Plasma Concentrations Of Apolipoprotein Research Articles

Plasma Apolipoprotein Concentrations Are Highly Altered in Severe Intensive Care Unit COVID-19 Patients: Preliminary Results from the LIPICOR Cohort Study.

SARS-CoV-2 infection goes beyond acute pneumonia, as it also impacts lipid metabolism. Decreased HDL-C and LDL-C levels have been reported in patients with COVID-19. The lipid profile is a less robust biochemical marker than apolipoproteins, components of lipoproteins. However, the association of apolipoprotein levels during COVID-19 is not well described and understood. The objective of our study is to measure plasma levels of 14 apolipoproteins in patients with COVID-19 and to evaluate the relationships between apolipoprotein levels, severity factors and patient outcomes. From November to March 2021, 44 patients were recruited on admission to the intensive care unit because of COVID-19. Fourteen apolipoproteins and LCAT were measured by LC-MS/MS in plasma of 44 COVID-19 patients on admission to the ICU and 44 healthy control subjects. Absolute apolipoprotein concentrations were compared between COVID-19 patients and controls. Plasma apolipoproteins (Apo) A (I, II, IV), C(I, II), D, H, J and M and LCAT were lower in COVID-19 patients, whereas Apo E was higher. COVID-19 severity factors such as PaO2/FiO2 ratio, SO-FA score and CRP were correlated with certain apolipoproteins. Lower Apo B100 and LCAT levels were observed in non-survivors of COVID-19 versus survivors. To conclude, in this study, lipid and apolipoprotein profiles are altered in COVID-19 patients. Low Apo B100 and LCAT levels may be predictive of non-survival in COVID-19 patients.

Plasma concentrations of apolipoproteins and incident cardiovascular diseases in patients with type 2 diabetes

Background and Aims : Apolipoproteins govern lipoprotein metabolism. Here we evaluated the association of their plasma concentrations with major cardiovascular events (MACE) and coronary artery diseases (CAD) in subjects with type 2 diabetes (T2D).

Plasma apolipoprotein concentrations and new-onset diabetes in subjects with prediabetes

Plasma apolipoprotein concentrations and new-onset diabetes in subjects with prediabetes

Plasma apolipoprotein concentrations and incident diabetes in subjects with prediabetes

BackgroundThe identification of circulating biomarkers associated with the risk of type 2 diabetes (T2D) is useful for improving the current prevention strategies in the most at-risk patients. Here, we aimed to investigate the association of plasma apolipoprotein concentrations in prediabetes subjects with the incidence of new-onset T2D during follow-up.MethodsIn the IT-DIAB prospective study, 307 participants with impaired fasting glucose levels (fasting plasma glucose [FPG]: 110–125 mg/dL) were followed yearly for 5 years. The onset of T2D was defined as a first FPG value ≥ 126 mg/dL during follow-up. Apolipoprotein (apo)A-I, A-II, A-IV, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a) plasma concentrations were determined by mass spectrometry. Correlations between apolipoproteins and metabolic parameters at baseline were assessed by Spearman’s coefficients. Kaplan–Meier curves were drawn using a ternary approach based on terciles and incident T2D. The association between plasma apolipoproteins concentrations and the incidence of T2D was determined using Cox proportional-hazards models.ResultsDuring a median follow-up of 5-year, 115 participants (37.5%) developed T2D. After adjustment for age, sex, body mass index, FPG, HbA1c, and statin use, the plasma levels of apoC-I, apoC-II, apoC-III, apoE, apoF, apoH, apoJ, and apoL1 were positively associated with a high risk for T2D. After further adjustment for plasma triglycerides, only apoE (1 SD natural-log-transformed hazard ratio: 1.28 [95% confidence interval: 1.06; 1.54]; p = 0.010), apoF (1.22 [1.01; 1.48]; p = 0.037), apoJ (1.24 [1.03; 1.49]; p = 0.024), and apoL1 (1.26 [1.05; 1.52]; p = 0.014) remained significantly associated with the onset of T2D. Kaplan–Meier survival curves also showed that the lower third of plasma apoE levels (< 5.97 mg/dL) was significantly associated with a lower risk of conversion to T2D (log-rank test, p = 0.002) compared to the middle and upper thirds.ConclusionsThe plasma apoE levels are positively associated with the risk of T2D in prediabetes subjects, independently of traditional risk factors. The possible associations of apoF, apoJ, and apoL1 with T2D risk also pave the way for further investigations.Trial registration This trial was registered at clinicaltrials.gov as NCT01218061 and NCT01432509

