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4. Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility

Author

Guigas, B., de Leeuw van Weenen, J. E., van Leeuwen, N., Simonis-Bik, A. M., van Haeften, T. W., Nijpels, G., Houwing-Duistermaat, J. J., Beekman, M., Deelen, J., Havekes, L. M., Penninx, B. W. J. H., Vogelzangs, N., van ‘t Riet, E., Dehghan, A., Hofman, A., Witteman, J. C., Uitterlinden, A. G., Grarup, N., Jrgensen, T., Witte, D. R., Lauritzen, T., Hansen, T., Pedersen, O., Hottenga, J., Romijn, J. A., Diamant, M., Kramer, M. H. H., Heine, R. J., Willemsen, G., Dekker, J. M., Eekhoff, E. M., Pijl, H., de Geus, E. J., Slagboom, P. E., and ‘t Hart, L. M.

Published
2014
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12. Working group on epidemiology & prevention of the european society of cardiology: Proceedings of meeting held at Shannon May 14th–17th, 1998

Author

Sullivan, P. A., Murphy, D., Sullivan, P. A., Keogh, S., Sullivan, P. A., Nash, P., Kaarisalo, M. M., Marttila, J., Immonen-Raiha, P., Salomaa, V., Torppa, J., Tuomilehto, J., Siani, A., Racone, R., Ragone, E., Stinga, F., Strazzullol, P., Cappuccio, F. P., Trevisan, M., Farinaro, E., Mellone, C., Fox, K. F., Cowie, M. R., Wood, D. A., Coats, A. J., Poole Wilson, P. A., Sutton, G. C., Yarnell, J., Sweetnam, P., Thomas, H., Piwonski, J., Piotrowski, W., Pytlak, A., Wannamethee, S. G., Shaper, A. G., Walker, M., Sharpe, P. C., Young, I. S., Hasselwander, O., McMaster, D., Mercer, C., McGrath, L. T., Evans, A. E., Thomas, F., Guize, L., Ducimetiere, P., Benetos, A., Rosolova, H., Simon, J., Mayer, O., Sefrna, F., Mayer, O., Šimon, J., Rosolova, H., Racek, J., Trefil, L., Marin-Tarlea, M., Carp, C., Apetrei, E., Ginghina, C., Serban, I., Florica, N., Ceck, C., Patrascoiu, M., Ginghina, C., Carp, C., Apetrei, E., Tarlea, M., Cioranu, R., Florica, N., Ceck, C., Vaduva, M., Mihaescu, D., Lapadat, M., Ashton, W. D., Wood, D., Nanchahahal, K., Kelleher, C. C., Brennan, P. J., Howarth, D., Meade, T. W., Kelleher, C. C., Fallon, U. B., McCarthy, U., O’Donnell, M. M. K., Dineen, B., Jousilahti, P., Vartiainen, E., Tuomilehto, J., Puska, P., Kastarinen, M., Nissinen, A., Salomaa, V., Vartiainen, E., Jousilahti, P., Tuomilehto, J., Puska, P., Rosengren, A., Wedel, H., Wilhelmsen, L., Liese, A. D., Hense, H. W., Keil, U., Keil, U., Liese, A. D., Hense, H. W., Filipiak, B., Döring, A., Stieber, J., Lowel, H., De Laet, C., Brasseur, D., Kahn, A., Wautrecht, J. C., Decuyper, J., Boeynaems, J. M., Jousilahti, P., Vartiainen, E., Tuomilehto, J., Sundvall, J., Puska, P., Marques-Vidal, P., Ferrières, J., Haas, B., Evans, A., Amouyel, P., Luc, G., Ducimetiere, P., Marques-Vidal, P., Ferrieres, J., Arveiler, D., Montaye, M., Evans, A., Ducimetiere, P., Fuentes, R., Notkola, I. -L., Shemeikka, S., Tuomilehto, J., Nissinen, A., Mak, R., De BacquerBacquer, D., De Backer, G., Stam, M., Koyuncu, R., de Smet, P., Kornitzer, M., Braeckman, L., De Backer, G., De Bacquer, D., Claeys, L., Delanghe, J., De Bacquer, D., Kornitzer, M., De