Human apoB contributes to increased serum total apo(a) level in LPA transgenic mice
© Teivainen et al; licensee BioMed Central Ltd. 2004
Received: 20 April 2004
Accepted: 11 May 2004
Published: 11 May 2004
The Lp(a) lipoprotein (Lp(a)) consists of the polymorphic glycoprotein apolipoprotein(a) (apo(a)), which is attached by a disulfide bond to apolipoprotein B (apoB). Apo(a), which has high homology with plasminogen, is present only in primates and hedgehogs. However, transgenic mice and rabbits with high serum apo(a) levels exist. Liver is the main site for apo(a) synthesis, but the site of removal is uncertain. To examine differences between transgenic mice expressing the LPA gene and mice capable of forming Lp(a) particles, LPA-YAC transgenic mice and hAPOB transgenic mice were crossed and their offspring examined.
Comparison of LPA-YAC with LPA-YAC/hAPOB transgenic mice showed that LPA-YAC/hAPOB transgenic mice have higher serum total apo(a) and total cholesterol level than mice lacking the hAPOB gene. However, hepatic apo(a) mRNA level was higher in LPA-YAC transgenic mice than in LPA-YAC/hAPOB transgenic mice. Feeding of a high-cholesterol/high-fat diet to male LPA-YAC transgenic mice with or without the hAPOB gene resulted in reduced serum total apo(a) and hepatic apo(a) mRNA level.
In conclusion, the higher serum total apo(a) level in LPA-YAC/hAPOB transgenic mice than in LPA-YAC transgenic mice is not caused by increased apo(a) synthesis. Lower hepatic apo(a) mRNA level in LPA-YAC/hAPOB than in LPA-YAC transgenic mice may suggest that the increase in total apo(a) level is a result of apo(a) accumulation in serum. Furthermore, observed higher serum total cholesterol level in LPA-YAC/hAPOB transgenic mice than either in wild type or LPA-YAC transgenic mice may further suggest that human APOB transgenicity is a factor that contributes to increased serum total apo(a) and cholesterol levels. Our results on reduced serum total apo(a) and hepatic apo(a) mRNA levels in HCHF fed male LPA-YAC transgenic mice confirm earlier findings in females, and show that there are no sex difference in mechanisms for lowering apo(a) level in response to HCHF feeding.
Association between Lp(a) lipoprotein (Lp(a) , and coronary heart disease was first demonstrated in 1974 . Afterwards, numerous studies have confirmed that high plasma level of Lp(a) is an independent risk factor for atherosclerotic and thrombotic disease . The intact Lp(a) molecule consists of the highly polymorphic glycoprotein apolipoprotein(a) (apo(a)), which is attached through a disulfide bond to apolipoprotein B-100 (apoB-100) of low density lipoprotein (LDL).
Gene encoding for apo(a) (LPA), which expression is mainly confined to the liver, is tightly linked to plasminogen (PLG) gene on chromosome 6 and is homologous to PLG [4, 5]. This sequence similarity indicates that the human LPA gene evolved from a duplicated PLG gene during primate evolution [6, 7]. Interestingly, in addition to humans, Old World monkeys, great apes and hedgehogs are the only species, which express LPA naturally [8–10].
Varying numbers of KIV structures account for the size variation of apo(a) whose size is inversely related to plasma Lp(a) level . Furthermore, recent studies in transgenic animal models have shown that 50% of human Lp(a) is catabolized by the liver [12, 13], but the mechanism for uptake is unclear. Study of WHHL transgenic rabbits expressing human apo(a) showed that defect LDL receptor (LDLR) lead to marked accumulation of plasma Lp(a) . However, despite structural similarity of Lp(a) to LDL, the LDLR does not seem to be involved significantly in Lp(a) removal in humans [15–17].
Studies in female mice transgenic for LPA-yeast artificial chromosome (LPA-YAC), which contains a 40 kilobase (kb) LPA-PLG intergenic region , have shown that feeding of a high-fat diet reduces serum apo(a) and hepatic apo(a) mRNA level [19, 20]. In contrast, serum apo(a) levels in mice transgenic for human apo(a) cDNA are stable despite high-fat feeding , which suggests that the effect of fat-rich diet on apo(a) levels in LPA-YAC transgenic mice is most likely exerted through regulatory elements located within the LPA-PLG intergenic region.
