Premature Atherosclerosis in Patients with Familial Chylomicronemia Caused by Mutations in the Lipoprotein Lipase Gene

Benlian, Pascale; Gennes, J. L. De; Foubert, L.; Zhang, Hanfang; Gagné, Stéphane M.; Hayden, Michael R.

doi:10.1056/nejm199609193351203

Cited by 277 publications

(183 citation statements)

References 34 publications

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“…Subsequent studies found more compelling data, even after multivariate analysis, relating elevated triglyceride levels and the risk of CAD (15,16). Moreover, it has been reported that the elevated triglyceride level characteristic of familial LPL deficiency is associated with premature atherosclerosis (17). It has also been reported that mutations in the LPL gene that are not associated with complete LPL deficiency nonetheless increase the risk of ischemic heart disease (18) and progression of CAD (19).…”

Section: Discussionmentioning

confidence: 99%

Autoantibodies to lipoprotein lipase and dyslipidemia in systemic lupus erythematosus

Reichlin

Fesmire

Quintero-Del-Rio

et al. 2002

Arthritis & Rheumatism

114

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Objective. To demonstrate the binding of bovine lipoprotein lipase (LPL) by IgG from sera obtained from patients with systemic lupus erythematosus (SLE) and other rheumatic diseases, and the relationship of anti-LPL to triglyceride levels in SLE.Method. Binding of LPL by IgG from sera obtained from patients with SLE and other rheumatic diseases was measured by an enzyme-linked immunosorbent assay technique. Lipid profiles for fasting blood samples obtained from SLE patients and control subjects were determined.Results. Sera obtained from 105 patients with SLE were assessed for reactivity with LPL, and 49 (47%) of the results were positive. Sera obtained from patients with rheumatoid arthritis (RA) (n ‫؍‬ 80), Sjögren's syndrome (n ‫؍‬ 30), polymyositis and dermatomyositis (n ‫؍‬ 30), and progressive systemic sclerosis (n ‫؍‬ 31) were also studied, and 10 (13%), 3 (10%), 12 (40%), and 13 (42%), respectively, were positive for reactivity with LPL. It was determined that all affinity-purified antidouble-stranded DNA (dsDNA) antibodies and 4 of 5 monoclonal anti-dsDNA antibodies bound to LPL. The binding of IgG depleted of anti-dsDNA to LPL indicates a second anti-LPL activity in SLE. Measurements of fasting lipid levels in SLE patients with anti-LPL revealed a strong positive correlation of antibody levels and total serum triglycerides, apolipoprotein B, and apolipoprotein E concentrations.Conclusion. Antibodies to LPL occurred in 47% of SLE patients and in a similar percentage of patients with polymyositis or systemic sclerosis. The prevalence of these antibodies was less in patients with RA or Sjögren's syndrome. It is hypothesized that the elevated triglyceride levels in SLE patients are in part attributable to anti-LPL, and this lipid abnormality could contribute to the premature atherosclerosis known to be present in patients with SLE.

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Section: Discussionmentioning

confidence: 99%

Autoantibodies to lipoprotein lipase and dyslipidemia in systemic lupus erythematosus

Reichlin

Fesmire

Quintero-Del-Rio

et al. 2002

Arthritis & Rheumatism

114

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“…Homozygous deficiency of LPL is rare, occurring at a frequency of one per million in most populations and leading to severe chylomicronaemia (Brunzell, 1995). Heterozygous LPL deficiency is much more frequent at about 1 per 500, and has been shown to associate with familial combined hyperlipidemia, type IV hyperlipoproteinemia, diabetes mellitus, pregnancy-induced hypertriglyceridemia and coronary artery disease (Takagi et al, 1994;Ma et al, 1994;Mailly et al, 1995;Benlian et al, 1996). It can also appear as a decrease in HDL-cholesterol levels (Pimstone et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Genotype-phenotype studies of six novelLPL mutations in Chinese patients with hypertriglyceridemia