Effects of different ratios of medicine dosage for propofol and sevoflurane on postoperative cognitive function in elderly patients with mild cognitive impairment

Objective To evaluate the effects of different ratios of medicine dosage for propofol and sevoflurane on postoperative cognitive function in elderly patients with mild cognitive impairment. Methods Ninety-six patients of both sexes, aged 65-75 yr, weighing 60-80 kg, of American Society of Anesthesiologists physical status Ⅰ or Ⅱ, scheduled for elective lower limb fracture operation under general anesthesia, with mild cognitive impairment before surgery, were assigned into 4 groups (n=24 each) using a random number table: propofol group (group P), sevoflurane group (group S) and different ratios of medicine dosage for propofol and sevoflurane groups (group PS1 and group PS2). Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) were used to evaluate the cognitive function of patients at 1 day before operation (T0) and 7 days after operation (T1). Venous blood samples were collected at T0 and T1 for determination of the concentrations of plasma apolipoprotein J (ApoJ) and soluble CD14 (sCD14) by enzyme-linked immunosorbent assay. Results Compared with group S, MMSE and MoCA scores were significantly increased and plasma concentrations of ApoJ and sCD14 were decreased at T1, and the incidence of postoperative cognitive dysfunction was decreased in P, PS1 and PS2 groups (P 0.05). Conclusion Combination of propofol 1.2 μg/ml given by target-controlled infusion and 0.7-1.2% sevoflurane inhalation for maintenance of anesthesia does not aggravate the postoperative cognitive dysfunction in elderly patients with mild cognitive impairment. Key words: Propofol; Anesthetics, inhalation; Cognition disorders; Postoperative complications; Aged

Apolipoprotein H expression is associated with IL28B genotype and viral clearance in hepatitis C virus infection

HCV requires host lipid metabolism for replication, and apolipoproteins have been implicated in the response to treatment. We examined plasma apolipoprotein concentrations in three cohorts of patients: mono-infected patients with symptomatic acute hepatitis C (aHCV); those undergoing treatment for chronic hepatitis C (cHCV); and HIV/HCV co-infected patients being treated for their chronic hepatitis C. We also evaluated associations between apolipoproteins and IL28B polymorphisms, a defined genetic determinant of viral clearance. Plasma apolipoprotein H (ApoH) levels were significantly higher in patients who achieved spontaneous clearance or responded to pegylated-interferon/ribavirin therapy. Strikingly, patients carrying the IL28B rs12979860 CC SNP correlated with the plasma concentration of ApoH in all three cohorts. Both ApoH and IL28B CC SNP were associated with HCV clearance in univariate analysis. Additional multivariate analysis revealed that the association between IL28B and HCV clearance was closely linked to that of Apo H and HCV clearance, suggesting that both belong to the same biological pathway to clearance. The association between IL28B CC SNP and ApoH was not observed in healthy individuals, suggesting that early post-infection events trigger differential ApoH expression in an IL28B allele dependent manner. This relationship identifies ApoH as the first induced protein quantitative trait associated with IL28B, and characterises a novel host factor implicated in HCV clearance.

Assessment of plasma prothrombotic factors in patients with Buerger's disease

The pathogenesis of Buerger' disease (thrombangiitis obliterans; TAO) remains unknown, although a strong association with tobacco use has been established. Blood coagulation and fibrinolytic factors as well as selected clinical chemistry parameters have been evaluated in 37 patients with Buerger's disease. Median levels of prothrombotic factors were higher in patients with TAO than in healthy control: annexin V (P < 0.0003), factor VII (P < 0.0001), factor VIII (P < 0.0000001), factor XI (P < 0.000003), homocysteine (P < 0.014) and fibrinogen (P = 0.00007). Patients with Buerger's disease also showed higher median plasma levels of urokinase type plasminogen activator (uPA) (P < 0.000004), its receptor (uPAR) (P < 0.0008) and uPA complex with plasminogen activator inhibitor 1 (uPA-PAI-1) P < 0.000006). In contrast, plasma concentrations of apolipoprotein A and folic acid were lower in patients with TAO than in control (P < 0.004 and P < 0.0006; respectively). Higher plasminogen (P < 0.05) and cholesterol (P < 0.003), as well as lower folic acid (P < .0.05) levels were noted in the smokers group than in nonsmoking patients. We found higher plasminogen (P < 0.05), factor VII (P < 0.05), total lipids (P < 0.003), cholesterol (P < 0.05) and triglycerides (P < 0.002) levels in patients requiring surgical treatment for limb-threatening ischaemia than the patients treated only conservatively. These findings suggest an important role of haemostatic risk factors in the pathogenesis of Buerger's disease, with special regard to hyperhomocysteinemia that might be aggravated by low serum folic acid level. In patients with aggressive clinical course, disturbances in serum lipids were more pronounced. Further studies are warranted to establish whether diet supplementation of folic acid as well as normalization of lipids balance might influence the clinical course of TAO.

