Hyperlipoproteinemias type III

Hyperlipoproteinemia, Type III, is a rare hereditary disease (also called familial dysbetalipoproteinemia) manifested by the occurrence of an uncommon P-lipo-protein form. Cholesterol and triglyceride contents in the patients may occasion-ally be 2-5 times superior to the norm. 

U5. Utermann, G., Jaescbke, M., and Menzel, J., Familial hyperlipoproteinemia type III Deficiency of a specific apolipoprotein (apo E-III) in the very-low-density lipoproteins. FEBS Lett. 56, 352-355 (1975). 

The opposite error can occur if the Friedewald equation is used in patients with type III hyperlipoproteinemia. Type III hyperlipoproteinemia is characterized in part by the presence of p-VLDL, not normally present in the blood. Biochemically, p-VLDL occurs in the VLDL, density range, but is much richer in cholesterol than normal VLDL with a ratio of triglyceride/cholesterol on the order of 3 1. Application of the factor [triglyceride]/5 in type Ills would underestimate VLDL cholesterol and in turn overestimate LDL cholesterol. Thus a patient with type III hyperlipoproteinemia may appear to have an artifactually high LDL cholesterol concentration. 

Lipoprotein formed by hydrolysis of triglycerides in VLDL elevated in type III hyperlipoproteinemia. 

Familial type III hyperlipoproteinemia (broad beta disease, remnant removal disease, familial dysbetalipoproteinemia) Deficiency in remnant clearance by the liver is due to abnormality in apo E. Patients lack isoforms E3 and E4 and have only E2, which does not react with the E receptor. Increase in chylomicron and VLDL remnants of density < 1.019 (P-VLDL). Causes hypercholesterolemia, xanthomas, and atherosclerosis. 

Mann, W.A., Meyer, N., Weber, W., Meyer, S., Greten, H., and Beisiegel, U. (1995) Apolipoprotein E isoforms and rare mutations parallel reduction in binding to cells and to heparin reflects severity of associated type III hyperlipoproteinemia./. Lipid Res. 36, 517. 

Type III hyperlipoproteinemia may be treated with fibrates or niacin. Although fibrates have been suggested as the drugs of choice, niacin is a reasonable alternative because of the lack of data supporting a cardiovascular mortality benefit from fibrates and because of their potentially serious adverse effects. Fish oil supplementation may be an alternative therapy. 

Sandholzer, C., Feussner, G., Brunzell, J., and Utermann, G., Distribution of apolipopro-tein(a) in the plasma from patients with lipoprotein lipase deficiency and with type III hyperlipoproteinemia. J. Clin. Invest. 90, 1958-1965 (1992). 

Chappell, D.A. (1989) High receptor binding affinity of lipoproteins in atypical dysbetahpo-proteinemia (type III hyperlipoproteinemia). J. Clin. Invest., 84, 1906-1915. 

G3. Ganesan, D., Bradford, R. H., Ganesan, W., McConathy, W. J., Alaupovic, P., and Hazzard, W. R., Substrate specificity and polypeptide activation of postheparin plasma lipoprotein lipase in type III hyperlipoproteinemia (broad disease). CireukUion 46, Suppl. II, 248 (1972). 

Familial dysbetalipoproteinemia (type III) is characterized by the accumulation of chylomicron and VLDL remnants, which are enriched in cholesterol compared to their precursors. The primary molecular cause of familial dysbetalipoproteinemia (type III) is the homozygous presence of the apolipoprotein E2 (apoE2) isoform, which is associated with recessive inheritance of the disorder [62]. However, only 1 in 50 homozygotes for apoE2 will develop type III hyperlipoproteinemia, which is clinically characterized by palmar and tuberous xanthomas, arcus lipoides, and premature atherosclerosis of coronary, peripheral, and cerebral arteries. Precipitating factors include diabetes mellitus, renal disease, hemochromatosis, but also familial hypercholesterolemia. In addition, some rare mutations in the apoE gene have been found to cause dominant and more penetrant forms of type III hyperlipoproteinemia. 

Fredrickson DS, Morganroth J, Levy RI (1975) Type III hyperlipoproteinemia an analysis of two contemporary definitions. Ann Intern Med 82 150-157... 

Mahley RW, Huang Y, Rail SC Jr (1999) Pathogenesis of type III hyperlipoproteinemia (dys-betalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res 40 1933-1949... 

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). 