Recent studies on PPARα suggest that PPARα is of major importance for regulation of serum levels of apoB and production of apoB-containing lipoproteins [22, 23], but the possible role of PPARα in determining Lp(a) serum level is unclear. The DNase I hypersensitive site (DH) II enhancer part of the LPA-PLG intergenic region contains the gene for peroxisome proliferators-activated receptor (PPAR) α binding site [24, 25]. DH II increases the activity of the LPA promoter by over 7-fold in reporter-gene assays in HepG2 cells in vitro . This together with recent co-transfection assays, which showed that PPARα increased the effect of the DHII enhancer on LPA transcriptional activity may indicate that PPARα plays a role also in determining plasma Lp(a) level .
In order to examine differences between transgenic mice only expressing the LPA gene and transgenic mice capable of forming Lp(a) particles, LPA-YAC transgenic and mice transgenic for the human APOB (hAPOB) gene were crossed and their offspring examined. The study revealed that serum total apo(a) levels in LPA-YAC trangenic mice also expressing the hAPOB gene were higher than in LPA-YAC transgenic animals lacking hAPOB. However, hepatic apo(a) mRNA level in LPA-YAC transgenic mice was higher than in LPA-YAC/hAPOB transgenic mice. Furthermore, we showed that feeding of a high-cholesterol/high-fat (HCHF) diet to male LPA-YAC transgenic mice, which on a standard mouse diet exhibit much lower serum total apo(a) level than female mice, reduced serum total apo(a) and hepatic apo(a) mRNA level in a similar manner as previously shown in female mice [19, 20]. The lack of significant variation in hepatic PPARα mRNA levels between wild type (WT) and LPA-YAC transgenic mice or between mice fed either a semi-synthetic mouse diet (AIN-76) or the HCHF diet, may indicate that neither LPA transgenicity nor high-fat feeding have a significant impact on expression of PPARα.
Serum apo(a) level
Serum total cholesterol and triglycerides in male mice
Serum triglycerides (TG) and serum total cholesterol (TC) levels in male WT, LPA-YAC transgenic and LPA-YAC/hAPOB transgenic mice
1.8 ± 0.3
1.2 ± 0.3
1.9 ± 0.2
2)1.1 ± 0.2
1)3.1 ± 0.2
2)1.4 ± 0.1
5.2 ± 0.4
6.3 ± 0.2
5.3 ± 0.2
5.7 ± 0.2
6.0 ± 0.3
3)15.0 ± 0.9
Apo(a), PPARα and LDLR mRNA levels in male mice
LPA expression level in different tissues of 1-year old male LPA-YAC transgenic mice on a regular RMI(E)SQC mouse diet
Observation of higher serum levels of total apo(a) (figure 1 & 2) in LPA-YAC/hAPOB transgenic mice than in LPA-YAC transgenic mice are in agreement with the results of Callow et al . Our finding of lower hepatic apo(a) mRNA levels (figure 3) in LPA-YAC/hAPOB transgenic mice than in mice having the LPA gene only, suggest that the elevated serum Lp(a) levels in LPA-YAC/hAPOB transgenic mice are not due to increased hepatic apo(a) mRNA transcription rate. Furthermore, analysis of LPA expression in different tissues (table 2) indicates that no other organs than the liver, can produce significant amounts of apo(a).
LDL can be removed from the circulation by the LDL receptor (LDLR), which binds to the apoB-100 part of LDL . The efficient assembly of Lp(a) in mice transgenic for both LPA and hAPOB and higher efficiency of Lp(a) assembly with the human apoB-100 than with mouse apoB-100 [29, 30] may suggest that measured total apo(a) level in LPA-YAC/hAPOB transgenic mice consist mainly of human Lp(a) particles.
Because mouse LDLR has low capacity to bind human apoB-100 containing particles , elevated serum total apo(a) level may theoretically be secondary effect of reduced clearance rate of human apoB containing particles via the LDLR dependent pathway in LPA-YAC/hAPOB transgenic mice. Support for this comes from study, which showed that overexpression of LDLR in mice leads to accelerated metabolism of injected human Lp(a) particles . Furthermore, it is notable that serum Lp(a) levels in LDLR-/-/LPA transgenic mice are similar whether or not the human APOB gene is also present . Since triglyceride-rich apoB particles have increased affinity to apo(a) in man [34, 35], it seems likely that the human apoB part of the Lp(a) molecule in mouse serum may associate with TG containing particles, which may explain why hAPOB transgenicity also contributes to increased serum TG levels.
