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At least 19 recordsLinked to original sources

PubMed1976

The metabolism of low density lipoprotein in endogenous hypertriglyceridaemia.

The metabolism of low density lipoprotein (LDL) was studied in eighteen hypertriglyceridaemic patients by injecting autologous radioiodinated LDL. Over 95% of the label was bound to the protein moiety of LDL and therefore the metabolic data reflect the fate and distribution of LDL apoprotein (apo B). The hypertriglyceridaemic subjects included ten with Type V, five with Type IV, two with Type III and one with Type IIb hyperlipoproteinaemia. For comparison identical studies were carried out in seven normal subjects and five patients with heterozygous familial hyperbetalipoproteinaemia (Type IIa). The groups differed considerably in mean LDL-cholesterol concentration. The patients with Type V lipoprotein pattern had significantly lower LDL-cholesterol concentration (mean 0.754 g/1) than the normal group (mean 1.237 g/1). Raised LDL-cholesterol levels were observed in all patients with heterozygous familial hyperbetalipoproteinaemia. The synthetic rate of LDL-apoprotein was found to be similar in all three groups (hypertriglyceridaemic, normal and hypercholesterolaemic). The highest synthetic rate was observed in the patient with Type IIb pattern. However, the fractional catabolic rate (FCR) of LDL-apoprotein differed significantly. The highest mean FCR was found in the Type V group (0.65 +/- 0.17 day-1) compared with 0.41 +/- 0.09 day-1 in the normal group and 0.185 +/- 0.05 day-1 in the Type IIa group. A strong inverse correlation was found between FCR and LDL apoprotein concentration in the whole series (r = -0.90, p less than 0.001) as well as within the Type V group (r = -0.87, p less than 0.01). These data indicate that the low plasma levels of LDL frequently observed in patients with very high plasma triglyceride levels are due to a high removal rate of LDL in these patients rather than to abnormal LDL synthesis.

Adult↗

PubMed1976

Gemfibrozil: effect on serum lipids, lipoproteins, postheparin plasma lipase activities and glucose tolerance in primary hypertriglyceridaemia.

The hypolipidaemic effect of a new drug, gemfibrozil (CI-719), was studied for 20 weeks in 20 patients with primary type IIb, III, IV or V hyperlipoproteinaemia. Baseline recordings of serum cholesterol (9.1 mmol/l), triglyceride (3.79 mmol/l) and ultra-centrifugally isolated lipoproteins were obtained during a six-week pretreatment period with stable diet and body weight. With 800 mg of gemfibrozil per day given in two divided doses, the mean serum triglyceride and cholesterol levels were decreased by 44.6% and 10.5% respectively, during 20 treatment weeks. Only 2 patients were completely resistant to the hypolipidaemic action of the drug. Serum triglyceride was brought down to normal levels in 9 subjects. After 12 weeks of treatment the mean VLDL-triglyceride, VLDL-cholesterol, and LDL-triglyceride were reduced by 48.5%, 57.6%, and 22.7% respectively, while the HDL-cholesterol rose by 16%. The LDL-cholesterol increased slightly but significantly during treatment in type IV patients and decreased in type IIb patients. The change of LDL-cholesterol showed an inverse correlation with the initial LDL-cholesterol level (r=-0.87). The postheparin plasma lipoprotein lipase and hepatic lipase activities, determined separately by an immunochemical method, increased during four weeks of gemfibrozil treatment (+18.1% and +20.6% respectively), but neither of these changes was significantly correlated with the changes in any of the serum lipid or lipoprotein levels. Oral glucose tolerance was not influenced by the treatment, but one-hour plasma insulin increased slightly during administration of the drug. One patient discontinued the drug after eight weeks because of generalized allergic eczema, but no other side effects were recorded. It is concluded that gemfibrozil is highly effective in reducing elevated serum VLDL levels. The simultaneous elevation of LDL in type IV patients needs more attention and study. The mechanism of the hypolipidaemic action of the drug is so far obscure, but it might partly be due to an increased efficiency in VLDL removal by an increased activity of lipoprotein lipase.

