Lipoproteins hypercholesterolemia

The hver and many extrahepatic tissues express the LDL (B-lOO, E) receptor. It is so designated because it is specific for apo B-IOO but not B-48, which lacks the carboxyl terminal domain of B-lOO containing the LDL receptor ligand, and it also takes up lipoproteins rich in apo E. This receptor is defective in familial hypercholesterolemia. Approximately 30% of LDL is de-... 

Han KH, Han KO, Green SR, Quehenberger O. Expression of the monocyte chemoattractant protein-1 receptor CCR2 is increased in hypercholesterolemia. Differential effects of plasma lipoproteins on monocyte function. J Lipid Res 1999 40(6) 1053-1063. 

Hyperlipemia may manifest itself by an increased concentration of lipids, or certain groups thereof. For example, hypercholesterolemia and hypertriglyceri-demia may be mentioned in this connection. Since practically all the blood plasma lipids make part of lipoproteins, hyperlipemias may be reduced to one of the hyper-lipoproteinemia forms which differ in the varied ratios of plasma lipoproteins of different groups. 

Sanllehy C, Casals E, Rodriguez-Vil-lar C, Zambon D, Ojuel J, Ballesta AM, et al. Lack of interaction of apolipo-protein E phenotype with the lipoprotein response to lovastatin or gemfibrozil in patients with primary hypercholesterolemia. Metabolism 1998 47 560-565. 

Marz W, Grutzmacher P, Paul D, Siekmeier R, Schoeppe W, Gross W. Effects of lovastatin [20-80 mg daily) on lipoprotein fractions in patients with severe primary hypercholesterolemia. Int J Clin Pharmacol Ther 1994 32 92-97. 

The answer is a. (Katzung, p 590.) Bile acids are absorbed primarily in the ileum of the small intestine. Cholestyramine binds bile acids, preventing their reabsorption in the jejunum and ileum. Up to 10-fold greater excretion of bile acids occurs with the use of resins. The increased clearance leads to increased cholesterol turnover of bile acids. Low-density lipoprotein receptor upregulation results in increased uptake of LDL. This does not occur in homozygous familial hypercholesterolemia because of lack of functioning receptors. 

Familial hypercholesterolemia (FH), an autosomal dominant disorder of lipoprotein metabolism, is caused by absent or defective LDL receptors. Several studies indicated that Lp(a) levels were approximately doubled in FH heterozygotes, compared to their unaffected family members or non-FH controls (H30, L14, M20, M21, U8, W13, W14). 

L14. Leitersdorf, E., Friedlander, Y., Bard, J.-M., Fruchard, J.-C., Eisenberg, S., and Stein, Y., Diverse effect of ethnicity on plasma lipoprotein(a) levels in heterozygote patients with familial hypercholesterolemia. J. Lipid Res. 32, 1513-1519 (1991). 

M19. Matsunaga, A., Handa, K., Mori, T., Moryama, K., Hidaka, K., Yuki, M., Sasaki, J., and Arakawa, K., Effects of nieritrol on levels of serum lipids, lipoprotein(a) and fibrinogen in patients with primary hypercholesterolemia. Atherosclerosis [Pg.126]

M., Lockley, P., and Miller, J. P., Serum lipoprotein(a) in patients heterozygous for familial hypercholesterolemia, their relatives, and unrelated control populations. Arterioscler. Thromb. 11, 940-946 (1991). 

Seed, M., Hopplicher, F., Reaveley, D., McCarthy, S., Thompson, G. R., Boerwinkle, E., and Utermann, G, Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N. Engl. 

Sorensen, K. E., Celermajer, D. S., Georgakopoulos, D., Hatcher, G., Betteridge, D. J., and Deanfield, J. E., Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. J. Clin. Invest. 93, 50-55 (1994). 

Soutar, A. K., McCarthy, S. N., Seed, M., and Knight, B. L., Relationship between apopro-tein(a) phenotype, lipoprotein(a) concentration in plasma and low-density lipoprotein (LDL) receptor function in a large kindred with Familial Hypercholesterolemia due to the Pro Leu mutation in the LDL-receptor gene. J. Clin. Invest. 88, 483-492 (1991). 

T4. Tato, F., Keller, C., Schuster, H., Spengel, F., Wolfram, G., and Zollner, N., Relation of lipoprotein(a) to coronary heart disease and duplex sonographic findings of the carotid arteries in heterozygous and familial hypercholesterolemia. Atherosclerosis (Shannon. Irel.) 101, 69-77 (1993). 

Monotherapy - Administered alone as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) in patients with primary (heterozygous familial and nonfamilial) hypercholesterolemia. 

The choice of target cells is another point worthy of discussion. In some instances, this choice is pre-determined, e.g. treatment of the genetic condition familial hypercholesterolemia would require insertion of the gene coding for the low-density lipoprotein receptor specifically in hepatocytes. 

Patients with HL deficiency present with hypercholesterolemia and hypertriglyceridemia, and accumulate VLDL remnants, triglyceride-rich LDL, and HDL [84]. These remnants mainly derive from a reduced catabolism of apoB-containing lipoproteins [82]. The disorder appears to be inherited in an autosomal recessive trait and is associated with an increased risk for coronary artery disease [8]. 

Familial hypercholesterolemia (FH) is one of the most common genetic disorders in lipoprotein metabolism, and causes elevated cholesterol levels. This autosomal dominant disorder with a prevalence of about 1/500 in Western countries is caused by mutations in the LDLR gene. The LDLR defect impairs the catabolism of LDL and results in elevation of plasma LDL-cholesterol. Untreated heterozygous FH patients have 2-3 times elevated cholesterol levels and have a 100-fold increased risk to die... 

Blache D, Bouthillier D, Davignon J (1983) Simple, reproducible procedure for selective measurement of lipoprotein lipase and hepatic lipase. Clin Chem 29 154-158 Bodamer OA, Bercovich D, Schlabach M, Ballantyne C, Zoch D, Beaudet AL (2002) Use of denaturing HPLC to provide efficient detection of mutations causing familial hypercholesterolemia. Clin Chem 48 1913-1918... 

Neff D, Ruschitzka F, Hersberger M, Enseleit F, Hurlimann D, Noll G, Luscher T, Hanseler E (2003) Detection of a novel exon 4 low-density lipoprotein receptor gene deletion in a swiss family with severe familial hypercholesterolemia. Clin Chem Lab Med 41 266-271... 

The initial steps in BA synthesis are characterised by the introduction of a hy-droxylic group in the la position, or in position 27, followed by another in the la position into the cholesterol nucleus. Both synthetic pathways (the neutral and the acidic pathways) possess a distinct microsomal 7-oxysterol hydroxylase, which is regulated by different genes. The most recently described disorder of BA synthesis is cholesterol 7a-hydroxylase deficiency, in which their decreased production through the classical pathway is partially balanced by activation of the alternative pathway. Cholesterol levels increase in the liver, with a consequent low-density lipoprotein hypercholesterolemia, and cholesterol gallstones may result, although there is no liver disease. In contrast, a defect in the conversion of 27-hydroxy-cholesterol to la,27-dihydroxy-cholesterol due to deficiency of the oxysterol 7a-hydroxylase specific for the alternate pathway, causes severe neonatal liver disease [8]. 

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.]... 

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