et al. 2002

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We screened 160 unrelated Chinese hypertriglyceridemic subjects for sequence alterations in the promoter and the 10 exons of the lipoprotein lipase (LPL) gene. We identified one reported mutation (L252R), one common polymorphism (S447X), and six novel mutations: V181I, C283Y, S298R and S338F (found in single individuals), L252V (in two individuals), and A71T (in three individuals). Screening of family members of the above probands revealed a total of 19 mutation carriers, most of whom, though not all, displayed reduced LPL activity and mass when compared to normolipidemic control subjects. In in vitro expression studies, A71T, V181I, L252R, L252V and C283Y decreased the specific activity of the gene product. Interestingly, S298R had no effect on the catalytic activity while S338F increased it. A71T and C283Y reduced the secretion of the mutant proteins significantly while V181I, S298R and S338F had mild effects only. The total LPL mass of all the mutant constructs was reduced compared to that of the wild type construct, probably due to the instabilities of the mutant mRNA or the mutant protein. The heterogeneity in phenotypic effects of these mutations is a likely consequence of their variable effects on proteoglycan binding, conformation and interactions with other secondary genetic or environmental factors.

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“…It has been proposed that LPL protein lacking any lipase activity may function as a bridge between apoB-containing lipoproteins and proteoglycans on vessel walls, thereby retaining atherogenic lipoproteins on endothelial cells, and leading to the progression of atherosclerosis (7,14). In fact, patients with complete LPL deficiency, whereby both enzymatic activity and protein mass are absent, reportedly exhibit a nonatherogenic phenotype (15,16), while patients with missense mutations which result in the absence of LPL activity with retention of the LPL protein are prone to atherogenesis (4,(6)(7)(8). Therefore, functionally inactive R243H-LPL protein may have played a role in the development of the severe atherosclerosis observed in this patient.…”

Section: Discussionmentioning

confidence: 84%

“…Considering these observations together, severe hypertriglyceridemia due to LPL However, in contrast to heterozygosity for the LPL gene mutations (11), a complete absence of LPL activity due to homozygous or compound heterozygous mutations has generally been considered to be non-atherogenic (12), because the CM particles, in which triglycerides are not hydrolyzed, are thought not to penetrate the vessel walls due to their large sizes (3). On the other hand, in recent years, several reports have indicated that atherosclerotic diseases do, in fact, develop in patients with some forms of LPL deficiency (4)(5)(6)(7)(8). This issue thus remains controversial.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, it was believed that LPL deficiency does not lead to atherosclerosis development, because CM particles are too large to penetrate the endothelium of the arterial wall (3). However, in recent years, there have been several reports indicating that patients with LPL deficiency do, in fact, show accelerated atherosclerosis (4)(5)(6)(7)(8). Therefore, whether or not hypertriglyceridemia caused by LPL deficiency leads to atherosclerosis remains a controversial topic.…”

Section: Introductionmentioning

confidence: 99%

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Lipoprotein Lipase Deficiency (R243H) in a Type 2 Diabetes Patient with Multiple Arterial Aneurysms

et al. 2016

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Lipoprotein lipase (LPL) deficiency is a rare monogenic disorder that manifests as severe hypertriglyceridemia. Whether or not LPL deficiency accelerates the development of atherosclerosis remains controversial. We herein report a 66-year-old woman who was homozygous for the R243H LPL mutation. She had developed multiple arterial aneurysms and systemic atherosclerosis despite good control of other atherogenic risk factors, including diabetes. Furthermore, although intensive pharmaceutical therapies had been minimally effective, medium chain triglyceride (MCT) therapy reduced the serum triglyceride levels. Thus, this case suggests important role that mutated LPL protein plays in the progression of atherosclerosis and that MCT therapy is potentially effective, even for severe hypertriglyceridemia due to LPL deficiency.

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Premature Atherosclerosis in Patients with Familial Chylomicronemia Caused by Mutations in the Lipoprotein Lipase Gene

Abstract: Premature atherosclerosis can occur in patients with familiar chylomicronemia as a result of mutations in the lipoprotein lipase gene. Defective lipolysis may increase susceptibility to atherosclerosis in humans.

Cited by 277 publications

References 34 publications

Autoantibodies to lipoprotein lipase and dyslipidemia in systemic lupus erythematosus

Autoantibodies to lipoprotein lipase and dyslipidemia in systemic lupus erythematosus

Genotype-phenotype studies of six novelLPL mutations in Chinese patients with hypertriglyceridemia

Lipoprotein Lipase Deficiency (R243H) in a Type 2 Diabetes Patient with Multiple Arterial Aneurysms

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