Adolescent↗

PubMed1977

Improved direct determination of serum cholesterol in low-density lipoproteins with use of polycations.

The previously described procedure of direct determination of LDL-cholesterol after selective extraction of VLDL and HDL with polycations and a polycation-exchange resin has been improved by using dodecoylated poly(ethyleneimine) instead of poly(ethyleneimine). The acyl derivative has a higher affinity for lipoproteins. Disc-electrophoretic patterns of lipoproteins separated by this procedure correspond to patterns of apolipoproteins in VLDL and HDL, a finding that corroborates the conclusion that the mechanism of the selective binding of certain lipoproteins to lipophilic water-soluble polycations is based on hydrophobic interaction between the polymer and lipids located at the surface of lipoprotein particles. The procedure offers a simple possibility for direct LDL-cholesterol and LDL-triglyceride determination and for the isolation of VLDL and HDL. The mechanism of the reaction has a biochemical correlate in the action of phospholipase A2 on phospholipids.

Cation Exchange Resins↗

PubMed1978

[Diagnosis of primary hypercholesteremia--a classification of genetic factors as causes for myocardial infarct].

Cultvated lymphocytes of patients with myocardial infarction with a primary hypercholesterolaemia as well as of unconspicuous control persons take up LDL-cholesterol labelled by 125iodine. Here is evident that lymphocytes of patients with a primary hypercholesterolaemia may incorporate significantly less LDL-cholesterol than healthy control persons. Supplementing the serum lipid determinations and the lipid electrophoresis the described radiochemical investigations at the model of lymphocytes make possible a biochemically exact diagnosis of the primary hypercholesterolaemia and thus an evident genetic analysis of the patients with infarctions.

Adolescent↗

PubMed2026

LDLR Variant Classification Through Activity-Normalized Prime Editing Screening.

BACKGROUND: Inherited variants in the LDL (low-density lipoprotein) receptor (LDLR) gene are the most common cause of familial hypercholesterolemia, significantly increasing coronary artery disease risk. Early identification of pathogenic LDLR variants enables prompt lipid-lowering therapy and cascade testing of at-risk relatives; however, most LDLR variants observed in the population have uncertain or absent clinical classifications, leaving many patients without actionable information. METHODS: We developed the first activity-normalized prime editing screening pipeline to measure the impact of 5184 LDLR coding variants on LDL-cholesterol (LDL-C) uptake. Each prime editing guide RNA is paired with a genotypic outcome reporter to correct for variable editing efficiency, overcoming a key limitation of previous pooled genome editing screens. A statistical framework further improves variant effect estimates by jointly analyzing all missense variants at each amino acid position. RESULTS: We show that prime editing of the reporter construct correlates with endogenous variant installation frequency, validating the activity normalization approach. The resulting scores capture a continuous spectrum of functional effects, robustly separate pathogenic versus benign ClinVar variants, and show concordance with LDL-C levels in UK Biobank participants. We calibrate functional evidence strengths to the ACMG/AMP variant interpretation framework, enabling integration into a clinical variant classification workflow. By combining functional, computational, population, and contextual evidence, 322 of 434 LDLR variants currently classified as variants of uncertain significance, conflicting, or absent from ClinVar appear to meet evidence thresholds for reclassification and can be prioritized for expert review, substantially expanding the pool of actionable variant classifications. The screen also reveals a cluster of gain-of-function variants in LDLR class A repeat 5, at least some of which enhance LDL-C uptake through increased apolipoprotein B interaction, with implications for therapeutic genome editing. Last, prime editing uniquely detects splice-altering coding variants missed by cDNA-based screens and pathogenicity predictors, revealing an advantage of endogenous variant installation. CONCLUSIONS: Altogether, activity-normalized prime editing provides a scalable framework for LDLR variant classification that substantially expands the proportion of variants with evidence for genetic diagnosis and reveals novel biology with therapeutic relevance.