Backer, G., Cífkova, R., Pit’ha, J., Červenka, L., Šejda, T., Lanska, V., Škodová, Z., Stavek, P., Poledne, R., Cífková, R., Duskova, A., Hauserová, G., Hejl, Z., Lánská, V., Škodova, Z., Pistulková, H., Poledne, R., Hubáček, J., Pit’ha, J., Stávek, P., Lánská, V., Cífková, R., Faleiro, L. L., Rodrigues, D., Fonseca, A., Martins, M. C., Norris, R. M., Nyyssönen, K., Seppänen, K., Salonen, R., Kantola, M., Salonen, J. T., Parviainen, M. T., De Henauw, S., Myny, K., Doyen, Z., Van Oyen, H., Tafforeau, J., Kornitzer, M., De Backer, G., Benetos, A., Thomas, F., Guize, L., Immonen-Räihä, P., Kaarisalo, M., Marttila, R. J., Torppa, J., Tuomilehto, J., Houterman, S., Hofman, B., Witteman, J. C. M., Verschuren, W. M. M., van de Vijver, L. P. L., Kardinaal, A. F. M., Grobbee, D. E., van Poppel, G., Princen, H. M. G., Kornitzer, M., Doven, M., Koyuncu, R., De Bacquer, D., Myny, K., De Backer, G., Tafforeau, J., Van Oven, H., Doyen, M., Koyuncu, R., Kornitzer, M., De Bacquer, D., Myny, K., De Backer, G., Tafforeau, J., Van Oyen, H., de Bree, A., Verschuren, W. M. M., Blom, H. J., Mulder, I., Smit, H. A., Menotti, A., Kromhout, D., Van den Hoogen, P. C. W., Hofman, A., Witteman, J. C. M., Feskens, E. J. M., Štika, L., Bruthans, J., Wierzbicka, M., Bolinska, H., Voutilainen, S., Nyyssönen, K., Salonen, R., Lakka, T. A., Salonen, J. T., Lakka, H -M., Lakka, T. A., Salonen, J. T., Tuomainen, T-P., Nyyssonen, K., Salonen, J. T., Punnonen, K., Yarnell, J., Patterson, C., Thomas, H., Sweetnam, P., Smith, W. C. S., Campbell, S. E., Cardy, A., Phillips, D. O., Helms, P. J., Squair, J., Smith, W. C. S., Cardy, A., Phillips, D. O., Helms, P. J., Squair, J., Smith, W. C. S., Cardy, A., Phillips, D. O., Helms, P. J., Squair, J., Pytlak, A., Piotrowski, W., Rywik, S., Waskiewicz, A., Sygnowska, E., Szczesniewska, D., Sygnowska, E., Waskiewicz, A., Wagrowska, H., Polakowska, M., Rywik, S., Broda, G., Jasinski, B., Piotrowski, W., Elandt-Johnson, R. C., Wagrowska, H., Kupsé, W., Szczesniewska, D., Platonov, D. Y., Haapanen, N., Miilunpalo, S., Vuori, I., Pasanen, M., Oja, P., Urponen, H., Kopp, M. S., Skrabski, A., Szedmák, S., Boaz, M., Biro, A., Katzir, Z., Matas, T., Smetana, S., Green, M., Whincup, P. H., Morris, R., Walker, M., Lennon, L., Thomson, A., Ebrahim, S. J. B., Refsum, H., Ueland, P. M., Perry, I. J., Boer, J. M. A., Kuivenhoven, J. A., Feskens, E. J. M., Schouten, E. G., Havekes, L. M., Seidell, J. C., Kastelein, J. J. P., Kromhout, D., Oomen, C. M., Feskens, E. J. M., Rasanen, L., Nissinen, A., Fidanza, F., Menotti, A., Kok, F. J., Kromhout, D., Sileikiene, L., Klambienne, J., Milasauskiene, Z., Cappuccio, F. P., Siani, A., Barba, G., Russo, L., Ragone, E., Strazzullo, P., Farinaro, E., Trevisan, M., Schnohr, P., Parner, J., Lange, P., Meleady, R., Graham, I. M., Ueland, P. M., Refsum, H., Blom, H., Whitehead, A. S., Daly, L. E., Stefanovic, B., Boskovic, D., Mitrovic, P., Perunicic, J., Vukcevic, V., Radovanovic, N., Terzic, B., Mrdovic, I., Orilc, D., Matic, G., Vasiljevic, Z., Mitrovic, P., Boskovic, D., Stefanovic, B., Perunicic, J., Vukcevic, V., Mrdovic, I., Radovanovic, N., Orlic, D., Matic, G., Milentijevic, B., Rajic, D., Mitrovic, N., Boskovic, S., Vasiljevic, Z., Marin-Tarlea, M., Carp, C., Apetrei, E., Serban, I., Ceck, C., Patrascsoiu, M., Florica, N., Mihaescu, D., Murphy, C., Meleady, R., Ingram, S., Love, J., Graham, I., Graham, I. M., Meleady, R., van Berkel, T. F. M., Deckers, J. W., and De Bacquer, D.

