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At least 19 recordsLinked to original sources

PubMed1998

Expression of LDL receptor, VLDL receptor, LDL receptor-related protein, and scavenger receptor in rabbit atherosclerotic lesions: marked induction of scavenger receptor and VLDL receptor expression during lesion development.

BACKGROUND: Atherosclerotic lesions contain foam cells that arise from monocyte-macrophages and smooth muscle cells (SMCs) by excessive uptake of lipoproteins. There are many candidate receptors for the lipid accumulation, such as LDL receptor (LDLR), VLDL receptor (VLDLR), LDL receptor-related protein (LRP), and scavenger receptors (SRs). However, little quantitative information exists on the expression of these receptors in normal and atherosclerotic arteries. METHODS AND RESULTS: Competitive reverse transcription-polymerase chain reaction and in situ hybridization were used for the studies in New Zealand White (NZW) and Watanabe heritable hyperlipidemic (WHHL) rabbit aortic intima-medias. NZW rabbits were fed a 1% cholesterol diet for 0 (control group), 3, 6, or 14 weeks. LDLR mRNA expression was low in aortic intima-medias of all groups. Of the analyzed receptors, LRP had the highest expression in the control group, and its mRNA was induced threefold in the 14-week group, the aortas of which had extensive lesions. SR expression was low and VLDLR expression moderate in the control group. Both receptors were highly induced during cholesterol feeding (SRs, 3-fold and 270-fold induction; VLDLR, 15-fold and 100-fold induction in the 3-week and 14-week groups, respectively). Comparable results were obtained from WHHL rabbits: high basal LRP mRNA in normal intima-medias; moderate induction of LRP and marked induction of SRs and VLDLR in fatty streaks and fatty plaques. In situ hybridization indicated that LRP and VLDLR were expressed in SMCs and macrophages. VLDLR expression was also observed in endothelial cells. SR expression was detected only in macrophages. CONCLUSIONS: SR and VLDLR mRNAs were highly induced in atherosclerotic lesions. VLDLR and LRP may be involved in the formation of both SMC-and macrophage-derived foam cells, whereas SRs play an important role in lipid uptake in macrophages.

Animals↗

PubMed2005

Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice.

The very low density lipoprotein receptor (VLDLR), low density lipoprotein receptor (LDLR), and low density lipoprotein receptor-related protein (LRP) are the three main apolipoprotein E-recognizing endocytic receptors involved in the clearance of triglyceride (TG)-rich lipoproteins from plasma. Whereas LDLR deficiency in mice results in the accumulation of plasma LDL-sized lipoproteins, VLDLR or LRP deficiency alone only minimally affects plasma lipoproteins. To investigate the combined effect of the absence of these receptors on TG-rich lipoprotein levels, we have generated unique VLDLR, LDLR, and LRP triple-deficient mice. Compared with wild-type mice, these mice markedly accumulated plasma lipids and lipases. These mice did not show aggravated hyperlipidemia compared with LDLR and LRP double-deficient mice, but plasma TG was increased after high-fat diet feeding. In addition, these mice showed a severely decreased postprandial TG clearance typical of VLDLR-deficient (VLDLR-/-) mice. Collectively, although VLDLR deficiency in LRP- and LDLR-/- mice does not aggravate hyperlipidemia, these triple-deficient mice represent a unique model of markedly delayed TG clearance on a hyperlipidemic background.

Alleles↗

PubMed2006

Cholesteryl ester transfer protein (CETP) expression enhances HDL cholesteryl ester liver delivery, which is independent of scavenger receptor BI, LDL receptor related protein and possibly LDL receptor.

Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that mediates the transfer and exchange of cholesteryl ester (CE) and triglyceride (TG) between plasma lipoproteins, and also plays an important role in HDL metabolism. Previous studies have indicated that, compared to wild type mice, human CETP transgenic mice had significantly lower plasma HDL CE levels, which was associated with enhancement of HDL CE uptake by the liver. However, the mechanism of this process is still unknown. To evaluate the possibility that this might be directly mediated by CETP, we utilized CETP transgenic (CETPTg) mice with liver scavenger receptor BI (SR-BI) deficiency [i.e., PDZK1 gene knockout (PDZK1O)], and with receptor associated protein (RAP) overexpression, to block LDL receptor-related protein (LRP) and LDL receptor (LDLR). We found that (1) CETPTg/PDZK1O mice have significantly lower HDL-C than that of PDZK1 KO mice (36%, p<0.01); (2) CETPTg and CETPTg/PDZK1O mice have same HDL-C levels; (3) CETPTg/PDZK1O/RAP mice had significant lower plasma HDL-C levels than that of PDZK1O/RAP ones (50%, p<0.001); (4) there is no incremental transfer of HDL CE radioactivity to the apoB-containing lipoprotein fraction in mice expressing CETP; and (5) CETPTg/PDZK1O/RAP mice had significant higher plasma and liver [(3)H]CEt-HDL turnover rates than that of PDZK1O/RAP ones (50% and 53%, p<0.01, respectively). These results suggest that CETP expression in mouse increases direct removal of HDL CE in the liver and this process is independent of SR-BI, LRP, and possibly LDLR.