CRISPR screening↗

PubMed1978

[Relationship between the plasma concentration of the high density lipoproteins (HDL) and the intravenous fat tolerance in normo-and hypertriglyceridaemics].

The relationship between the plasma concentration of high-density-lipoprotein(HDL)-cholesterol, very-low-density-lipoprotein(VLDL)-triglycerides, and low-density-lipoprotein(LDL)-cholesterol and the fractional removal rate (K2) of an intravenously administered fat emulsion (Intralipid) was investigated in 13 normo- and 34 hypertriglyceridaemics. A highly significant correlation (p less than 0,001) between the plasma concentration of HDL-cholesterol and the fractional removal rate of exogenous triglycerides was found for both groups. No significant relationship existed between the concentration of VLDL-triglycerides and of LDL-cholesterol and the removal rate of exogenous triglycerides. These observations suggest a major role of HDL in the removal of plasma triglycerides.

Adolescent↗

PubMed1977

[Effect of clofibrate on lipoprotein-lipids in patients with type IV hyperlipoproteinaemia (author's transl)].

The effect of clofibrate treatment (1.5 g/day for four weeks) on triglycerides, cholesterol and phospholipids in very low density lipoproteins (VLDL), low density lipoproteins (LDL) and high density lipoproteins (HDL) was investigated in 12 patients with type IV hyperlipoproteinaemia. The decrease of serum triglycerides was due to the reduction of VLDL-triglycerides. Furthermore, LDL-hypertriglyceridemia was normalised by clofibrate. -- There existed a significant decrease of VLDL- und HDL-cholesterol as well as of VLDL-phospholipids. The changes in LDL-cholesterol and LDL-phospholipids by clofibrate depended on their initial concentrations which were negatively correlated to the serum triglycerides before treatment. -- The normalisation of lipid concentrations in VLDL and LDI could be explained by a stimulated delipidation of the apo B-lipoproteins.

Adult↗

PubMed2026

Parental longevity and polygenic longevity scores in relation to ageing-related factors in a population of 70-year-olds followed over six years: The Gothenburg H70 Birth Cohort Study.

As societies age, a deeper understanding of ageing-related factors that contribute to longevity is needed. We therefore investigated possible longevity factors (social, medical, and biological) in relation to parental longevity (PL) and polygenic longevity scores (PGLSs). We examined 1126 70-year-olds from the Swedish population-based Gothenburg H70 Birth Cohort study in 2014-2016 (response rate 72%), with follow-up in 2019-2022 (response rate 77.6%). Comprehensive examinations included self-reported information on parents' ages, socioeconomic factors, mental, cardiovascular, and neurological health, anthropometry, laboratory data, and genotyping to construct two continuous PGLSs variables (with and without the APOE locus). PL groups were categorised as high if both parents survived to age 85 (17.2%); medium if one parent had survived (43.3%), and low if neither parent had survived to age 85 (39.4%). Higher PL and higher PGLSs were related to less hypertension, higher educational level, better childhood, and current socioeconomic status. In addition, higher PL was associated with higher MMSE score, total cholesterol, HDL-cholesterol (HDL-c) and LDL-cholesterol (LDL-c), lower BMI, homocysteine and inflammatory markers (IL-6, CRP) levels, and less smoking, whereas higher PGLSs was related to less myocardial infarction. At follow-up, high-PL was associated with less increase in plasma pTau217. PGLSs were mainly related to socioeconomic and cardiovascular factors, while individuals with long-lived parents, in addition, had several other characteristics of longevity, such as less inflammation, homocysteine, and markers of dementia. PL may be a proxy for biological ageing and used as a screening for ageing-related disorders in the context of prevention.