Plasma concentrations of apolipoproteins A-I, B, and M in patients with critical limb ischemia

Objectives Apolipoproteins affect development of atherosclerosis, but their involvement in the pathogenesis of critical limb ischemia (CLI), a severe form of atherosclerosis, has not previously been examined. Design and methods ApoA-I, apoB, and apoM were measured in plasma from 196 CLI subjects and 214 control individuals from the background population. Results Cases had lower levels of the apolipoproteins, as compared to controls; apoA-I, 1.23 vs. 2.08 g/L; apoB, 0.93 vs. 1.04 g/L; apoM, 0.75 vs. 0.91 μmol/L ( p < 0.0001 for all three). ApoA-I and apoM correlated negatively with inflammatory markers and positively to 1- and 3-year survival rates, whereas apoB did not. In multivariate analyses, apoA-I, but not apoB and apoM, was independently associated with CLI, the odds ratio being 0.015. Conclusions In subjects with CLI, plasma concentrations of apoA-I, apoB and apoM were significantly lower than in control individuals, but only apoA-I was independently associated to CLI.

Plasma concentrations of apolipoproteins A-I, B and M in patients with abdominal aortic aneurysms

Objectives Apolipoproteins play important roles in the development of atherosclerosis but their involvement in the pathogenesis of abdominal aortic aneurysm (AAA) is poorly understood. The aim was to investigate whether apoA-I, apoB and apoM are independently associated with AAA. Design and methods Plasma apoA-I, apoB and apoM were measured in 343 patients with AAA and in 214 elderly apparently healthy control individuals from the background population. Results AAA patients had lower apolipoprotein levels, as compared to healthy individuals: apoA-I, 1.62 vs. 2.08 g/L; apoB, 0.91 vs. 1.04 g/L; apoM, 0.72 vs. 0.91 μmol/L ( p < 0.0001 for all three). In multivariate analyses, apoA-I and apoB were associated with AAA, odds ratios (95% confidence intervals) being 0.53 (0.43–0.64) and 0.86 (0.75–0.998), respectively. Conclusions ApoA-I, apoB and apoM levels were significantly lower in patients with AAA than in the control individuals, but only apoA-I and apoB were independently associated to AAA.

Eggs distinctly modulate plasma carotenoid and lipoprotein subclasses in adult men following a carbohydrate-restricted diet

We previously reported that carbohydrate restriction (CR) (10–15% en) during a weight loss intervention lowered plasma triglycerides (TG) by 45% in male subjects ( P<.001). However, those subjects with a higher intake of cholesterol provided by eggs (640 mg additional cholesterol, EGG group) had higher concentrations of high-density lipoprotein (HDL) cholesterol ( P<.0001) than the individuals consuming lower amounts (0 mg of additional cholesterol, SUB group). The objectives of the present study were to evaluate whether CR and egg intake (1) modulate circulating carotenoids and (2) affect the concentrations of plasma apolipoproteins (apo), lipoprotein size and subfraction distribution. CR decreased the number of large and medium very low-density lipoprotein cholesterol subclasses ( P<.001), while small low-density lipoprotein (LDL) were reduced ( P<.001). In agreement with these observations, a decrease in apo B ( P<.01) was observed. In addition, CR resulted in a 133% increase in apo C-II and a 65% decrease in apo C-III ( P<.0001). Although an increase of the larger LDL subclass was observed for all subjects, the EGG group had a greater increase ( P<.05). The EGG group also presented a higher number of large HDL particles ( P<.01) compared to the SUB group. Regarding carotenoids, CR resulted in no changes in dietary or plasma α- or β-carotene and β-cryptoxanthin, while there was a significant reduction in both dietary and plasma lycopene ( P<.001). In contrast, dietary lutein and zeaxanthin were increased during the intervention ( P<.05). However, only those subjects from the EGG group presented higher concentrations of these two carotenoids in plasma, which were correlated with the higher concentrations of large LDL observed in the EGG group. These results indicate that CR favorably alters VLDL metabolism and apolipoprotein concentrations, while the components of the egg yolk favor the formation of larger LDL and HDL leading to an increase in plasma lutein and zeaxanthin.

