Lipoprotein metabolism in familial hypercholesterolemia.
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ABSTRACT:
SUBMITTER: Chemello K
PROVIDER: S-EPMC8050012 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
Publications
Lipoprotein metabolism in familial hypercholesterolemia.
Chemello Kévin K García-Nafría Javier J Gallo Antonio A Martín Cesar C Lambert Gilles G Blom Dirk D
Journal of lipid research 20210303
Familial hypercholesterolemia (FH) is one of the most common genetic disorders in humans. It is an extremely atherogenic metabolic disorder characterized by lifelong elevations of circulating LDL-C levels often leading to premature cardiovascular events. In this review, we discuss the clinical phenotypes of heterozygous and homozygous FH, the genetic variants in four genes (LDLR/APOB/PCSK9/LDLRAP1) underpinning the FH phenotype as well as the most recent in vitro experimental approaches used to ...[more]
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Project description:BackgroundLow density lipoprotein (LDL) and Lipoprotein (Lp)(a) are proatherogenic apolipoprotein (apo) B-containing members of the non-high-density lipoprotein (non-HDL) family of particles. Elevated plasma levels of LDL cholesterol (C), non-HDL-C, and apo B are defining features of heterozygous familial hypercholesterolemia (HeFH), but reports of elevated plasma Lp(a) concentration are inconsistent.MethodsWe performed retrospective chart reviews of 256 genetically characterized patients with hypercholesterolemia and 272 control subjects from the Lipid Genetics Clinic at University Hospital in London, Ontario. We evaluated pairwise correlations between plasma levels of Lp(a) and those of LDL-C, non-HDL-C and apo B.ResultsMean Lp(a) levels were not different between individuals with hypercholesterolemia and control subjects. No correlations were found between Lp(a) and LDL-C or non-HDL-C levels in controls or patients with hypercholesterolemia; all r values < 0.079 and all P values > 0.193. Borderline weak correlations between Lp(a) and apo B were identified in patients r = 0.103; P = 0.112) and controls (r = 0.175; P = 0.005). Results were similar across genotypic subgroups.ConclusionsLp(a) levels are independent of LDL-C and non-HDL-C; in particular Lp(a) levels are not increased in patients with hypercholesterolemia and molecularly proven HeFH. Apo B was only weakly associated with Lp(a). Elevated Lp(a) does not cause FH in our clinic patients. Genetic variants causing HeFH that raise LDL-C do not affect Lp(a), confirming that these lipoproteins are metabolically distinct. Lp(a) cannot be predicted from LDL-C and must be determined separately to evaluate its amplifying effect on atherosclerotic risk in patients with hypercholesterolemia.
| S-EPMC10837708 | biostudies-literature
Project description:ObjectivesIt is well known that familial hypercholesterolemia (FH) is a common inherited disorder that can markedly elevate the level of plasma LDL cholesterol. However, little data exists regarding the clinical impact of the plasma triglyceride (TG)-rich lipoprotein fraction, including VLDL and IDL, in FH. Thus, we assessed the hypothesis that the mutations in the LDL receptor modulate lipoprotein metabolism other than the LDL fraction.Design and methodsWe investigated plasma lipoprotein with a one-step ultracentrifugation method for 146 controls (mean age=61.4±17.1 yr, mean LDL cholesterol=92.7±61.2 mg/dl), 213 heterozygous mutation-determined FH subjects (mean age=46.0±18.0 yr, mean LDL cholesterol=225.1±61.2 mg/dl), and 16 homozygous/compound heterozygous mutation-determined FH subjects (mean age=26.9±17.1 yr, mean LDL cholesterol=428.6±86.1 mg/dl). In addition, we evaluated cholesterol/TG ratio in each lipoprotein fraction separated by ultracentrifugation.ResultsIn addition to total cholesterol and LDL cholesterol levels, VLDL cholesterol (19.5±10.4, 25.2±19.3, 29.5±21.4 mg/dl, respectively) and IDL cholesterol (8.3±3.7, 16.8±11.5, 40.0±37.3 mg/dl, respectively) exhibited a tri-model distribution according to their status in LDL receptor mutation(s). Moreover, the ratios of cholesterol/TG of each lipoprotein fraction increased significantly in heterozygous FH and homozygous/compound heterozygous FH groups, compared with that of controls, suggesting that the abnormality in LDL receptor modulates the quality as well as the quantity of each lipoprotein fraction.ConclusionsOur results indicate that cholesterol in TG-rich lipoproteins, including VLDL and IDL, are significantly higher in FH subjects, revealing a tri-modal distribution according to the number of LDL receptor mutations.
| S-EPMC5597709 | biostudies-literature
Project description:Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups <0.0001); however, subjects with FH/M- and lp(a) score ≥1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level ≥190 mg/dL (or from 68% to 50%, considering a more conservative formula). Conclusions Our study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH.