APOE↗

PubMed1976

Neonatal screening for hyperlipoproteinemia. Methods for direct estimation of cord serum VLDL + LDL.

The early detection of hyperlipoproteinemia in newborn infants has so far been based upon estimation of cord blood total lipids (cholesterol and triglyceride) and lipoprotein-lipids (VLDL-, LDL- and HDL-cholesterol). To be able to make a direct estimation of cord serum beta-lipoproteins (VLDL + LDL) two quite different methods were modified, one immunological and the other turbidimetric. Good correlations were found to VLDL- + LDL-cholesterol isolated in the ultracentrifuge (r = 0.848 and 0.831, respectively). If neonatal screening for hyperlipoproteinemia is considered, we recommend the very easy and inexpensive turbidimetric method. Furthermore, using cord serum, two conventional precipitation methods with heparin-CaCl2 and heparin-MnCl2 were compared by ultracentrifugation and high correlations were found (r = 0.923 and 0.899, respectively). A clamping study showed that following early clamping of the cord, the concentration of cord serum lipids and lipoproteins did not change markedly within the first five minutes. Storing experiments showed that serum should be separated within the first 12 h to avoid unpredictable changes in the concentration of cord serum lipids and lipoproteins.

Animals↗

PubMed2025

GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study.

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.

Humans↗

PubMed1976

[Sitosterol in familial hyperlipoproteinemia type II. A randomized double-blind cross-over study].

The effect of beta-sitosterol on the lipid and lipoprotein level was evaluated in a randomised double-blind cross-over trial in 24 patients with primary familial type II hyperlipoproteinaemia over a period of 16 weeks. All patients completed the trial, however 10 of them had to be excluded from the evaluation due to fluctuations of their body weight or unreliable drug intake. Sitosterol lowered the total cholesterol level by 12.5% (P less than 0.01) from 9.96 mmol/l (3.69 g/l) to 8.37 mmol/l (3.23 g/l). The LDL-cholesterol level was lowered by 19.5% (P less than 0.05). The sitosterol concentration in plasma was consistently lower than 0.3% of total cholesterol. No side effects or tachyphylaxis was observed in the course of the trial. A return to normal of an increased serum cholesterol level by a combination of a lipid lowering diet and sitosterol monotherapy was only achieved in one patient.

Adolescent↗

PubMed1977

[Familial hypobetalipoproteinaemia and diabetes mellitus (author's transl)].

In a 60-year-old patient with manifest diabetes mellitus and in his 63-year-old brother with latent diabetes mellitus hypobeta-lipoproteinaemia was diagnosed. Cholesterol values were around 1,8 mmol/1 in whole serum samples. The LDL-cholesterol fraction was 1,04 mmol/1. The beta-lipoprotein band in the lipoprotein electrophoresis was markedly reduced. Apolipoprotein B measured by radial immuno-diffusion was about 30% of the normal for age. The components of LDL were normal. Values of hepatic triglyceride lipase and lipoprotein lipase in heparinised plasma were within the normal range. The simultaneous occurrence of hypobetalipoproteinaemia and diabetes mellitus is described here for the first time.

Adult↗

PubMed1976

Degradation of cationized low density lipoprotein and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts.

Cultured fibroblasts derived from patients with homozygous familial hypercholesterolemia, which lack functional low density lipoprotein (LDL) receptors, fail to bind, take up, or degrade the lipoprotein with high affinity; therefore LDL-cholesterol is not made available for suppression of cholesterol synthesis or activation of cholesteryl ester formation. When LDL was given a positive charge by reaction with N,N-dimethyl-1,3-propanediamine (cationized LDL), the rate of degradation of the lipoprotein was increased by more than 100-fold in the homozygous familial hypercholesterolemia fibroblasts. Degradation of cationized LDL was inhibited by chloroquine, suggesting that it occurred in cellular lysosomes. Although the cationized LDL entered the cell through a mechanism independent of the LDL receptor, the cholesterol liberated from the degradation of the lipoprotein became available for suppression of cholesterol synthesis and stimulation of cholesteryl ester formation in the homozygous familial hypercholesterolemia fibroblasts. The rate of degradation of albumin by fibroblasts was also increased by more than 100-fold when this protein was coupled to N,N-dimethyl-1,3-propanediamine. The ability to deliver a protein to lysosomes by giving it a strong positive charge may have potential relevance not only to familial hypercholesterolemia, but also to inborn errors of metabolism that involve deficiencies in lysosomal enzymes.