Raisins and walking alter appetite hormones and plasma lipids by modifications in lipoprotein metabolism and up-regulation of the low-density lipoprotein receptor

The purpose of this study was to determine the effects of consuming raisins, increasing steps walked, or a combination of these interventions on lipoprotein metabolism and appetite hormones by assessing plasma apolipoprotein concentrations, cholesterol ester transfer protein activity, low-density lipoprotein (LDL) receptor messenger RNA (mRNA) abundance, and plasma ghrelin and leptin concentrations. Thirty-four subjects (17 men and 17 postmenopausal women) were matched for weight and sex and randomly assigned to consume 1 cup raisins per day (RAISIN), increase the amount of steps walked per day (WALK), or a combination of both interventions (RAISIN + WALK). The subjects completed a 2-week run-in period, followed by a 6-week intervention. Ribonucleic acid was extracted from mononuclear cells, and LDL receptor mRNA abundance was quantified by use of reverse transcriptase polymerase chain reaction. Plasma apolipoproteins were measured by Luminex (Austin, TX) technology. Apoproteins A-1, B, C-II, and E and cholesterol ester transfer protein activity were not altered for any of the groups. In contrast, apolipoprotein C-III was significantly decreased by 12.3% only in the WALK group ( P < .05). Low-density lipoprotein receptor mRNA abundance was increased for all groups after the intervention ( P < .001). There was a significant group effect for plasma leptin ( P = .026). Plasma concentrations increased for RAISIN and RAISIN + WALK. Similarly, plasma ghrelin concentrations were elevated postintervention for both groups consuming raisins ( P < .05). These data suggest that walking and raisin consumption decrease plasma LDL cholesterol by up-regulating the LDL receptor and that raisin consumption may reduce hunger and affect dietary intake by altering hormones influencing satiety.

Effects of different doses of atorvastatin on human apolipoprotein B-100, B-48, and A-I metabolism

Nine hypercholesterolemic and hypertriglyceridemic subjects were enrolled in a randomized, placebo-controlled, double-blind, crossover study to test the effect of atorvastatin 20 mg/day and 80 mg/day on the kinetics of apolipoprotein B-100 (apoB-100) in triglyceride-rich lipoprotein (TRL), intermediate density lipoprotein (IDL), and LDL, of apoB-48 in TRL, and of apoA-I in HDL. Compared with placebo, atorvastatin 20 mg/day was associated with significant reductions in TRL, IDL, and LDL apoB-100 pool size as a result of significant increases in fractional catabolic rate (FCR) without changes in production rate (PR). Compared with the 20 mg/day dose, atorvastatin 80 mg/day caused a further significant reduction in the LDL apoB-100 pool size as a result of a further increase in FCR. ApoB-48 pool size was reduced significantly by both atorvastatin doses, and this reduction was associated with nonsignificant increases in FCR. The lathosterol-campesterol ratio was decreased by atorvastatin treatment, and changes in this ratio were inversely correlated with changes in TRL apoB-100 and apoB-48 PR. No significant effect on apoA-I kinetics was observed at either dose of atorvastatin. Our data indicate that atorvastatin reduces apoB-100- and apoB-48-containing lipoproteins by increasing their catabolism and has a dose-dependent effect on LDL apoB-100 kinetics. Atorvastatin-mediated changes in cholesterol homeostasis may contribute to apoB PR regulation.

