate in the liver and intestine.]... 

Schmitz, G., Assmann, G., Rail, S. C., Jr., and Mahley, R. W., Tangier disease Defective recombination of a specific Tangier apolipoprotein A-I isoform (pro-apo A-I) with high density lipoproteins. Proc. Natl. Acad. Sci. U.S.A. 80, 6081-6085 (1983). 

Chylomicron remnants and very low density lipoprotein (VLDL) remnants are rapidly removed from the circulation by receptor-mediated endocytosis. ApoE, the major apolipoprotein of the chylomicron in the brain, binds to a specific receptor and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. Defects in apolipoprotein E result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants (Mahley et al., 1999). In the brain, lipidated apoE binds aggregated in a isoform-speciflc manner, apoE4 being much more effective than the other forms,... 

H. Tangier disease, lliere is an absence of HDL due to a defect in Apolipoprotein AI. Serum cholesterol levels are low. Cellular cholesterol is high. Cholesterol cannot be transported back to the liver and, instead, accumulates in phagocytic cells. The tonsils are orange (like a Tangerine) and enlarged. There are various neurologic problems and corneal opacities. 

Remnant removal disease (RRD, also called remnant lipaemia, familial dysbetalipoproteinemia) (uncommon) in which there is a defect of apolipoprotein E. This is the major ligand that allows internalisation and subsequent metabolism of remnant particles derived from VLDL and chylomicrons. The consequence is accumulation of VLDL remnants called intermediate density lipoprotein (IDL) with cholesterol and triglycerides usually in the range 6-9 mmol/1. Patients experience severe macrovascular disease (as above). 

The clinical picture is characterized by xanthomas, particularly on the tendons (especially the Achilles tendon). Xanthomas consist of cholesterol and cholestanol. The enzyme defect also results in disturbed vitamin D metabolism. Osteoporosis is thus observed quite often, with a tendency towards spontaneous fractures. (208) Striking clinical features are cerebral functional disorders (from deviant behaviour to severe dementia, motor disturbances and convulsions) as well as peripheral neurological symptoms caused by cholestanol deposits. (211) High concentrations of apolipoprotein B and cholestanol are found in the CSF. (213) Treatment is based on the administration of chenodeoxycholic acid (750 mg/day). Effectiveness is improved if HMG-CoA reductase inhibitors (e. g. pravastatin) are used concomitantly. (207, 212)... 

Fic. 11. Effect of receptor-binding-defective forms of apolipoprotein E on the hepatic clearance of plasma lipoproteins. Defective forms of apoE result in reduced clearance of chylomicron remnants, VLDLs, and IDLs and their accumulation in plasma. The chylomicron remnants and VLDLs are enriched in cholesteryl esters as the result of CETP activity, and together they constitute the /3-VLDLs, which are a hallmark of type 111 hyperlipoproteinemia. A block in the conversion of IDLs to LDLs by hepatic lipase by the presence of an abnormal apoE form also is indicated. 

Tybjaerg-Hansen A, Gallagher J, Vincent J, Houlston R, Talmud P, Dunning AM, et al. Familial defective apolipoprotein B-lOO detection in the United Kingdom and Scandinavia, and clinical characteristics of ten cases. Atherosclerosis 1990 80 235-42. 

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