Biological Transport↗

PubMed1976

Combined para-aminosalicylic acid and dietary therapy in long-term control of hypercholesterolemia and hypertriglyceridemia (Types IIa and IIb hyperlipoproteinemia).

The hypolipidemic effect of PAS-C-diet treatment was studied in 63 patients with Types IIa and IIb hyperlipoproteinemia for 6-36 months. Serum lipids and body weights of all patients were stabilized by a low cholesterol-saturated fat-refined carbohydrate diet before the initiation of an eight-week placebo-drug single-blind crossover study. During the placebo period the plasma lipids levels, mean +/- SD: cholesterol 355 +/- 63.5 mg%, triglyceride 141 +/- 68.7 mg%, and LDL-cholesterol 279 +/- 56.8 mg% were lowered to 274 +/- 53.1 mg+, 98 +/- 40.6 mg%, and 209 +/- 52.9 mg%, respectively (P less than 0.001 in each instance), with 7.5-11.0 grams of PAS-C/day given in one to three divided doses. In ten patients who have completed three years of treatment similar results were obtained. They showed no tendency to develop drug tolerance. Eight had watery diarrhea during the initial period which promptly subsided with interruption of drug therapy. Reintroduction of PAS-C in smaller dose (4.5 g/day) with gradual increment to effective dosage level was tolerated by all. No hematologic, hepatic, and ophthalmologic abnormalities were demonstrated by periodic monitoring. The hypoplipidemic effect of the drug was found to be diminished by alcohol and caloric excess.

Adolescent↗

PubMed1975

Role of the low density lipoprotein receptor in regulating the content of free and esterified cholesterol in human fibroblasts.

The transfer of normal human fibroblasts from medium containing whole serum to medium devoid of lipoproteins produced a 90 percent decrease in the cellular content of cholesteryl esters and a 30 percent decrease in the free cholesterol content. When these lipoprotein-deprived cells were subsequently incubated with human low density lipoprotein (LDL), there was a 7-fold increase in the cellular content of esterified cholesterol and a 1.6-fold increase in the cellular content of free cholesterol. The concentration at which LDL produced its half-maximal effect in elevating cellular sterol content (30 mug/ml of LDL-cholesterol) was similar to the half-maximal concentration previously reported for high affinity binding of LDL to its cell surface receptor. High density lipoprotein (HDL) and whole serum from a patient with abetalipoproteinemia (neither of which contains a component that binds to the LDL receptor) did not produce a significant increase in the content of either cholesterol or cholesteryl esters in normal cells. Furthermore, in fibroblasts from patients with the homozygous form of familial hypercholesterolemia, which lack functional LDL receptors, LDL had no effect in raising the cellular content of either free or esterified cholesterol even when present in the medium at concentrations as high as 450 mug sterol/ml. It is concluded that LDL-receptor interactions constitute an important biochemical mechanism for the regulation of the cholesterol content of normal human fibroblasts. Moreover, when considered in light of current concepts of LDL metabolism in intact mammals, the present data suggest that a major function of plasma LDL may be to transport cholesterol from its site of synthesis in liver and intestine to its site of uptake in peripheral tissues.

Abetalipoproteinemia↗

PubMed2025

Robust pleiotropy-decomposed polygenic scores identify distinct contributions to elevated coronary artery disease polygenic risk.