Animals↗

PubMed1998

Overexpression of cholesterol 7alpha-hydroxylase (CYP7A) in mice lacking the low density lipoprotein (LDL) receptor gene. LDL transport and plasma LDL concentrations are reduced.

This study was undertaken to determine the effect of transient overexpression of hepatic cholesterol 7alpha-hydroxylase on low density lipoprotein (LDL) cholesterol transport in mice lacking LDL receptors (LDL receptor-/-). Primary overexpression of hepatic 7alpha-hydroxylase in LDL receptor-/- mice was accompanied by a dose-dependent decrease in the rate of LDL cholesterol appearance in plasma (whole body LDL cholesterol transport) and a corresponding reduction in circulating LDL cholesterol levels. The increase in hepatic 7alpha-hydroxylase activity necessary to achieve a 50% reduction in plasma LDL cholesterol concentrations was approximately 10-fold. In comparison, cholestyramine increased hepatic 7alpha-hydroxylase activity approximately 3-fold and reduced plasma LDL cholesterol concentrations by 17%. This study demonstrates that augmentation of hepatic 7alpha-hydroxylase expression is an effective strategy for lowering plasma LDL concentrations even in animals with a genetic absence of LDL receptors.

Animals↗

PubMed2000

Decreased hepatic expression of the low-density lipoprotein (LDL) receptor and LDL receptor-related protein in aging rats is associated with delayed clearance of chylomicrons from the circulation.

Aging in both humans and rats is associated with the development of insulin resistance and the ensuing alterations in the plasma lipoprotein profile. In this study, young (2 months) and old (15 months) Sprague-Dawley (SD) rats were used to investigate age-related alterations in the chylomicron clearance pathway. Clearance from the blood of an intravenously injected bolus of 14C-labeled cholesterol ester (CE) and 3H-labeled triacylglycerol (TAG) lymph chylomicrons was markedly delayed in the old rats (P < .05). Hepatic expression of the two principal receptors of chylomicron remnant removal, the low-density lipoprotein (LDL) receptor and LDL receptor-related protein (LRP), was determined by ligand blotting and immunoblotting. The old rats expressed 43%+/-7% of the level of LDL receptor in the young animals (P < .05) and 45%+/-16% of the corresponding level of LRP (P < .05). The results suggest that the delayed clearance of chylomicron remnants in this animal model of aging and insulin resistance is due, at least in part, to a decrease in the hepatic expression of LDL receptor and LRP.

Aging↗

PubMed1996

Relative roles of the LDL receptor, the LDL receptor-like protein, and hepatic lipase in chylomicron remnant removal by the liver.

Studies were carried out in mice utilizing inhibitors of several cell surface molecules to evaluate their relative roles in chylomicron remnant removal. Anti-LDL receptor antibody inhibited approximately 45% of rapid remnant removal from plasma, prolonged their half life (63 s to 115 s) and reduced hepatic uptake by 45%. Receptor-associated protein (RAP) (1 mg/mouse), a high affinity inhibitor of the LDL receptor-related protein (LRP) and a low affinity inhibitor of the LDL receptor decreased remnant removal approximately 55%, prolonged the half life from 63 s to 230 s, and reduced hepatic uptake by 70%. RAP, but not anti-LDL receptor antibody, inhibited splenic uptake. With both injected together, an incremental effect was seen; plasma removal decreased 60%, T1/2 increased to 290 s, and hepatic uptake decreased by 80%. Thus, it is likely that virtually all of the very rapid removal of remnants from the plasma by the liver requires the presence of at least one of these members of the LDL receptor family. Anti-hepatic lipase antibody caused a small but significant delay in remnant removal from plasma and a larger decrease in hepatic uptake (22.5%). It doubled adrenal uptake. The anti-hepatic lipase antibody was not additive with either the anti-LDL receptor antibody or RAP. Anti-rat hepatic lipase antibody did not inhibit lipolysis by mouse hepatic lipase, suggesting that lipolysis is not the way hepatic lipase enhances remnant uptake. Hepatic lipase bound to remnants to a greater degree than it bound to other lipoproteins. Together these data suggest that hepatic lipase may serve as a binding site for chylomicron remnants, thereby enhancing their affinity for the liver surface, and thus removal by the proteins of the LDL receptor family. Other molecules may also play a role in removal from the circulation under conditions where the LDL receptor family receptors are absent or occupied.

