A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis

Reymer, P.W.A.; Gagné, Éric; Groenemeyer, B.E.; Zhang, H.; Forsyth, Isabel A.; Jansen, Hans; Seidell, Jacob C.; Kromhout, Daan; Lie, K.E.; Kastelein, John J.P.

doi:10.1038/ng0595-28

Cited by 232 publications

(162 citation statements)

References 33 publications

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“…Both genetic as well as acquired deficiencies of LPL are associated with high TG and low HDL levels in human and animal models (17,29). More recently, two mutations in the LPL gene were found to be associated with low plasma HDL-C levels (47,48). Our findings in the L2-MCK and L0-MCK mice contradict the current thinking of a simple relationship whereby increased LPL causes increased lipolysis, reduced TG, and increased HDL-C levels.…”

Section: Discussioncontrasting

confidence: 57%

Induced Mutant Mice Expressing Lipoprotein Lipase Exclusively in Muscle Have Subnormal Triglycerides yet Reduced High Density Lipoprotein Cholesterol Levels in Plasma

Levak-Frank¹,

Weinstock²,

Hayek³

et al. 1997

Journal of Biological Chemistry

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To determine the contribution of muscle lipoprotein lipase (LPL) to lipoprotein metabolism, induced mutant mice were generated that express human LPL exclusively in muscle. By cross-breeding heterozygous LPL knockout mice with transgenic mice expressing human LPL only in muscle, animals were obtained that express human LPL primarily in skeletal muscle on either the null (L0-MCK) or normal (L2-MCK) LPL backgrounds, and these were compared with control littermates (L2). Fed and fasted post-heparin plasma (PHP) LPL activities were increased 1.4-and 2.3-fold, respectively, in L2-MCK mice and were normal in L0-MCK mice compared with controls. The specific enzyme activities of human LPL in mouse plasma was comparable to human LPL in human PHP. Skeletal muscle LPL activity was increased in both L2-MCK and L0-MCK mice in the fed (6.6-fold) and fasted (4.2-fold in L2-MCK; and 3.4-fold in L0-MCK) states. Adipose tissue LPL mRNA and activity were not detectable in L0-MCK mice. Growth and body mass composition were similar among all groups. In the fasted and fed state, L2-MCK mice had 31% and 53% reductions, respectively, in plasma triglycerides (TG), compatible with increased PHP LPL activity. Unexpectedly, both in the fasted and fed state the L0-MCK mice also had reduced TG (22%), despite normal PHP LPL activities. Very low density lipoprotein (VLDL) turnover studies revealed that the decreased TG were due to increased particle fractional catabolic rate in both L2-MCK and L0-MCK mice. Despite reduced TG, both L2-MCK and L0-MCK mice showed reduced high density lipoprotein (HDL) cholesterol levels (16% and 19%, respectively). HDL turnover studies indicated increased HDL cholesteryl ester fractional catabolic rate in the L2-MCK and L0-MCK compared with control mice. In summary, these studies suggest that muscle LPL is particularly potent with regard to VLDL metabolism and is sufficient to compensate for the lack of LPL in other tissues with regard to lipolyzing VLDL particles. With regard to HDL, muscle LPL expression does not result in normal levels due to enhanced breakdown either by mediating accelerated HDL clearance or by failing to establish normal HDL particles that are then cleared more quickly than normal. These studies provide new insights on the tissue-specific effects of LPL on lipoprotein metabolism.

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Section: Discussioncontrasting

confidence: 57%

Induced Mutant Mice Expressing Lipoprotein Lipase Exclusively in Muscle Have Subnormal Triglycerides yet Reduced High Density Lipoprotein Cholesterol Levels in Plasma

Levak-Frank¹,

Weinstock²,

Hayek³

et al. 1997

Journal of Biological Chemistry

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“…Studies of lipid lowering drugs have shown that vascular function is improved by LPL-mediated generation of free fatty acids (10). Furthermore, humans with mutations in the promoter region of LPL are at increased risk for developing atherosclerosis (11). In macrophages, LPL is known to mediate increased uptake of lipoproteins and to induce TNF-␣.…”

mentioning

confidence: 99%

Differential Effects of Lipoprotein Lipase on Tumor Necrosis Factor-α and Interferon-γ-mediated Gene Expression in Human Endothelial Cells