Published
1998
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28. Hematopoietic α7 nicotinic acetylcholine receptor deficiency increases inflammation and platelet activation status, but does not aggravate atherosclerosis

Author

Kooijman, Sander, Meurs, I., van der Stoep, M., Habets, K. L., Lammers, B., Berbée, J. F P, Havekes, L. M., van Eck, M., Romijn, J. A., Korporaal, S. J A, Rensen, P. C N, Kooijman, Sander, Meurs, I., van der Stoep, M., Habets, K. L., Lammers, B., Berbée, J. F P, Havekes, L. M., van Eck, M., Romijn, J. A., Korporaal, S. J A, and Rensen, P. C N

Published
2015

29. Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility

Author

Guigas, B, de Leeuw van Weenen, J E, van Leeuwen, N, Simonis-Bik, A M, van Haeften, T W, Nijpels, G, Houwing-Duistermaat, J J, Beekman, M, Deelen, J, Havekes, L M, Penninx, B W J H, Vogelzangs, N, van 't Riet, E, Dehghan, A, Hofman, A, Witteman, J C, Uitterlinden, A G, Grarup, Niels, Jørgensen, Torben, Witte, D R, Lauritzen, T, Hansen, Torben, Pedersen, O, Hottenga, J, Romijn, J A, Diamant, M, Kramer, M H H, Heine, R J, Willemsen, G, Dekker, J M, Eekhoff, E M, Pijl, H, de Geus, E J, Slagboom, P E, 't Hart, L M, Guigas, B, de Leeuw van Weenen, J E, van Leeuwen, N, Simonis-Bik, A M, van Haeften, T W, Nijpels, G, Houwing-Duistermaat, J J, Beekman, M, Deelen, J, Havekes, L M, Penninx, B W J H, Vogelzangs, N, van 't Riet, E, Dehghan, A, Hofman, A, Witteman, J C, Uitterlinden, A G, Grarup, Niels, Jørgensen, Torben, Witte, D R, Lauritzen, T, Hansen, Torben, Pedersen, O, Hottenga, J, Romijn, J A, Diamant, M, Kramer, M H H, Heine, R J, Willemsen, G, Dekker, J M, Eekhoff, E M, Pijl, H, de Geus, E J, Slagboom, P E, and 't Hart, L M

Abstract

AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans.METHODS: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for Type 2 diabetes susceptibility in up to 25 000 people (8148 with Type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis.RESULTS: rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for Type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*10(-4) ) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*10(-4) ) but again not in men (P = 0.34).CONCLUSION: The present data identify DRD2/ANKK1 as a potential sex-specific Type 2 diabetes susceptibility gene.

Published
2014

30. Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin

Author

Kuhnast, S., primary, van der Tuin, S. J. L., additional, van der Hoorn, J. W. A., additional, van Klinken, J. B., additional, Simic, B., additional, Pieterman, E., additional, Havekes, L. M., additional, Landmesser, U., additional, Luscher, T. F., additional, Willems van Dijk, K., additional, Rensen, P. C. N., additional, Jukema, J. W., additional, and Princen, H. M. G., additional

Published
2014
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31. Transgenic mouse models to study the role of the macrophage scavenger receptor class A in atherosclerosis

Author

de Winther, M. P., Gijbels, M. J., van Dijk, K. W., Havekes, L. M., Hofker, M. H., and Other departments