Suggestion for a role of LDLR in Lp(a) clearance comes also from studies in rabbits, where apoB, in contrast to mice, associates with human apo(a) forming Lp(a) particles . A defect in LDLR in LPA transgenic WHHL rabbits is accompanied by accumulation of Lp(a) in plasma . Since mice or rabbits do not normally have apo(a), the mechanism of Lp(a) removal in these animals may well differ from that in man, where the LDLR does not seem to affect Lp(a) metabolism [15–17].
The fall in serum apo(a) and hepatic apo(a) mRNA levels (figure 2 and 3) in male transgenic mice on the HCHF diet agrees with observations by Acquati et al and Huby et al, who showed that hepatic apo(a) mRNA and serum apo(a) levels fell in female LPA transgenic mice after two weeks fat feeding [19, 20]. Man, who naturally express LPA, do not have significant variation in plasma Lp(a) levels despite of changes in diet . This indicates that man possesses LPA control mechanisms that are different from those in mice. This agrees with the fact that CYP7A1, which regulates the initial step in the pathway of cholesterol metabolism and bile acid synthesis, is increased during cholesterol feeding in rats and mice, but not in humans . Rodents' capacity to convert cholesterol into bile acids by liver X receptor-α mediated stimulation of CYP7A1 transcription has been suggested to account for some of the differences in response to fat intake between humans and rodents . Furthermore, PPARα, which binds to the DHII enhancer part of LPA-PLG intergenic region , and is of importance for production of apoB and apoB-containing lipoproteins , was recently shown to be regulated by bile acids in humans but not in rodents . Since cholesterol feeding promotes bile acid synthesis in rodents , our results showing similar hepatic PPARα mRNA levels between the AIN-76 and HCHF fed mice may give further support to the notion that bile acids do not increase PPARα mRNA levels in mice. Further studies will be needed to elucidate whether or not the species-specific differences in cholesterol and bile acid metabolism is a key to understanding the mechanism(s), which cause the reduction on apo(a) transcription in HCHF fed transgenic mice.
The reduced hepatic LDLR mRNA level seen in HCHF fed WT mice and LPA-YAC/hAPOB transgenic mice (figure 5) is in agreement with previous results, which showed that hepatic LDLR level in mice is reduced in response to HCHF feeding . This may suggest that the human apoB can interact sufficiently, although less than mouse apoB, with mouse LDLR to increase intracellular level of cholesterol and down regulate expression of the LDLR. Because of the small number of HCHF fed LPA-YAC transgenic mice in our study, the absence of an effect of feeding on LDLR mRNA level must be confirmed in further studies.
On the HCHF diet both WT mice and transgenic mice developed fatty livers (not shown). Since hepatic level either of housekeeping genes or PPARα mRNA was not reduced in response to the HCHF feeding, it seems clear that the decreased apo(a) mRNA level detected in the livers of HCHF fed transgenic mice was not due to a general decrease in liver function.
In conclusion, we have shown that serum total apo(a) level is higher in LPA-YAC/hAPOB transgenic mice than in mice that are transgenic for the LPA gene alone. The higher level is not caused by increased apo(a) synthesis. Lower hepatic apo(a) mRNA level in LPA-YAC/hAPOB than in LPA-YAC transgenic mice may suggest that the increase in total apo(a) level is a result of apo(a) accumulation in serum. Our results on reduced serum total apo(a) and hepatic apo(a) mRNA level in HCHF fed male LPA-YAC transgenic mice confirm earlier findings in females, and show that there are no sex difference in mechanisms for lowering apo(a) level in response to HCHF feeding.
Materials and methods
Mice possessing a 270 kb YAC with a human genomic DNA clone containing the intact LPA gene and a 70 kb LPA-like gene with extensive 60 kb flanking regions on both sides and mice possessing the intact hAPOB gene in FVB genetic background have been described previously [18, 27]. Non-transgenic FVB mice were purchased from Harland (Bicester, England). For experiments in Oslo, mice were bred at The Laboratory Animal Unit, which is fully accredited by AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care and Use), at The Norwegian School for Veterinary Science. The Norwegian Animal Research Authority approved the experiments and all animal experiments were performed in accordance with the Norwegian Gene Technology Act of 1994 and the European Community Directive of 24 November 1986.