Kota

Ramana

Tenorio

et al. 2005

Journal of Biological Chemistry

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“…This yields P 2 and H 2 alleles in the presence of restriction sites. Coding sequence polymorphisms in exon 2 (Asp 9 -Asn), 6 (Asn 291 -Ser) and 9 (Ser 447 -Ter) were genotyped as previously described [24,32,38], yielding alleles G and A, R 1 and R 2 , and C and G respectively in the presence and absence of the restriction sites (Table 2).…”

Section: Methodsmentioning

confidence: 99%

“…We and others have previously found that genetic variants of LPL relate to dyslipidaemia and atherosclerosis, including concentrations of triglycerides [24,25,26,27,28,29], high density lipoprotein cholesterol (HDL-C) [24,25,30,31,32], and total cholesterol [25,29,31], development [24,25,33] and severity [24,26] of coronary artery disease, familial combined hyperlipidaemia [34,35] and familial chylomicronaemia [36]. Recently, no relationship was found between an exonic LPL polymorphism and Type I diabetic nephropathy [37], although a potent effect of total cholesterol, triglycerides and apo-B was noted on DN.…”

mentioning

confidence: 99%

Lipoprotein lipase gene variants relate to presence and degree of microalbuminuria in Type II diabetes

et al. 2002

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Aims/hypothesis. Lipids and lipoproteins, particularly triglyceride rich lipoproteins, could influence the development and progression of microalbuminuria in diabetes. Lipoprotein lipase gene variants have been found to correlate with lipid/lipoprotein concentrations, especially hypertriglyceridaemia. We assessed the influence of this gene on microalbuminuria in Type II (insulin-dependent) diabetes mellitus. Methods. Microalbuminuria was determined quantitatively in 386 sequential Type II diabetic patients by measurement of the albumin-to-creatinine ratio (ACR). DNA was analysed for two common intronic LPL single nucleotide polymorphisms (Pvu II, intron 6, and Hind III, intron 8), and three common exonic mutations (Asp 9 -Asn, exon 2, Asn 291 -Ser, exon 6, and Ser 447 -Ter, exon 9). Results. Individuals with P 2 P 2 (Pvu II) and H 2 H 2 (Hind III) genotypes had significantly greater ACRs (P 2 P 2 vs P 1 P 1 +P 1 P 2 , 5.0±0.5 vs 3.4±0.3, p=0.0004 and H 2 H 2 vs H 1 H 1 +H 1 H 2 , 4.3±0.4 vs 3.4±0.3, p=0.04). Logistic regression analysis demonstrated that only the P 2 P 2 genotype (p=0.0004), systolic BP (p=0.008) and creatinine (p=0.031) were independently associated with the presence of microalbuminuria/proteinuria. P 2 homozygotes were 170% more likely to have microalbuminuria or proteinuria, O.R. 2.7 (1.6-4.5, p=0.0001), 150% more likely to have microalbuminuria, O.R. 2.5 (1.5-4.3, p=0.001), and 330% more likely to have proteinuria, O.R. 4.3 (1.6-11.4, p=0.004). There were no associations of microalbuminuria with any of the exonic polymorphisms. Conclusion/interpretation. Genetic variants of lipoprotein lipase correlate with presence and severity of microalbuminuria in Type II diabetes, independent of effect on serum lipids. This association is only apparent in genetic variants demonstrating greatest heterozygosity. [Diabetologia (2002) 45:905-913]

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A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis

Cited by 232 publications

References 33 publications

Induced Mutant Mice Expressing Lipoprotein Lipase Exclusively in Muscle Have Subnormal Triglycerides yet Reduced High Density Lipoprotein Cholesterol Levels in Plasma

Induced Mutant Mice Expressing Lipoprotein Lipase Exclusively in Muscle Have Subnormal Triglycerides yet Reduced High Density Lipoprotein Cholesterol Levels in Plasma

Differential Effects of Lipoprotein Lipase on Tumor Necrosis Factor-α and Interferon-γ-mediated Gene Expression in Human Endothelial Cells

Lipoprotein lipase gene variants relate to presence and degree of microalbuminuria in Type II diabetes

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