Abstract

Several in vivo studies have been performed on the role of the macrophage scavenger receptor class A (SR-A) in atherosclerosis using SR-A knockout mice. The results indicate both an antiatherogenic and a proatherogenic role of SR-A, depending on the nature of the animal model serving as the athero-susceptible background. To study the role of SR-A in a different model, we generated a transgenic mouse model with high level expression of the human SR-A gene using a 180 Kb yeast artificial chromosome (MSR1 transgenic mice). These mice show increased expression of SR-A according to the natural expression pattern. The MSR1 transgenic mice were crossed onto a low-density lipoprotein receptor deficient background and were fed a high fat diet for 10 weeks. After this period, the size of the atherosclerotic lesions in the proximal aorta was measured. Surprisingly, atherosclerosis was significantly reduced in the MSR1 transgenic mice. In a second study, the effect of SR-A was examined in APOE-3 Leiden mice providing a different athero-susceptible background. To exclude nonmacrophage effects, bone marrow was transplanted from MSR1 mice and wild-type littermates to APOE-3 Leiden transgenic mice. After 8 weeks on a high fat diet, atherosclerosis in the mice that had received MSR1 bone marrow was reduced compared with mice that had received wild-type bone marrow. This difference reached statistical significance when individual cholesterol exposure of the mice was taken into account. Both experiments indicated an antiatherogenic role of the SR-A. This observation cannot be explained easily by SR-A function in foam cell formation because in MSR1 macrophages in vitro foam cell formation is increased. Alternatively, however, SR-A may affect the activation of macrophages. Hence the response to lipopolysaccharide was measured in MSR1-transgenic macrophages. These macrophages showed a reduction in their activation in response to lipopolysaccharide, as measured by nitric oxide production. These data show that an elevated level of SR-A expression reduces atherosclerosis, potentially by modifying the response of macrophages to activation signals in the plaque

Published
2000

32. Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands

Author

Lombardi, M. P., Redeker, E. J., Defesche, J. C., Kamerling, S. W., Trip, M. D., Mannens, M. M., Havekes, L. M., Kastelein, J. J., and Other departments

Abstract

Mutations in the LDL receptor are responsible for familial hypercholesterolemia (FH). At present, more than 600 mutations of the LDL receptor gene are known to underlie FH. However, the array of mutations varies considerably in different populations. Therefore, the delineation of essentially all LDL receptor gene mutations in a population represents a prerequisite for the implementation of nation-wide genetic testing for FH. In this study, the frequency and geographical distribution of 13 known mutations were evaluated in a cohort of 1223 FH patients. We identified 358 mutation carriers, representing 29% of the FH cohort. Four mutations (N543H-2393de19, 1359--1G-->A, 313 + 1 G-->A and W23X) occurred with a relatively high frequency, accounting for 22.4% of the entire study cohort. Two of these common FH mutations (N543H-2393de19 and 1359 - 1G-->A) showed a preferential geographic distribution. Second, to further expand the array of LDL receptor gene mutations, we conducted mutation analysis by denaturing gradient gel electrophoresis (DGGE) in 141 children with definite FH. A mutation was identified in 111 patients, involving 16 new single base substitutions and four small deletions and insertions, which brings the number of different FH-causing mutations in our country up to 61. Our data indicate that an estimate of the prevalence of specific mutations, as well as the compilation of a database of all FH-causing mutations in a given country, can facilitate selection of the most appropriate molecular diagnostic approach

Published
2000

33. Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism

Author

Eric Sijbrands, Hoffer, M. J. V., Meinders, A. E., Havekes, L. M., Frants, R. R., Smelt, A. H. M., Knijff, P., and Gaubius instituut TNO

Subjects
Adult, Male, Apolipoprotein E2, Cholesterol, VLDL, Gene Expression, Hyperlipidemias, Polymorphism, Single Nucleotide, Hyperlipoproteinemia type III, Hyperinsulinemia, Apolipoproteins E, Hyperinsulinism, Xanthomatosis, Humans, Apolipoproteins C, Apolipoproteins A, Aged, Aged, 80 and over, Family Health, Apolipoprotein C-III, Apolipoprotein A-I, Cholesterol, HDL, Homozygote, nutritional and metabolic diseases, Cholesterol, LDL, Middle Aged, Pedigree, Haplotypes, Xanthomas, Female, Apolipoprotein E, Promoter Regions (Genetics)
Abstract

More than 90% of patients with type III hyperlipoproteinemia are homozygous carriers of the apolipoprotein (apo) E*2 allele. The great majority of these apoE2(Arg158→Cys) homozygotes in the general population, however, are normolipidemic. Apparently, expression of the hyperlipidemic state requires additional genetic and/or environmental factors, suggesting a multifactorial etiology. To elucidate these additional risk factors, we analyzed normolipidemic and hyperlipidemic apoE2 homozygotes. Hyperinsulinemia was observed in 27 of 49 apoE2 homozygotes and associated with elevated lipid levels: hyperinsulinemic apoE2 homozygotes had type III hyperlipoproteinemia 6 times more often than apoE2 homozygotes with normal insulin levels (odds ratio 6.2, P=0.02). We screened the normolipidemic and hyperlipidemic apoE2 homozygotes for common variants in candidate genes involved in lipolysis-the APOA1-C3-A4 gene cluster, lipoprotein lipase, and hepatic lipase-and analyzed for associations with the expression of hyperlipidemia. In the hyperinsulinemic group, the 7 carriers of the SstI polymorphism (S2) in the APOC3 gene displayed severely elevated VLDL cholesterol (P(insulin by SstI)

