Autosomal dominant familial dysbetalipoproteinemia: A pathophysiological framework and practical approach to diagnosis and therapy

Koopal, Charlotte; Marais, A. David; Westerink, Jan; Visseren, Frank L.J.

doi:10.1016/j.jacl.2016.10.001

Cited by 39 publications

(27 citation statements)

References 111 publications

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“…As previously described, the EFAD (5xFAD +/− / APOE +/+ ) mice are homozygous for APOE2 , APOE3 , or APOE4 and heterozygous for the 5x familial AD (5xFAD) mutations [62, 63]. Although APOE2 is considered neuroprotective, 100% of APOE2 +/+ mice have type III hyperlipoproteinemia, compared to only 15% of human ε2/2 carriers [67–69]; thus, E2FAD mice were excluded from the current study. At 4 M, fecal samples were obtained from the 4 cohorts (9 ♂E3FAD, 8 ♂E4FAD, 19 ♀E3FAD, 12 ♀E4FAD) by individually placing mice in clean disposable Styrofoam cups.…”

Section: Methodsmentioning

confidence: 99%

Synergistic effects of APOE and sex on the gut microbiome of young EFAD transgenic mice

Weng

Parikh

Naqib

et al. 2019

Mol Neurodegeneration

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BackgroundAlzheimer’s disease (AD) is a fatal neurodegenerative disease. APOE4 is the greatest genetic risk factor for AD, increasing risk up to 15-fold compared to the common APOE3. Importantly, female (♀) APOE4 carriers have a greater risk for developing AD and an increased rate of cognitive decline compared to male (♂) APOE4 carriers. While recent evidence demonstrates that AD, APOE genotype, and sex affect the gut microbiome (GM), how APOE genotype and sex interact to affect the GM in AD remains unknown.MethodsThis study analyzes the GM of 4-month (4 M) ♂ and ♀ E3FAD and E4FAD mice, transgenic mice that overproduce amyloid-β 42 (Aβ42) and express human APOE3+/+ or APOE4+/+. Fecal microbiotas were analyzed using high-throughput sequencing of 16S ribosomal RNA gene amplicons and clustered into operational taxonomic units (OTU). Microbial diversity of the EFAD GM was compared across APOE, sex and stratified by APOE + sex, resulting in 4-cohorts (♂E3FAD, ♀E3FAD, ♂E4FAD and ♀E4FAD). Permutational multivariate analysis of variance (PERMANOVA) evaluated differences in bacterial communities between cohorts and the effects of APOE + sex. Mann-Whitney tests and machine-learning algorithms identified differentially abundant taxa associated with APOE + sex.ResultsSignificant differences in the EFAD GM were associated with APOE genotype and sex. Stratification by APOE + sex revealed that APOE-associated differences were exhibited in ♂EFAD and ♀EFAD mice, and sex-associated differences were exhibited in E3FAD and E4FAD mice. Specifically, the relative abundance of bacteria from the genera Prevotella and Ruminococcus was significantly higher in ♀E4FAD compared to ♀E3FAD, while the relative abundance of Sutterella was significantly higher in ♂E4FAD compared to ♂E3FAD. Based on 29 OTUs identified by the machine-learning algorithms, heatmap analysis revealed significant clustering of ♀E4FAD separate from other cohorts.ConclusionsThe results demonstrate that the 4 M EFAD GM is modulated by APOE + sex. Importantly, the effect of APOE4 on the EFAD GM is modulated by sex, a pattern similar to the greater AD pathology associated with ♀E4FAD. While this study demonstrates the importance of interactive effects of APOE + sex on the GM in young AD transgenic mice, changes associated with the development of pathology remain to be defined.

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Section: Methodsmentioning

confidence: 99%

Synergistic effects of APOE and sex on the gut microbiome of young EFAD transgenic mice

Weng

Parikh

Naqib

et al. 2019

Mol Neurodegeneration

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“…Current knowledge concerning how PCSK9 inhibitors work indicates that the interaction between LDL particles and the LDL receptor is effected by PCSK9 such that the LDL receptor (as well as the LDL particle) is ultimately destroyed and never recycled back to the hepatic cellular surface. Remnant particles have a somewhat different pathway for clearance [ 11 ]; as the larger TRL particles such as VLDL have their triglyceride content reduced by lipase hydrolysis, they eventually become IDL or smaller VLDL particles. Given sufficient time, they can eventually become LDL particles.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors on Nonfasting Remnant Cholesterol in a Real World Population