Production of LDL from VLDL in the plasma With these modifications, the VLDL is converted in the plasma to LDL. An intermediate-sized particle, the intermediate-density lipoprotein (IDL) or VLDL remnant, is observed during this transition. IDLs can also be taken up by cells through receptor-mediated endocytosis that uses apo E as the ligand. [Note Apolipoprotein E is normally present in three isoforms, E2, E3, and E4. Apo E2 binds poorly to receptors, and patients who are homozygotic for apo E2 are deficient in the clearance of chylomicron remants and IDLs. The individuals have familial type III hyperlipoproteinemia (familial dysbetalipoproteinemia, or broad beta disease), with hypercholesterolemia and premature atherosclerosis. Not yet understood is the fact that the E4 isoform confers increased susceptibility to late-onset Alzheimer disease.]... 

The isoforms of apoE were first clearly demonstrated by Utermann et al., who showed on one-dimensional isoelectric focusing of VLDL apolipoproteins that there were four major isoforms of apoE (U3— U5). These were named, from acidic to basic, apoE-1, apoE-2, apoE-3, and apoE-4. Patients with Type I1 hyperlipoproteinemia (dysbetalipoproteinemia) were, in virtually all cases, deficient in apoE-3 (U3-U6). Only 27% of subjects had apoeE-4, but this band was not associated with any particular abnormality. However, individuals deficient in apoE-3 were also deficient in apoE-4 (U6). Utermann suggested that the genetic pattern of apoE isoforms could be explained if there was a single genetic locus for apoE which could produce three apoE phenotypes, i.e., apoE-N (normal), apoE-D (deficient, associated particularly with the Type III disorder), and apoE-ND (U4, U6). 

In normolipidemic subjects, apoE is found not only in HDLc-like particles but also in two other fractions associated with triglyceride-rich lipoproteins. These are VLDL, and a lipoprotein class intermediate in size between VLDL and LDL (G3). The latter may be the normal counterpart of the (3-VLDL which accumulates in Type III hyperlipoproteinemia and in cholesterol-fed animals. 

ApoE-containing VLDL in hyperlipidemic subjects has been shown to be both the product of particles less rich in apoE (as judged by the apoE apoC ratio) and the precursor of apoE-rich intermediate-density lipoprotein (N2). In cholesterol-fed dogs (F5) and humans with Type III hyperlipoproteinemia (F5, K3) there is evidence (based on the form of apoB, B-48, or B-100, and the response to fasting) that apoE-rich (3-VLDL contains remnants of both VLDL and chylomicrons. 

While practically all subjects with Type III hyperlipoproteinemia appear to be homozygous for apoE-2 (i.e., to have the E-2IE-2 genotype), most subjects who are homozygotes for apoE-2 do not develop Type III hyperlipoproteinemia. Indeed, about 1% of the population is an E-2/E-2 homo-... 

F5. Fainaru, M., Mahley, R. W., Hamilton, R. L., and Innerarity, T. L., Structural and metabolic heterogeneity of (J-very low density lipoproteins from cholesterol-fed dogs and from humans with Type III hyperlipoproteinemia. J. Lipid Res. 23, 702-714 (1982). 

H21. Hazzard, W. R., Wamick, G. R., Utermann, G., Albers, J. J., and Lewis, B., The complex genetics of Type III hyperlipoproteinemia Influence of co-inherited monogenic hyperlipidemia upon the phenotypic expression of apolipoprotein E3 deficiency. In Atherosclerosis V (A. M. Gotto, Jr., L. C. Smith, and B. Allen, eds.), pp. 260-263. Springer-Verlag, Berlin and New York, 1980. 

Type I lipoproteinemia is generally caused by the inability of the organism to clear chylomicrons. The problem may be defective ApoC-II or a defective lipoprotein lipase. Very often, chylomicron clearance may be affected by injection of heparin, which apparently releases hepatic lipase from the liver into the circulation. ApoE disorders may be associated with type III lipoproteinemia, in which clearance of IDL is impeded. Increases in circulatory LDL are usually caused by a decrease in tissue receptors specific for ApoB-100. An extreme case of type Ha hyperlipoproteinemia is familial hypercholesterolemia, in which serum cholesterol levels may be as high as 1000 mg/dL and the subjects may die in adolescence from cardiovascular disease. There is total absence of ApoB-100 receptors. Mild type Ila and lib lipoproteinemias are the most commonly occurring primary lipoproteinemias in the general population. 

Patients with familial type III hyperlipoproteinemia develop the following... 

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,... 

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