Animals↗

PubMed1988

Efficient expression of retroviral vector-transduced human low density lipoprotein (LDL) receptor in LDL receptor-deficient rabbit fibroblasts in vitro.

Familial hypercholesterolemia is caused by a genetic deficiency of the low density lipoprotein (LDL) receptor. The Watanabe heritable hyperlipidemic (WHHL) rabbit, which is also defective in LDL receptor activity, provides an excellent animal model of homozygous familial hypercholesterolemia. As a step toward development of effective gene therapy for familial hypercholesterolemia, we have constructed a transmissible retroviral vector containing a full-length human cDNA for the LDL receptor. WHHL fibroblasts infected in vitro expressed the human receptor efficiently, as indicated by RNA and ligand blotting studies. Infected fibroblasts bound and degraded a monoclonal antibody specific for the human LDL receptor (IgGC7) in a manner comparable to that seen with normal human fibroblasts. Human LDL was also degraded by infected WHHL cells and promoted cholesterol esterification to the same degree as seen in normal human fibroblasts. Although technical problems remain to be solved, these studies show that, in principle, gene therapy may be possible for familial hypercholesterolemia patients.

Animals↗

PubMed1985

The association of LDL receptor activity, LDL cholesterol level, and clinical course in homozygous familial hypercholesterolemia.

Patients with homozygous familial hypercholesterolemia (FH), reveal a marked heterogeneity in plasma cholesterol levels, response to diet as well as drug treatment, and clinical course. Low-density lipoprotein (LDL) receptor activities were assessed by the rate of 14C-oleate cholesteryl ester biosynthesis in fibroblasts from 13 FH homozygotes in tissue culture. The receptor activity of the individual patients was highly correlated with initial pretreatment plasma cholesterol and LDL cholesterol levels (P less than .001, r = -0.89). In addition, the LDL receptor activity was positively correlated with the age of onset of angina based on the Cox model (P less than .035, likelihood ratio = 6.71). An association was also noted between LDL receptor activity and cholesterol reduction with drugs. These data provide direct evidence for the correlation between the heterogeneity of the LDL receptor and the expression of the clinical manifestations of homozygous FH. The determination of pretreatment plasma cholesterol level and LDL receptor activity in patients with homozygous FH provide useful parameters on which to base predictions of the clinical progression of cardiovascular disease. These parameters may also influence the selection of a program for diet and drug therapy. Patients with markedly elevated plasma cholesterol levels and very low LDL receptor activity should be considered to be candidates for multiple drug therapy, and portacaval shunt, and/or periodic plasma exchanges.

Adolescent↗

PubMed2001

C-terminal fragment of alpha1-antitrypsin activates human monocytes to a pro-inflammatory state through interactions with the CD36 scavenger receptor and LDL receptor.

Monocyte scavenger receptor, CD36 has been implicated in the pathogenesis of atherosclerosis as a major oxidised LDL receptor mediating lipid accumulation and foam cell formation. Previously, we found that treatment of monocyte cultures with the carboxyl terminal fragment of alpha1-antitrypsin (C-36) increases lipid binding and uptake, induces LDL receptor mRNA and CD36 receptor protein expression, and also significantly increases production of pro-inflammatory molecules. To assess the role of the CD36 receptor in proatherogenic monocyte activation by the C-36 fragment, we tested whether specific anti-CD36 receptor antibodies would block the effects of C-36 on monocyte activation. We find that pre-incubation of cells with anti-LDL and anti-CD36 receptor antibodies (10 microg/ml) blocks binding of 125I-C-36 by about 50%. Similarly, cells pre-incubated with oxidised LDL or native LDL at concentrations from 2.5 to 10 microg/ml showed a loss of 125I-C-36 binding (up to 49 and 57%) and uptake (up to 47 and 59.8%), respectively. In parallel experiments, monocytes were first incubated for 1 or 6 h with anti-CD36 antibodies (10 microg/ml) prior to adding C-36 peptide. Anti-CD36 antibodies suppressed C-36-induced production of gelatinase B, monocyte chemoattractant protein-1, interleukin-6 and cellular oxygen consumption to control levels, whereas levels of TNFalpha were unaffected. In contrast, saturation of LDL receptors with excess of anti-LDL (20 microg/ml) significantly inhibited C-36 induced TNFalpha levels. Results indicate that the C-36 peptide binds to both LDL and CD36 scavenger receptors which involves selective upregulation of pro-inflammatory molecules and activation of the respiratory burst in human monocytes. This also supports important roles for CD36 and LDL receptors in atherogenesis and suggests that blockade of CD36 receptor can be protective in pro-inflammatory activation of human monocytes.