et al. 2018

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Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have demonstrated significant effects on low-density lipoprotein (LDL) cholesterol and nonhigh density lipoprotein (HDL) cholesterol. To date, there have been limited reports on the effect of PCSK9 inhibitors on remnant cholesterol. Objectives Assess the effect of PCSK9 inhibitors on nonfasting remnant cholesterol in a real world population. Identify whether pretreatment triglyceride levels are associated with PCSK9 inhibition success as indicated by changes in remnant cholesterol levels. Methods Patients in our adult lipid clinic (n = 109) receiving PCSK9 inhibition for atherosclerotic cardiovascular disease or familial hypercholesterolemia who had available pre- and post-PCSK9 inhibition standard nonfasting lipid data were, retrospectively, selected for data analysis. Remnant cholesterol was the difference between non-HDL and LDL cholesterol. LDL cholesterol was measured directly and calculated from Friedewald and Martin/Hopkins methods. Data were analyzed using repeated measures ANOVA and multivariable linear regression for differential effects on remnant and LDL cholesterol based upon pretreatment nonfasting triglyceride levels. Results Remnant cholesterol as well as total, LDL, non-HDL cholesterol, and triglycerides decreased significantly (P<0.001) after PCSK9 inhibition. Patients with higher pretreatment triglyceride levels showed greater decrease in remnant cholesterol after PCSK9 inhibition (P<0.001) than those with lower pretreatment triglycerides. Conclusions In patients receiving PCSK9 inhibitors, remnant cholesterol as determined from nonfasting blood was reduced in proportion to pretreatment triglycerides.

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“…ε2ε2 subjects, thereby severely limiting remnant lipoprotein clearance [15]. In obese and diabetic mice, it was shown that lower HSPG-R status in an insulin resistant state is caused by Sulf2, an extracellular sulphatase and heparin sulphate remodeling enzyme that disrupts the structure of HSPG-R by removing 6-O sulphate groups [16,18].…”

Section: Tablementioning

confidence: 99%

“…In ε2 homozygotes, remnant lipoproteins cannot be cleared efficiently from the circulation by the LDL-R, but in most subjects this is of little consequence because the second remnant clearing receptor, the heparan sulphate proteoglycan receptor (HSPG-R), functions normally. However, studies in mice have shown that, in an insulin resistant state, the HSPG-R is degraded by upregulation of sulfatase 2 (Sulf2) [15]. This mechanism could be causally implicated in the extensive remnant accumulation seen in FD [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Adiposity and the development of dyslipidemia in APOE ε2 homozygous subjects: A longitudinal analysis in two population-based cohorts

et al. 2021

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Background and aims: Familial dysbetalipoproteinemia (FD), characterized by remnant lipoprotein accumulation and premature cardiovascular disease, occurs in homozygous carriers of the APOE ε2 allele, but genetic predisposition alone does not suffice for the clinical phenotype. Cross-sectional studies suggest that a second metabolic hitnotably adiposity or insulin resistanceis required, but the association between these risk factors and development of FD has not been studied prospectively. Methods: For this study, we evaluated 18,987 subjects from two large prospective Dutch population-based cohorts (PREVEND and Rotterdam Study) of whom 118 were homozygous APOE ε2 carriers. Of these, 69 subjects were available for prospective analyses. Dyslipidemialikely to be FDwas defined as fasting triglyceride (TG) levels >3 mmol/L in untreated subjects or use of lipid lowering medication. The effect of weight, body mass index (BMI), waist circumference, type 2 diabetes mellitus and non-TG metabolic syndrome on development of dyslipidemia was investigated.Results: Eleven of the 69 ε2ε2 subjects (16%) developed dyslipidemialikely FDduring follow-up. Age-, sexand cohort-adjusted risk factors for the development of FD were BMI (OR 1.19; 95%CI 1.04-1.39), waist circumference (OR 1.26 95%CI 1.01-1.61) and presence of non-TG metabolic syndrome (OR 4.39;) at baseline. Change in adiposity during follow-up was not associated with development of dyslipidemia.Conclusions: Adiposity increases the risk of developing an FD-like lipid phenotype in homozygous APOE ε2 subjects. These results stress the importance of healthy body weight in subjects at risk of developing FD.

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Autosomal dominant familial dysbetalipoproteinemia: A pathophysiological framework and practical approach to diagnosis and therapy

Cited by 39 publications

References 111 publications

Synergistic effects of APOE and sex on the gut microbiome of young EFAD transgenic mice

Synergistic effects of APOE and sex on the gut microbiome of young EFAD transgenic mice

The Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors on Nonfasting Remnant Cholesterol in a Real World Population

Adiposity and the development of dyslipidemia in APOE ε2 homozygous subjects: A longitudinal analysis in two population-based cohorts

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