BACKGROUND: Polygenic risk score (PRS) have proved to offer robust risk prediction for coronary artery disease (CAD). However, the global CAD PRS summarizes the joint effects of all the markers in the genome, masking potential genetic heterogeneity that may be important for disease interpretation and targeted interventions. METHODS: Using summary-level data, we identified 43 significant CAD-related traits based on genetic correlations, and further classified them into eight pleiotropy clusters based on their biological functions. We then partitioned the genome into 2,353 near-independent regions. Variants in each region were assigned to the trait most genetically similar to CAD, and then were labeled with the corresponding pleiotropy cluster. We grouped variants without labels into a ninth, non-specific cluster. The Pleiotropy Decomposed (PD) PRSs for each of the nine clusters were calculated using variants assigned to each cluster for 407,903 samples of European ancestry from the UK Biobank (UKBB). RESULTS: We decomposed the CAD PRS into nine PD-PRSs and further stratified individuals with high CAD-PRS into nine subgroups. Each PD-PRS accounted for a higher proportion of the global CAD-PRS within its corresponding subgroup than in the remaining subjects with high CAD-PRS (e.g., 25.2% (0.07) vs. 10.06% (0.07) for lipids-PD-PRS). Additionally, these subgroups showed distinct clinical features. For example, in the lipids-related subgroup, lipoprotein(a) and LDL-cholesterol levels were 67.5% and 18.3% higher, respectively, compared to the remaining high-risk individuals. Furthermore, significant interactions were observed between blood pressure and BP PD-PRS, and between current smoking and respiratory system PD-PRS. CONCLUSION: Our findings suggest that PD-PRSs may reveal substantial genetic and phenotypic heterogeneity among individuals with high CAD-PRS. The unique PD-PRS compositions of each individual can highlight the relative importance of different pleiotropic regions.

Humans↗

PubMed2026

Lipoprotein(a): Actionable today, treatable tomorrow?

BACKGROUND: Lipoprotein(a) (Lp(a)) is an atherogenic, low-density lipoprotein (LDL)-like particle whose concentrations, mostly genetically determined, are elevated in about 20% of individuals. It is a major and under-recognised independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. OBJECTIVE: To review current evidence, international recommendations and future directions around testing and management of elevated Lp(a). DISCUSSION: Among other high-risk groups, measuring Lp(a) is recommended in people with ASCVD or aortic valve stenosis, especially if they are of young-onset, familial, unusually severe or progressive. Indeed, some international guidelines advocate measuring Lp(a) in all adults as part of cardiovascular risk assessment. While specific Lp(a)-lowering therapies are not yet available, risk-reducing measures for people with raised Lp(a) include addressing absolute ASCVD risk by diet and lifestyle measures, along with pharmacological LDL-cholesterol reduction. Aspirin might also have a role in primary prevention. Lp(a)-lowering therapies that act by preventing its formation are the subjects of ongoing clinical trials focused on cardiovascular outcomes, the first of which is expected to report in late 2026.

Humans↗

PubMed1977

Plasma high-density lipoprotein cholesterol level. Influence of risk factor intervention.

Determinants of circulating high density lipoproteins (HDL) were sought in 301 men studied during a year of participation in a coronary prevention program. Mean plasma HDL-cholesterol concentration rose by 2.8 mg/dl (6%) in the group receiving multifactor intervention, but the change did not differ significantly from that in the comparison group. Larger changes in both directions were seen in many individuals. Multiple regression analysis of these changes indicates that increased plasma HDL levels occur when plasma triglyceride level is decreased, cigarette smoking is reduced, and habitual alcohol intake is increased. Increases in the concentration of HDL-cholesterol also tended to accompany adherence to the fat-controlled diet, reduction in LDL-cholesterol level, and loss of body weight. Conventional coronary prevention programs are unlikely to have an adverse influence on this new, risk-lowering factor.

Adult↗