To develop mice capable of forming Lp(a) particles, LPA-YAC transgenic mice and hAPOB transgenic mice were crossed. Sentinel animals were used to run a full felasa-style health-monitoring scheme and mice were found to be healthy.
The presence of the LPA gene and the hAPOB gene was demonstrated by PCR analysis . For the analysis of hAPOB transgenicity sense primer TGGAAACGGAGAAATTATGGA and antisense primer CACTTGGCAAATACAATTCCTG were used.
Mice were housed in a room with 12 h light/dark cycle and 55% relative humidity at 21°C. Mice were kept on the regular RMI(E)SQC mouse diet (Special Diet Services, Witham, Essex, England) until the start of the feeding experiment.
Four 1-year old male LPA-YAC transgenic mice and two 1-year old male wild type mice were sacrificed for the study of LPA expression pattern. For the study of serum total apo(a) level prior to the feeding experiment, six female and seven male LPA-YAC transgenic as well as five female and fifteen male LPA-YAC/hAPOB transgenic mice were bled.
Age at the start and number of mice fed different diets for 7 weeks
Analysis of serum total apo(a), total cholesterol and triglycerides level
Serum total apo(a) level was measured using a radioimmuno assay (RIA) kit (Mercodia AB, Uppsala, Sweden). This method is based on direct sandwich technique in which two monoclonal antibodies are directed against separate antigenic determinants of apo(a). Results are given in units per liter (U/L). According to the manufacturer, results must be multiplied by 0.07 to obtain values in mg/dL, and levels below 1.2 mg/dL (17 U/L) are considered as background noise. For details of test's reliability to measure serum apo(a) level see Berg et al .
Serum TC and TG level was measured using enzymatic, colorimetric methods (Modular Analytics, Roche Diagnostics, F-Hoffmann-La Roche Ltd, Basel, Switzerland) at Fürst AS, Oslo, Norway.
Tissue preparation for mRNA analysis
For RNA preparations, tissue samples were washed in ice-cold saline, submerged in RNAlater™ buffer (Ambion Diagnostics, Cambridgeshire, England) and stored at -70°C until analysis.
Primer and probe sequences for cyclophilin, β-actin, LPA, PPARα and LDLR genes used in qPCR
Total RNA from 100–300 mg of tissues was isolated after homogenisation in 1 ml Trizol reagent according to the manufacturer's recommendations (Invitrogen Co, Carlsbad, CA, USA). RNA was treated with Dnase I (Ambion Ltd, Cambridgeshire, England) and 5 μg of total RNA was reverse-transcribed using pd(N)6 random primers (First strand cDNA synthesis kit, Amersham Biosciences, Little Chalfont Buckinghamshire, England).
Variation in A) β-actin and B) cyclophilin mRNA levels in five mouse livers submitted to qPCR. Calculations of variations were based on measured Ct value at the same threshold level.
No. of observations
No. of observations
LPA primers and probe (Eurogentech, Seraing, Belgium) were designed to bind specifically to the KV part of the LPA gene. Because of the high degree of sequence homology between the LPA and PLG genes, specificity of LPA primers and probes was tested by running PCR reactions with different concentrations of plasmid containing PLG gene or LPA plasmid construct without KV (a kind gift from Dr. S. Frank, University of Graz, Austria). There was no detectable PCR product when these plasmids were used as templates in the PCR reaction. cDNA made from RNA isolated from the liver of WT mouse was used as a negative control when analyzing the transgenes.
Because of poor RNA quality, two samples were excluded from analysis.
The non-parametric Mann-Whitney test was used to analyse differences between groups. All data from serum analysis are presented as mean ± SEM. In the case of mRNA data, results are presented as median value of normalized mRNA level.
List of abbreviations
= high-cholesterol/high-fat (diet)
= low density lipoprotein
= LDL receptor
- LPA :
= gene encoding for apolipoprotein(a)
= total cholesterol
= wild type (mouse)
This work was supported by a grant from the Norwegian Research Council (grant nr 134426/140). We want to thank Unni Risøen and Marit Sletten for their skilful technical assistance and the Laboratory Animal Unit at the Norwegian School of Veterinary Science for raising and health monitoring the animals.