Published
1999

34. Effects of fenofibrate on hyperlipidemia and postprandial triglyceride metabolism in human apolipoprotein C1 transgenic mice

Author

Jong, M. C., Dahlmans, V. E. H., Hans Princen, Hofker, M. H., Havekes, L. M., and Gaubius Instituut TNO

Subjects
Hyperlipidemias, Mice, Transgenic, Apo C, LDL-receptor, Procetofen, Mice, Health, Antilipemic Agents, Transgenic mice, Animals, Humans, lipids (amino acids, peptides, and proteins), Apolipoproteins C, Triglycerides
Abstract

To study the in vivo role of apolipoprotein (apo) C1 in lipoprotein metabolism, we have generated transgenic mice expressing the human apo C1 gene. Apo C1 is a small 6.6 kDa protein that is primarily synthesized by the liver and is present on chylomicrons, very low density lipoproteins (VLDL) and high density lipoproteins (HDL). In recent years, studies by our group have shown that apo C1 transgenic mice develop hyperlipidemia due to an accumulation of VLDL-sized lipoprotein particles. The underlying metabolic defect in apo C1 transgenic mice is an impaired uptake of VLDL particles by the liver. Although a role for apo C1 in human disease remains to be established, data presented in the current paper show that apo C1 transgenic mice are an instructive model of hyperlipidemia to (i) elucidate possible mechanisms underlying this disorder and (ii) test the activity and mode of action of hypolipidemic drugs.

Published
1998

35. The insulin sensitizing effect of topiramate involves KATPchannel activation in the central nervous system

Author

Coomans, C P, primary, Geerling, J J, additional, van den Berg, S A A, additional, van Diepen, H C, additional, Garcia-Tardón, N, additional, Thomas, A, additional, Schröder-van der Elst, J P, additional, Ouwens, D M, additional, Pijl, H, additional, Rensen, P C N, additional, Havekes, L M, additional, Guigas, B, additional, and Romijn, J A, additional

Published
2013
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36. Hepatic lipid accumulation in transgenic mice carrying the apolipoprotein E3 Leiden gene

Author

Kuipers, F., Arjen Mensenkamp, Vangoor, H., Bloks, V., Hofker, M. H., Jong, M. C., Vanvlijmen, B. J. M., Havekes, L. M., Faculteit Medische Wetenschappen/UMCG, Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), and Vascular Ageing Programme (VAP)

Published
1997

37. Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death.

Author

Boesten, L S M, Zadelaar, S M, De Clercq, Sarah, Francoz, Sarah, van Nieuwkoop, A, Biessen, E A L, Hofmann, F, Feil, S, Feil, R, Jochemsen, A G, Zurcher, C, Havekes, L M, van Vlijmen, B J M, Marine, Jean-Christophe, Boesten, L S M, Zadelaar, S M, De Clercq, Sarah, Francoz, Sarah, van Nieuwkoop, A, Biessen, E A L, Hofmann, F, Feil, S, Feil, R, Jochemsen, A G, Zurcher, C, Havekes, L M, van Vlijmen, B J M, and Marine, Jean-Christophe

Abstract

p53 is a potent inhibitor of cell growth and an inducer of apoptosis. During embryonic development, Mdm2 and Mdm4 inhibit the growth suppressive activities of p53. However, whether tight surveillance of p53 activity is required in quiescent cells is unknown. To test this, conditional inactivation of mdm2 and mdm4 was carried out in smooth muscle cells (SMCs). Upon SMC-specific inactivation of mdm2, and not of mdm4, mice rapidly became ill and died. Necropsy showed small intestinal dilation, and histological analyses indicated a severe reduction in the number of intestinal SMCs. Increased p53 levels and activity were detected in the remaining SMCs, and the phenotype was completely rescued on a p53-null background. Interestingly, intestinal SMCs are caspase-3-negative and therefore did not undergo caspase-3-dependent apoptotic cell death. Together, Mdm2, but not Mdm4, prevents accumulation of active p53 in quiescent SMCs and thereby the induction of p53-mediated caspase-3-independent cell death., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2006

38. Mutations in the low density lipoprotein receptor gene of familial hypercholesterolemic patients detected by denaturing gradient gel electrophoresis and direct sequencing