| S-EPMC10227296 | biostudies-literature
Project description:Lipoprotein-apheresis (apheresis) removes LDL-cholesterol in patients with severe dyslipidemia. However, reduction is transient, indicating that the long-term cardiovascular benefits of apheresis may not solely be due to LDL removal. Microparticles (MPs) are submicron vesicles released from the plasma membrane of cells. MPs, particularly platelet-derived MPs, are increasingly being linked to the pathogenesis of many diseases. We aimed to characterize the effect of apheresis on MP size, concentration, cellular origin, and fatty acid concentration in individuals with familial hypercholesterolemia (FH). Plasma and MP samples were collected from 12 individuals with FH undergoing routine apheresis. Tunable resistive pulse sensing (np200) and nanoparticle tracking analysis measured a fall in MP concentration (33 and 15%, respectively; P < 0.05) pre- to post-apheresis. Flow cytometry showed MPs were predominantly annexin V positive and of platelet (CD41) origin both pre- (88.9%) and post-apheresis (88.4%). Fatty acid composition of MPs differed from that of plasma, though apheresis affected a similar profile of fatty acids in both compartments, as measured by GC-flame ionization detection. MP concentration was also shown to positively correlate with thrombin generation potential. In conclusion, we show apheresis nonselectively removes annexin V-positive platelet-derived MPs in individuals with FH. These MPs are potent inducers of coagulation and are elevated in CVD; this reduction in pathological MPs could relate to the long-term benefits of apheresis.
| S-EPMC4173999 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is the most frequent genetic disorder resulting in increased low-density lipoprotein cholesterol (LDL-C) levels from childhood, leading to premature atherosclerotic cardiovascular disease (ASCVD) if left untreated. FH diagnosis is based on clinical criteria and/or genetic testing and its prevalence is estimated as being up to 1:300,000−400,000 for the homozygous and ~1:200−300 for the heterozygous form. Apart from its late diagnosis, FH is also undertreated, despite the available lipid-lowering therapies. In addition, elevated lipoprotein(a) (Lp(a)) (>50 mg/dL; 120 nmol/L), mostly genetically determined, has been identified as an important cardiovascular risk factor with prevalence rate of ~20% in the general population. Novel Lp(a)-lowering therapies have been recently developed and their cardiovascular efficacy is currently investigated. Although a considerable proportion of FH patients is also diagnosed with high Lp(a) levels, there is a debate whether these two entities are associated. Nevertheless, Lp(a), particularly among patients with FH, has been established as a significant cardiovascular risk factor. In this narrative review, we present up-to-date evidence on the pathophysiology, diagnosis, and treatment of both FH and elevated Lp(a) with a special focus on their association and joint effect on ASCVD risk.
| S-EPMC9693181 | biostudies-literature
Project description:BackgroundPrevious studies have observed that high level of lipoprotein (a) [Lp(a)] was common in the phenotypic familial hypercholesterolemia (FH) and may explain part of the clinical diagnosis of FH.HypothesisWe aim to develop a modified model including Lp(a) and compare its diagnostic performance with Dutch Lipid Clinic Network (DLCN) criteria.MethodsData of 10 449 individuals were utilized for the model establishment (7806 for derivation and 2643 for validation) from January 2011 to March 2018. The novel score model was modified on the basis of DLCN. Furthermore, 718 patients were screened for LDLR, APOB, and PCSK9 gene mutations.ResultsThe novel modified model consisted of untreated low-density lipoprotein cholesterol (LDL-C) level, Lp(a), personal premature coronary heart disease (CHD), tendon xanthomas and family history of CHD and/or hypercholesterolemia. It has shown high discrimination (area under curve [AUC] 0.991, 95% confidence interval [CI[ 0.988-0.994, P < .001) for distinguishing clinical FH from non-FH diagnosed using DLCN. Furthermore, a concordance analysis was performed to compare the modified model with DLCN and it showed a good agreement with DLCN (κ = 0.765). External validation of the novel model also showed good accordance (κ = 0.700). Further genetic analysis showed that the agreements between the new model and mutation improved a little compared to that between DLCN and mutation.ConclusionsThe novel modified model, including Lp(a), could provide new insights into FH diagnosis in Chinese population with more concerns on the patients with high level of Lp(a).
| S-EPMC6788465 | biostudies-literature
Project description:Low-density lipoprotein (LDL) receptor (LDLR) mutations are the primary cause of familial hypercholesterolemia (FH). Class II LDLR mutations result in a misfolded LDLR retained in the endoplasmic reticulum (ER). We have developed a model of FH class II and CRISPR-corrected induced pluripotent stem cells (iPSC) capable of replicating mutant and repaired LDLR functions. We show here that iPSC and derived hepatocyte-like cells (HLC) replicate misfolded LDLR accumulation and restoration of LDLR function in CRISPR-corrected cells. It was reported that model cells overexpressing class II LDLR mutants result in endoplasmic reticulum (ER) accumulation of immature LDLR and activation of the unfolded protein response (UPR). We show here that statins induce a similar accumulation of immature LDLR that is resolved with class II correction. We also demonstrate that, although capable of UPR induction with tunicamycin treatment, unlike overexpression models, statin-treated class II iPSC and derived HLC do not induce the common UPR markers Grp78 (also known as HSPA5) or spliced XBP1 [XBP1 (S)]. Because statins are reported to inhibit UPR, we utilized lipoprotein-deficient serum (LPDS) medium, but still did not detect UPR induction at the Grp78 and XBP1 (S) levels. Our study demonstrates the recapitulation of mutant and corrected class II LDLR function and suggests that overexpression models may not accurately predict statin-mediated class II protein biology.