Arteriosclerosis↗

PubMed1997

Study on the Relationship between Lipoprotein(a) Receptor and LDL Receptor.

Lp(a) receptor and LDL receptor on rhesus monkey liver cellular membrane were studied by Western blotting, to investigate whether Lp(a) and LDL metabolize through the same route. The experiment demonstrated Lp(a) receptor ( 300kD) and LDL receptor ( 185kD) to be different kinds of receptors. The result reveals that Lp(a) has its own metabolic pathway.

Journal Article↗

PubMed1988

Overexpression of low density lipoprotein (LDL) receptor eliminates LDL from plasma in transgenic mice.

A complementary DNA encoding the human low density lipoprotein (LDL) receptor under control of the mouse metallothionein-I promoter was injected into fertilized mouse eggs, and a strain of mice expressing high levels of LDL receptors was established. After administration of cadmium, these mice cleared intravenously injected 125I-labeled LDL from blood eight to ten times more rapidly than did normal mice. The plasma concentrations of apoproteins B-100 and E, the two ligands for the LDL receptor, declined by more than 90 percent after cadmium treatment, but the concentration of another apoprotein, A-I, was unaffected. Therefore, overexpression of an endocytotic receptor can dramatically lower the ambient concentration of its ligand in vivo.

Animals↗

PubMed2004

NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.

The discovery of autosomal dominant hypercholesterolemic patients with mutations in the PCSK9 gene, encoding the proprotein convertase NARC-1, resulting in the missense mutations suggested a role in low density lipoprotein (LDL) metabolism. We show that the endoplasmic reticulum-localized proNARC-1 to NARC-1 zymogen conversion is Ca2+-independent and that within the zymogen autocatalytic processing site SSVFAQ [downward arrow]SIP Val at P4 and Pro at P3' are critical. The S127R and D374Y mutations result in approximately 50-60% and > or =98% decrease in zymogen processing, respectively. In contrast, the double [D374Y + N157K], F216L, and R218S natural mutants resulted in normal zymogen processing. The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients. The LDLR levels are also reduced in stable HepG2 cells overexpressing NARC-1 or its natural mutant S127R, and this reduction is abrogated in the presence of 5 mm ammonium chloride, suggesting that overexpression of NARC-1 increases the turnover rate of the LDLR. Adenoviral expression of wild type human NARC-1 in mice resulted in a maximal approximately 9-fold increase in circulating LDL cholesterol, while in LDLR-/- mice a delayed approximately 2-fold increase in LDL cholesterol was observed. In conclusion, NARC-1 seems to affect both the level of LDLR and that of circulating apoB-containing lipoproteins in an LDLR-dependent and -independent fashion.

Adenoviridae↗

PubMed2002

Macrophage-specific expression of class A scavenger receptors in LDL receptor(-/-) mice decreases atherosclerosis and changes spleen morphology.

Class A scavenger receptors (SR-A) have been implicated in the atherogenic process, although there have been conflicting reports as to their specific effect on the development of lesions. In part, this discord may arise because of the variable contribution of SR-A in the several cell types known to express this protein. To determine the effects of macrophage-specific SR-A expression in the atherogenic process, transgenic mice were created using the chicken lysozyme (lyso) promoter to drive expression of bovine SR-A (bSR-A). To express this gene in an atherosclerosis-susceptible strain, bone marrow cells from transgenic and non-transgenic littermates were used to repopulate lethally-irradiated female LDL receptor (LDLr)(-/-) mice. Following hematopoietic engraftment, mice were placed on a diet enriched in saturated fat and cholesterol. After 8 weeks, there was a modest, but statistically significant reduction in serum total cholesterol in LDLr(-/-) mice repopulated with lyso-bSR-A transgenic cells, due to decreased LDL-cholesterol. The extent of atherosclerosis was reduced in both cross-sectional analysis of the aortic root and en face analysis of the intimal surface of the aortic arch. In addition to changes in atherosclerosis, lyso-bSR-A repopulated LDLr(-/-) mice had a marked increase (3.6x) in spleen weights and a disruption of spleen white pulp formation. Therefore, macrophage-specific overexpression of SR-A resulted in reduced atherosclerosis in two vascular beds, reduced serum cholesterol concentrations, and changed the morphology of the spleen.