Author

Lombardi, P., Eric Sijbrands, Giessen, K., Smelt, A. H. M., Kastelein, J. J. P., Frants, R. R., Havekes, L. M., and Gaubius Instituut TNO

Subjects
Electrophoresis, Agar Gel, Base Sequence, Receptors, LDL, Molecular Sequence Data, Polymorphism (Genetics), Point Mutation, Support, Non-U.S. Gov't, Sequence Analysis, Hypercholesterolemia, Familial, DNA Primers, Human
Abstract

Familial hypercholesterolemia (FH) results from mutations in the low density lipoprotein receptor (LDLR) gene. We applied denaturing gradient gel electrophoresis (DGGE) to screen for sequence variations in the coding and splice site consensus sequences of the LDLR gene. For amplification of each exon by the polymerase chain reaction (PCR), optimal pairs of primers were designed by the MELT 87 computer algorithm. To increase the sensitivity, an artificial GC-clamp was included in either the 5'- or the 3'-end of each fragment. DGGE screening of 32 apparently unrelated heterozygous FH patients revealed 16 unique different aberrant DGGE patterns in 27 patients, while in a group of 32 normal subjects none of these DGGE patterns could be observed, suggesting that the aberrant patterns represent disease-causing mutations. Interestingly, 16 out of 27 patients showed an aberrant DGGE pattern in the part of the gene encoding the ligand binding domain (exons 2-6). Direct solid-phase sequencing of the corresponding exon-specific PCR products revealed the nature of the mutations: three nonsense, four splicing, two frameshift, one silent, and six missense mutations. Six of the mutations have been previously reported, while ten are novel mutations. These results indicate that DGGE provides a reliable method for the detection of the presence of point mutations in the LDLR gene of FH patients, thereby facilitating the introduction of rapid DNA diagnosis for this common and genetically heterogeneous disorder. Chemicals/CAS: DNA, 9007-49-2; DNA Primers; Receptors, LDL

Published
1995

44. Mdm2, but not Mdm4, protects terminally differentiated smooth muscle cells from p53-mediated caspase-3-independent cell death

Author

Boesten, L S M, primary, Zadelaar, S M, additional, De Clercq, S, additional, Francoz, S, additional, van Nieuwkoop, A, additional, Biessen, E A L, additional, Hofmann, F, additional, Feil, S, additional, Feil, R, additional, Jochemsen, A G, additional, Zurcher, C, additional, Havekes, L M, additional, van Vlijmen, B J M, additional, and Marine, J-C, additional

Published
2006
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49. APOE* 3Leiden. CETP transgenic mice as model for pharmaceutical treatment of the metabolic syndrome.

Author

van den Hoek, A. M., van der Hoorn, J. W. A., Maas, A. C., van den Hoogen, R. M., van Nieuwkoop, A., Droog, S., Offerman, E. H., Pieterman, E. J., Havekes, L. M., and Princen, H. M. G.

Subjects
ANTILIPEMIC agents, ATORVASTATIN, ROSIGLITAZONE, CHOLESTEROL esters, DYSLIPIDEMIA, FATTY liver prevention, THERAPEUTICS
Abstract

Aims This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE* 3Leiden.humanCholesteryl Ester Transfer Protein ( E3L. CETP) mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans. Methods Male obese, IR and dyslipidemic E3L. CETP mice were treated with antidiabetic drugs rosiglitazone, liraglutide or an experimental 11β-hydroxysteroid-dehydrogenase-1 ( HSD-1) inhibitor, or with hypolipidemic drugs atorvastatin, fenofibrate or niacin for 4-6 weeks. The effects on bw, IR and plasma and liver lipids were assessed. Results Rosiglitazone, liraglutide and HSD-1 inhibitor significantly decreased glucose and insulin levels or IR. Liraglutide and HSD-1 inhibitor also decreased bw. Atorvastatin, fenofibrate and niacin improved the dyslipidemia and fenofibrate and niacin increased high-density lipoprotein ( HDL) cholesterol. In addition, hepatic triglycerides were significantly decreased by treatment with rosiglitazone and liraglutide, while hepatic cholesterol esters were significantly decreased by rosiglitazone and atorvastatin. Conclusions We conclude that the E3L. CETP mouse is a promising novel translational model to investigate the effects of new drugs, alone or in combination, that affect IR, diabetic dyslipidemia and non-alcoholic fatty liver disease ( NAFLD). [ABSTRACT FROM AUTHOR]

Published
2014
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