| S-EPMC7157586 | biostudies-literature
Project description:Heterozygous familial hypercholesterolemia (HeFH) is a common autosomal-dominant inherited disorder associated with atherosclerotic cardiovascular disease (ASCVD). HeFH subjects have a higher lipoprotein(a), i.e. Lp(a), concentration than the general population. Patients with FH are exposed to elevated levels of LDL from birth and ox-LDL may induce other oxidation pathways. The aim of the study was to determine the levels of markers of oxidative stress and DNA damage in patients with HeFH and describe the effect of Lp(a) on the resulting damage. Higher DNA damage was identified in patients with HeFH compared to the normolipidemic ones, and ASCVD was associated with greater damage. Oxidative stress markers were elevated in HeFH patients; however, only ox-LDL was higher in the ASCVD group and its level correlated with DNA damage. A positive correlation was found between DNA damage and Lp(a) concentration in the HeFH patients. Higher levels of Lp(a) were associated with greater DNA damage, especially in patients with HeFH and ASCVD. In HeFH patients, the optimal Lp(a) cut-off point associated with ASCVD is > 23.45 nmol/L, i.e. much lower than for the general population; however this cut-off point needs validation in a larger group of HeFH patients.
| S-EPMC10830471 | biostudies-literature
Project description:Background and Aims: Elevated lipoprotein(a) [Lp(a)] and familial hypercholesterolemia (FH) are both inherited dyslipidemias that are independently associated with cardiovascular disease. Surrogate markers to assess signs of atherosclerosis, such as arterial stiffness, might be useful to evaluate the cardiovascular risk in young patients. The aim of this study is to evaluate the contribution of Lp(a) to arterial stiffness, as measured by carotid pulse wave velocity (cPWV) in young adults with FH. Methods: For this cross-sectional study, 214 children with FH who participated in a randomized controlled trial between 1997 and 1999 on the efficacy and safety of pravastatin were eligible. After 20 years, these patients were invited for a hospital visit, including cPWV assessment (by 4D flow MRI) and Lp(a) measurement. Linear mixed-effects models were used to evaluate the association between Lp(a) and cPWV. Results: We included 143 patients (mean [standard deviation] age: 31.8 [3.2] years) from 108 families. Median (interquartile range) cPWV was 1.62 (1.31-2.06) m/s. Both the unadjusted (ß = -0.0014 m/s per 1 mg/dL increase in Lp(a), 95% CI: -0.0052 to 0.0023, p = 0.455) and adjusted model (ß = -0.0005 m/s per 1 mg/dL increase in Lp(a), 95% CI: -0.0042 to 0.0032, p = 0.785) showed no significant association between Lp(a) and cPWV. Conclusions: Our findings indicate that Lp(a) levels are not associated with carotid arterial stiffness in young adults with FH. Possibly, High Lp(a) might cause atherosclerosis by mechanisms beyond arterial stiffness in young adults. Other surrogate markers of early signs of atherosclerosis may be more suitable to evaluate the Lp(a)-mediated contribution to atherosclerosis in young FH patients.
| S-EPMC11901005 | biostudies-literature
Project description:Gene polymorphisms associated so far with plasma lipid concentrations explain only a fraction of their heritability, which can reach up to 60%. Recent studies suggest that epigenetic modifications (DNA methylation) could contribute to explain part of this missing heritability. We therefore assessed whether the DNA methylation of key lipoprotein metabolism genes is associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels in patients with familial hypercholesterolemia (FH). Untreated FH patients (61 men and 37 women) were recruited for the measurement of blood DNA methylation levels at the ABCG1, LIPC, PLTP and SCARB1 gene loci using bisulfite pyrosequencing. ABCG1, LIPC and PLTP DNA methylation was significantly associated with HDL-C, LDL-C and triglyceride levels in a sex-specific manner (all P<0.05). FH subjects with previous history of coronary artery disease (CAD) had higher LIPC DNA methylation levels compared with FH subjects without CAD (P = 0.02). Sex-specific multivariable linear regression models showed that new and previously reported epipolymorphisms (ABCG1-CpGC3, LIPC-CpGA2, mean PLTP-CpGC, LPL-CpGA3, CETP-CpGA2, and CETP-CpGB2) significantly contribute to variations in plasma lipid levels (all P<0.001 in men and P<0.02 in women), independently of traditional predictors such as age, waist circumference, blood pressure, fasting plasma lipids and glucose levels. These results suggest that epigenetic perturbations of key lipoprotein metabolism genes are associated with plasma lipid levels, contribute to the interindividual variability and might partially explain the missing heritability of plasma lipid levels, at least in FH.
| S-EPMC4063831 | biostudies-literature