Animals↗

PubMed1993

A comparison of the roles of the low density lipoprotein (LDL) receptor and the LDL receptor-related protein/alpha 2-macroglobulin receptor in chylomicron remnant removal in the mouse in vivo.

Two cell surface molecules, the low density lipoprotein (LDL) receptor and the LDL receptor-related protein (LRP)/alpha 2-macroglobulin receptor, have been found to have a role in the removal of apoE-rich lipoproteins. To further study this process and to assess the relative contributions of these proteins to the removal of chylomicron remnants, we used an anti-LDL receptor antibody, activated alpha 2-macroglobulin and the 39-kDa receptor-associated protein (RAP) as inhibitors of chylomicron remnant removal in intact mice. The advantage of this study is that we were able to use the same litters of animals and batches of lipoprotein for the experiment. In cultured Chinese hamster ovary cells, the anti-LDL receptor antibody inhibited remnant uptake and degradation about 80% as well as did unlabeled remnants. It did not affect activated alpha 2-macroglobulin uptake or degradation. Activated alpha 2-macroglobulin did not inhibit remnant uptake in normal cells but is reported to block uptake in cells that lack LDL receptors. Chylomicron remnants blocked activated alpha 2-macroglobulin uptake as effectively as unlabeled activated alpha 2-macroglobulin. This confirmed that the two ligands are cross-competitors but suggests that the LDL receptor is the primary mediator of remnant uptake in cultured cells that express the LDL receptor. In vivo, pretreatment with the anti-LDL receptor antibody decreased remnant uptake 5 min after injection by one-third. The antibody did not affect the removal of activated alpha 2-macroglobulin. Activated alpha 2-macroglobulin had a small, but reproducible effect on remnant removal, decreasing it by about 7% at 5 min. Injection of chylomicron remnants affected activated alpha 2-macroglobulin removal slightly. A similar pattern, but somewhat greater effect was seen on the hepatic uptake of the ligands. Anti-LDL receptor antibody reduced chylomicron remnant uptake by about half, and activated alpha 2-macroglobulin reduced it by about 15%. Studies with RAP provided results generally similar to those with activated alpha 2-macroglobulin, although RAP appears to bind to a site not recognized by either remnants or activated alpha 2-macroglobulin in addition to sharing a site with these ligands. Together, these results add support for the hypothesis that, although both receptors can play a role in chylomicron remnant removal, in the normal mouse in vivo the LDL receptor plays a substantially greater role, making the role of the LRP difficult to appreciate. The same is true in cells that express LDL receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2001

Effects of plant stanol esters on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase mRNA expression in mononuclear blood cells of healthy men and women.

Functional foods enriched with plant stanols lower atherogenic LDL cholesterol concentrations. This effect is caused at least partly by a decreased intestinal cholesterol absorption. It has been suggested that LDL production is reduced after plant stanol consumption, but it is unknown whether LDL receptor expression is affected and contributes to the LDL-lowering effect of plant stanols. Markers for endogenous cholesterol synthesis (lathosterol) increase, but it is not known how this higher cholesterol synthesis is regulated at the molecular level. In a double-blind placebo controlled trial, we have found that compared with the control group (N=15), daily consumption of 3.8-4.0 g plant stanol esters (N=29) for 8 weeks increased LDL receptor mRNA levels in human mononuclear blood cells by 43% (P=0.003). LDL receptor protein concentrations on the surface of monocytes and T lymphocytes increased by 37% (P=0.003) and 25% (P=0.013), suggesting an increased translation. This increased protein expression appeared to be functional, since changes in serum LDL cholesterol correlated negatively with changes in LDL receptor mRNA levels (r=-0.361; P=0.015) and changes in LDL receptor protein expression in monocytes (r=-0.440; P<0.001) and T lymphocytes (r=-0.307; P=0.018). Based on these results, we suggest that the higher LDL receptor expression contributed to a lowered LDL formation along the apoB cascade. Whole body cholesterol synthesis increased, as indicated by the rise in serum cholesterol-standardized lathosterol concentrations, but the 34% increased HMG-CoA reductase mRNA concentrations did not reach statistical significance. Nor did it correlate significantly with changes in serum cholesterol-standardized lathosterol concentrations. This suggests that HMG-CoA reductase may be only partly regulated at a transcriptional level.