- Berg K: A New serum type system in man -The Lp system. Acta Pathol Microbiol Scand. 1963, 59: 369-382.View ArticlePubMedGoogle Scholar
- Berg K, Dahlen G, Frick MH: Lp(a) lipoprotein and pre-beta1-lipoprotein in patients with coronary heart disease. Clin Genet. 1974, 6: 230-235.View ArticlePubMedGoogle Scholar
- Djurovic S, Berg K: Epidemiology of Lp(a) lipoprotein: its role in atherosclerotic/thrombotic disease. Clin Genet. 1997, 52: 281-292.View ArticlePubMedGoogle Scholar
- Eaton DL, Fless GM, Kohr WJ, McLean JW, Xu QT, Miller CG, Lawn RM, Scanu AM: Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen. Proc Natl Acad Sci U S A. 1987, 84: 3224-3228.PubMed CentralView ArticlePubMedGoogle Scholar
- McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM: cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature. 1987, 330: 132-137. 10.1038/330132a0View ArticlePubMedGoogle Scholar
- Lawn RM, Boonmark NW, Schwartz K, Lindahl GE, Wade DP, Byrne CD, Fong KJ, Meer K, Patthy L: The recurring evolution of lipoprotein(a). Insights from cloning of hedgehog apolipoprotein(a). J Biol Chem. 1995, 270: 24004-24009. 10.1074/jbc.270.41.24004View ArticlePubMedGoogle Scholar
- Lawn R, Patthy L, Pesole G, Saccone C: Apolipoproteins(a): a puzzling evolutionary story. J Mol Evol. 1997, 44: 234-236.View ArticlePubMedGoogle Scholar
- Makino K, Abe A, Maeda S, Noma A, Kawade M, Takenaka O: Lipoprotein(a) in nonhuman primates. Presence and characteristics of Lp(a) immunoreactive materials using anti-human Lp(a) serum. Atherosclerosis. 1989, 78: 81-85.View ArticlePubMedGoogle Scholar
- Hixson JE, Britten ML, Manis GS, Rainwater DL: Apolipoprotein(a) (Apo(a)) glycoprotein isoforms result from size differences in Apo(a) mRNA in baboons. J Biol Chem. 1989, 264: 6013-6016.PubMedGoogle Scholar
- Laplaud PM, Beaubatie L, Rall S.C., Jr., Luc G, Saboureau M: Lipoprotein[a] is the major apoB-containing lipoprotein in the plasma of a hibernator, the hedgehog (Erinaceus europaeus). J Lipid Res. 1988, 29: 1157-1170.PubMedGoogle Scholar
- Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C: Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest. 1987, 80: 458-465.PubMed CentralView ArticlePubMedGoogle Scholar
- Liu R, Saku K, Kostner GM, Hirata K, Zhang B, Shiomi M, Arakawa K: In vivo kinetics of lipoprotein(a) in homozygous Watanabe heritable hyperlipidaemic rabbits. Eur J Clin Invest. 1993, 23: 561-565.View ArticlePubMedGoogle Scholar
- Frank S, Hrzenjak A, Kostner K, Sattler W, Kostner GM: Effect of tranexamic acid and delta-aminovaleric acid on lipoprotein(a) metabolism in transgenic mice. Biochim Biophys Acta. 1999, 1438: 99-110. 10.1016/S1388-1981(99)00044-XView ArticlePubMedGoogle Scholar
- Fan J, Challah M, Shimoyamada H, Shiomi M, Marcovina S, Watanabe T: Defects of the LDL receptor in WHHL transgenic rabbits lead to a marked accumulation of plasma lipoprotein[a]. J Lipid Res. 2000, 41: 1004-1012.PubMedGoogle Scholar
- Maartmann-Moe K, Berg K: Lp(a) lipoprotein enters cultured fibroblasts independently of the plasma membrane low density lipoprotein receptor. Clin Genet. 1981, 20: 352-362.View ArticlePubMedGoogle Scholar
- Armstrong VW, Harrach B, Robenek H, Helmhold M, Walli AK, Seidel D: Heterogeneity of human lipoprotein Lp[a]: cytochemical and biochemical studies on the interaction of two Lp[a] species with the LDL receptor. J Lipid Res. 1990, 31: 429-441.PubMedGoogle Scholar
