LDL-receptor deficiency

FRUEBis J, GONZALEZ v, siLVESTRE M and PALiNSKi w (1997) Effect of probucol treatment on gene expression of VCAM-1, MCP-1, and M-CSF in the aortic wall of LDL receptor-deficient rabbits during early sihsro genss.is, Arteriosclerosis, Thrombosis and Vascular Biology 17, 1289-302. 

Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest 1998 101(2) 353-363. 

Marsh MM, Walker VR, Curtiss LK, Banka CL (1999) Protection against atherosclerosis by estrogen is independent of plasma cholesterol levels in LDL receptor-deficient mice. J Lipid Res 40 893-900... 

Tangirala RK, Rubin EM, Palinski W (1995) Quantitation of atherosclerosis in murine models correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. J Lipid Res 36 2320-2328... 

The possibility exists that in the former studies several members from single FH families were included, and that the contribution of genetics to Lp(a) was exhibited, and not the relation between LDL-receptor deficiency and Lp(a) levels. 

Various animal species have been exploited in experimental atherosclerosis research, but nowadays most of the research is performed in mice [139]. This species has the advantage of developing atherosclerotic lesions in a relatively short period of time. The emergence of a broad variety of knock-out and transgenic mouse strains has led to a huge increase in the atherosclerosis research performed in this species. Mice are resistant to atherosclerosis when fed a normal low-fat chow diet, but they can develop atherosclerotic lesions after hypercholes-terolaemia has been induced. The three most widely used models in research on atherosclerosis are diet-induced, apoE deficiency-induced or LDL receptor deficiency-induced [139]. 

Rabbits are the second most used species in this type of research, in particular the LDL receptor deficient Watanabe heritable hyperlipidaemic rabbits. These animals show expression of VCAM-1 in atherosclerotic lesions [140], but resemblance to human lesions is generally low [139,141]. 

LDL receptor deficiency leads to extreme hypercholesterolemia and its sequelae by two mechanisms. -Failure to take up cholesterol bound to LDL particles leads to accumulation and consequent elevation of blood LDL cholesterol. 

COX-2 are mainly involved in PGI2 formation and in the inflammatory process. COX-2 is inducible, for example, by pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and the control of cell growth. It promotes early atherosclerotic lesion formation in LDL receptor-deficient mice in vivo, and COX-2 is the enzyme responsible for most of the metabolism of arachidonic acid in the macrophage. 

A person with an LDL-receptor deficiency was treated with lovastatin. As a consequence of the action of this drug, the person should have... 

W.G. Girod, S.P. Jones, N. Sieber, T.Y. Aw and D.J. Lefer, Effect of hypercholesterolaemia on myocardial ischemia-rcpcrfusion injury in LDL receptor-deficient mice, Arterioscler. Thromb. Vase. Biol. 19, 2776-2781 (1999). 

Terasaka N, Hiroshima A, Koieyama T, Ubukata N, Morikawa Y, Nakai D, Inaba T (2003) T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice. FEBS Lett 536 6-11... 

Tsimikas S, Palinski W, Witztum JL (2001) Circulating autoantibodies to oxidized LDL correlate with arterial accumulation and depletion of oxidized LDL in LDL receptor-deficient mice. Arterioscler Thromb Vase Biol 21 95-100... 

LDL-receptor deficiency. In the normal condition (a), VLDL produced by the liver loses triacylglycerol as free fatty acids (FFA) via lipoprotein lipase to peripheral tissues and then proceeds down the metabolic cascade to IDL and LDL. A major portion of these two lipoprotein species is taken up by the liver or peripheral tissues via the LDL (apo B, E) receptor. In individuals with down-regulated or genetically defective LDL receptors (b), the residence time in the plasma of IDL is increa.sed, a greater proportion being converted to LDL. LDL production and turnover time are increased, and total plasma cholesterol levels become grossly abnormal. 

Most of these concepts have arisen from detailed studies in cultured fibroblasts from normal subjects and from patients with the disease, FH. Lack of the above-described regulatory features in FH fibroblasts led to the conclusion that the abnormal phenotype is caused by lack of LDL receptor function, and thus, disruption of the LDL receptor pathway. In particular, the balance between extracellular and intracellular cholesterol pools is disturbed. Clinically, the most important effect of LDL receptor deficiency is hypercholesterolemia with ensuing accelerated development of atherosclerosis and its complications (Chapter 21). In the following sections, a detailed description of the... 

Currently there are two established methods for dealing with hypercholesterolemia in patients homozygous for LDL receptor deficiency. 

Li AC, Brown KK, Silvestre MJ, et al. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2000 106(4) 523-531. 

Kammerer, I., R. Ringseis, and K. Eder. 2011a. Feeding a thermally oxidised fat inhibits atherosclerotic plaque formation in the aortic root of LDL receptor-deficient mice. JoumglafNjMrUioT 105 190-9. 

Cholesterol synthesis inhibition leads to cell proUferation inhibition provided the cell has no alternative source of cholesterol, which is easily achieved in vitro by incubating the cells in the absence of Upoprotein in the medium (Vitols et al. 1994). In LDL-receptor deficient cells, the effect of cholesterol synthesis inhibition on cell growth is not prevented by adding LDL to the medium, illustrating the role of LDL receptor in the provision of cholesterol for cell proUferation (Cuthbert et al. 1986, MartInez-Botas etal. 1999). Lovastatin blocked HL-60 cell proUferation (MartInez-... 

In hypercholesterolemic LDL-receptor-deficient male mice NO-containing aspirin (30mg/kg x day) reduced significantly plasma LDL oxidation compared with aspirin (18mg/kg x day) and placebo, as shown by the significant reduction of malondialde-... 

E- and P-Selectins, play important roles in early and advanced stages of atherosclerosis in E- and P-selectin double (LDL receptor deficient) KO mice on an atherogenic diet, lesions were smaller but contained the same number of macrophages than control animals (LDL receptor deficient) (163). 

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