Cholesterol↗

PubMed1997

Importance of estrogen receptors in hepatic LDL receptor regulation.

Treatment with pharmacological doses of estrogen is the most potent way to stimulate hepatic LDL receptor expression in vivo. The mechanism for this effect is unclear, in part because of difficulties in inducing this stimulation in vitro. A fundamental question, whether estrogen receptors (ERs) mediate this stimulation, has not been addressed. The aim of the current study was to determine the involvement of ERs in the estrogen-induced stimulation of LDL receptors. Treatment of rats with high doses of ethynylestradiol for 7 days increased the hepatic LDL receptor protein and mRNA levels four- and threefold, respectively. LDL receptor stimulation in estrogen-treated rats was not due to their reduced food intake because hepatic LDL receptor expression did not increase in rats fasted for 72 hours. Treatment with antiestrogen (tamoxifen or clomiphene) abolished the LDL receptor stimulatory effect of ethynylestradiol at both the protein and mRNA levels. Antiestrogen alone had no effect on hepatic LDL receptor expression and did not influence the strong resistance to dietary cholesterol normally present in rats. It is concluded that ERs are critically involved in the induction of hepatic LDL receptor expression by ethynylestradiol. The known role of growth hormone for the expression of hepatic ERs may therefore play a role in the modulation of the effects of estrogen on cholesterol metabolism and hepatic LDL receptors in the rat.

Animals↗

PubMed1997

Lipoprotein lipase, LDL receptors and apo-lipoproteins in human fetal membranes at term.

Ultrastructurally, all cells of human fetal membranes strongly exhibit a large amount of lipid deposits throughout pregnancy. Their origin and function is still unknown. The aim of this study was to investigate the localization of key components of lipid metabolism in this tissue. Using immunohistochemical techniques, the distribution of lipoprotein lipase (LPL), low density lipoprotein receptors (LDL receptors), and apo-lipoprotein B and E was investigated in 20 human fetal membranes at term. In addition, electron microscopy was used to study the intracellular localization of lipoprotein-sized particles. Amnionic epithelium and trophoblast cells reacted strongly for LPL. LDL receptors and apo-lipoproteins were present in amnionic epithelium and fibroblasts of the amnion. In none of the investigated cells were lipoprotein-sized particles identified. Similar results were obtained in all 20 cases. The findings indicate that lipoprotein from the amniotic fluid or from the maternal circulation may serve as substrate for lipids in human fetal membranes.

Amnion↗

PubMed1995

FH Afrikaner-3 LDL receptor mutation results in defective LDL receptors and causes a mild form of familial hypercholesterolemia.

Three founder-related gene mutations (FH Afrikaner-1, -2, and -3) that affect the LDL receptor are responsible for 90% of the familial hypercholesterolemia (FH) in South African Afrikaners. Patients heterozygous for the FH Afrikaner-1 (FH1) mutation, which results in receptors having approximately 20% of normal receptor activity, have significantly lower plasma cholesterol levels and milder clinical symptoms than heterozygotes with the FH Afrikaner-2 mutation, which completely abolishes LDL receptor activity. In this study we re-created the FH3 mutation (Asp154-->Asn) in exon 4 by site-directed mutagenesis and analyzed the expression of the mutant receptors in Chinese hamster ovary cells. The mutation resulted in the formation of LDL receptors that are markedly defective in their ability to bind LDL, whereas binding of apoE-containing beta-VLDL is less affected. The mutant receptors are poorly expressed on the cell surface as a result of significant degradation of receptor precursors. The plasma cholesterol levels of 31 FH3 heterozygotes were similar to FH1 heterozygotes but significantly lower than FH2 heterozygotes. The FH1 and FH3 heterozygotes also tended to be less severely affected clinically (by coronary heart disease and xanthomata) than FH2 patients. This study demonstrates that mutational heterogeneity in the LDL receptor gene influences the phenotypic expression of heterozygous FH and that severity of expression correlates with the activity of the LDL receptor measured in vitro. The results further indicate that knowledge of the specific mutation underlying FH in heterozygotes is valuable in determining the potential risk of premature atherosclerosis and should influence the clinical management of FH patients.

Adult↗