- Armstrong VW, Walli AK, Seidel D: Isolation, characterization, and uptake in human fibroblasts of an apo(a)-free lipoprotein obtained on reduction of lipoprotein(a). J Lipid Res. 1985, 26: 1314-1323.PubMedGoogle Scholar
- Frazer KA, Narla G, Zhang JL, Rubin EM: The apolipoprotein(a) gene is regulated by sex hormones and acute-phase inducers in YAC transgenic mice. Nat Genet. 1995, 9: 424-431.View ArticlePubMedGoogle Scholar
- Acquati F, Hammer R, Ercoli B, Mooser V, Tao R, Ronicke V, Michalich A, Chiesa G, Taramelli R, Hobbs HH, Muller HJ: Transgenic mice expressing a human apolipoprotein[a] allele. J Lipid Res. 1999, 40: 994-1006.PubMedGoogle Scholar
- Huby T, Afzal V, Doucet C, Lawn RM, Gong EL, Chapman MJ, Thillet J, Rubin EM: Regulation of the expression of the apolipoprotein(a) gene: evidence for a regulatory role of the 5' distal apolipoprotein(a) transcription control region enhancer in yeast artificial chromosome transgenic mice. Arterioscler Thromb Vasc Biol. 2003, 23: 1633-1639. 10.1161/01.ATV.0000084637.01883.CAView ArticlePubMedGoogle Scholar
- Svindland A, Berg K, Eliassen K, Lawn RM, Djurovic S, Alestrom P, Noren T, Smith A: Histopathology of arterial lesions in LPA transgenic mice on cholesterol-enriched chow. Atherosclerosis. 2000, 153: 349-354. 10.1016/S0021-9150(00)00430-5View ArticlePubMedGoogle Scholar
- Linden D, Alsterholm M, Wennbo H, Oscarsson J: PPARalpha deficiency increases secretion and serum levels of apolipoprotein B-containing lipoproteins. J Lipid Res. 2001, 42: 1831-1840.PubMedGoogle Scholar
- Linden D, Lindberg K, Oscarsson J, Claesson C, Asp L, Li L, Gustafsson M, Boren J, Olofsson SO: Influence of peroxisome proliferator-activated receptor alpha agonists on the intracellular turnover and secretion of apolipoprotein (Apo) B-100 and ApoB-48. J Biol Chem. 2002, 277: 23044-23053. 10.1074/jbc.M110416200View ArticlePubMedGoogle Scholar
- Wade DP, Puckey LH, Knight BL, Acquati F, Mihalich A, Taramelli R: Characterization of multiple enhancer regions upstream of the apolipoprotein(a) gene. J Biol Chem. 1997, 272: 30387-30399. 10.1074/jbc.272.48.30387View ArticlePubMedGoogle Scholar
- Magnaghi P, Mihalich A, Taramelli R: Several liver specific DNAse hypersensitive sites are present in the intergenic region separating human plasminogen and apoprotein(A) genes. Biochem Biophys Res Commun. 1994, 205: 930-935. 10.1006/bbrc.1994.2754View ArticlePubMedGoogle Scholar
- Puckey LH, Knight BL: Interaction of oestrogen and peroxisome proliferator-activated receptors with apolipoprotein(a) gene enhancers. Biochem J. 2002, 366: 157-163.PubMed CentralView ArticlePubMedGoogle Scholar
- Callow MJ, Stoltzfus LJ, Lawn RM, Rubin EM: Expression of human apolipoprotein B and assembly of lipoprotein(a) in transgenic mice. Proc Natl Acad Sci U S A. 1994, 91: 2130-2134.PubMed CentralView ArticlePubMedGoogle Scholar
- Hospattankar AV, Law SW, Lackner K, Brewer H.B., Jr.: Identification of low density lipoprotein receptor binding domains of human apolipoprotein B-100: a proposed consensus LDL receptor binding sequence of apoB-100. Biochem Biophys Res Commun. 1986, 139: 1078-1085.View ArticlePubMedGoogle Scholar
- Cheesman EJ, Sharp RJ, Zlot CH, Liu CY, Taylor S, Marcovina SM, Young SG, McCormick SP: An analysis of the interaction between mouse apolipoprotein B100 and apolipoprotein(a). J Biol Chem. 2000, 275: 28195-28200.PubMedGoogle Scholar
- Trieu VN, McConathy WJ: The binding of animal low-density lipoproteins to human apolipoprotein(a). Biochem J. 1995, 309 (Pt 3): 899-904.View ArticleGoogle Scholar
- Corsini A, Mazzotti M, Villa A, Maggi FM, Bernini F, Romano L, Romano C, Fumagalli R, Catapano AL: Ability of the LDL receptor from several animal species to recognize the human apo B binding domain: studies with LDL from familial defective apo B-100. Atherosclerosis. 1992, 93: 95-103.View ArticlePubMedGoogle Scholar
- Hofmann SL, Eaton DL, Brown MS, McConathy WJ, Goldstein JL, Hammer RE: Overexpression of human low density lipoprotein receptors leads to accelerated catabolism of Lp(a) lipoprotein in transgenic mice. J Clin Invest. 1990, 85: 1542-1547.PubMed CentralView ArticlePubMedGoogle Scholar
- Sanan DA, Newland DL, Tao R, Marcovina S, Wang J, Mooser V, Hammer RE, Hobbs HH: Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: no accentuation by apolipoprotein(a). Proc Natl Acad Sci U S A. 1998, 95: 4544-4549. 10.1073/pnas.95.8.4544PubMed CentralView ArticlePubMedGoogle Scholar
- Trieu VN, McConathy WJ: Lipoprotein(a) binding to other apolipoprotein B containing lipoproteins. Biochemistry. 1990, 29: 5919-5924.View ArticlePubMedGoogle Scholar
- Ye SQ, Trieu VN, Stiers DL, McConathy WJ: Interactions of low density lipoprotein2 and other apolipoprotein B-containing lipoproteins with lipoprotein(a). J Biol Chem. 1988, 263: 6337-6343.PubMedGoogle Scholar
- Fan J, Araki M, Wu L, Challah M, Shimoyamada H, Lawn RM, Kakuta H, Shikama H, Watanabe T: Assembly of lipoprotein (a) in transgenic rabbits expressing human apolipoprotein (a). Biochem Biophys Res Commun. 1999, 255: 639-644. 10.1006/bbrc.1999.0242View ArticlePubMedGoogle Scholar
- Puckey L, Knight B: Dietary and genetic interactions in the regulation of plasma lipoprotein(a). Curr Opin Lipidol. 1999, 10: 35-40. 10.1097/00041433-199902000-00007View ArticlePubMedGoogle Scholar
- Chen JY, Levy-Wilson B, Goodart S, Cooper AD: Mice expressing the human CYP7A1 gene in the mouse CYP7A1 knock-out background lack induction of CYP7A1 expression by cholesterol feeding and have increased hypercholesterolemia when fed a high fat diet. J Biol Chem. 2002, 277: 42588-42595. 10.1074/jbc.M205117200View ArticlePubMedGoogle Scholar
- Chiang JY, Kimmel R, Stroup D: Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha). Gene. 2001, 262: 257-265. 10.1016/S0378-1119(00)00518-7View ArticlePubMedGoogle Scholar
- Pineda Torra, I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B: Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol. 2003, 17: 259-272. 10.1210/me.2002-0120View ArticleGoogle Scholar
- Yu L, Li-Hawkins J, Hammer RE, Berge KE, Horton JD, Cohen JC, Hobbs HH: Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest. 2002, 110: 671-680. 10.1172/JCI200216001PubMed CentralView ArticlePubMedGoogle Scholar
- Liu J, Zhang YL, Spence MJ, Vestal RE, Wallace PM, Grass DS: Liver LDL receptor mRNA expression is decreased in human ApoB/CETP double transgenic mice and is regulated by diet as well as the cytokine oncostatin M. Arterioscler Thromb Vasc Biol. 1997, 17: 2948-2954.View ArticlePubMedGoogle Scholar
- Berg K, Svindland A, Smith AJ, Lawn RM, Djurovic S, Alestrom A, Alestrom P, Eliassen K: Spontaneous atherosclerosis in the proximal aorta of LPA transgenic mice on a normal diet. Atherosclerosis. 2002, 163: 99-104. 10.1016/S0021-9150(01)00772-9View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.