Plasma concentrations of apolipoprotein B are modulated by a gene–diet interaction effect between the LFABP T94A polymorphism and dietary fat intake in French-Canadian men

Hyperapobetalipoproteinemia is a common feature of the metabolic syndrome and could result from the interaction between genetic and dietary factors. The objective of this study was to verify whether dietary fat intake interacts with the T94A polymorphism of the liver fatty acid-binding protein (LFABP) gene to modulate plasma apolipoprotein (apo) B levels. Dietary fat and saturated fat intakes were obtained by a dietitian-administered food frequency questionnaire and the LFABP T94A genotype was determined by a PCR-RFLP based method in 623 French-Canadian men recruited through the Chicoutimi Lipid Clinic (279 T94/T94, 285 T94/A94, and 59 A94/A94). The LFABP T94A polymorphism was not associated with plasma apo B levels when fat intake was not taken into consideration. However, in a model including the polymorphism, fat intake expressed as a percentage of total energy intake, the interaction term and covariates, the variance in apo B concentrations was partly explained by the LFABP T94A polymorphism (5.24%, p=0.01) and by the LFABP T94A ∗ fat interaction (6.25%, p=0.005). Results were similar when saturated fat replaced fat intake in the model (4.49%, p=0.02 for LFABP T94A and 6.43%, p=0.004 for the interaction). Moreover, in men consuming more than 30% of energy from fat, the odds ratio for having plasma apo B levels above 1.04 g/L for A94 carriers was of 0.40 ( p=0.02) compared to T94/T94 homozygotes. Results were similar for carriers of the A94 allele consuming more than 10% of energy from saturated fat (OR: 0.32, p=0.005). In conclusion, T94/T94 exhibit higher apo B levels whereas carriers of the A94 allele seem to be protected against high apo B levels when consuming a high fat and saturated fat diet. These findings reinforce the importance to take into account gene–diet interactions in the prevention and management of the metabolic syndrome.

Lipid-related genes and myocardial infarction in 4685 cases and 3460 controls: discrepancies between genotype, blood lipid concentrations, and coronary disease risk.

Blood lipid concentrations are causally related to the risk of coronary heart disease (CHD). Various associations between CHD risk and genes that moderately affect plasma lipid levels have been described, but previous studies have typically involved too few 'cases' to assess these associations reliably. The present study involves 4685 cases of myocardial infarction (MI) and 3460 unrelated controls without diagnosed cardiovascular disease. Six polymorphisms of four 'lipid-related' genes were genotyped. For the apolipoprotein E epsilon2/epsilon3/epsilon4 polymorphism, the average increase in the plasma ratio of apolipoprotein B to apolipoprotein A(1) (apoB/apoA(1) ratio) among controls was 0.082 (s.e. 0.007) per stepwise change from epsilon3/epsilon2 to epsilon3/epsilon3 to epsilon3/epsilon4 genotype (trend P < 0.0001). The case-control comparison yielded a risk ratio for MI of 1.16 (95% CI: 1.06, 1.27; P = 0.001) per stepwise change in these genotypes. But, this risk ratio was not as extreme as would have been expected from the corresponding differences in plasma apoB/apoA(1) ratio between genotypes. Hence, following adjustment for the measured level of the plasma apoB/apoA(1) ratio, the direction of the risk ratio per stepwise change reversed to 0.83 (95% CI: 0.74, 0.92; P < 0.001). Similarly, for the apolipoprotein B Asn4311Ser and Thr71Ile polymorphisms, genotypes associated with more adverse plasma apolipoprotein concentrations were associated with significantly lower risk of MI after adjustment for the apoB/apoA(1) ratio. The B2 allele of the cholesteryl ester transfer protein TaqIb polymorphism was associated with a significantly lower plasma apoB/apoA(1) ratio, but with no significant difference in the risk of MI. Finally, the lipoprotein lipase Asn291Ser and T4509C (PvuII) polymorphisms did not produce clear effects on either the plasma apoB/apoA(1) ratio or the risk of MI. It remains unresolved why some of these genetic factors that produce lifelong effects on plasma lipid concentrations have significantly less than the correspondingly expected effects on CHD rates in adult life.

Glycated apolipoprotein A-I assay by combination of affinity chromatography and latex immunoagglutination

The degree of glycation of plasma apolipoprotein A-I was measured by a combination of gel filtration, boronate affinity chromatography and latex immunoagglutination. The plasma concentrations of apolipoprotein A-I determined by this combination method (y) correlated well with those determined by turbidimetric immunoassay (x) (y= 1·12x + 1·9, r = 0·964). The inter- and intra-assay coefficients of variation in the glycated apolipoprotein A-I assay were 4·1–5·0% and 4·0–4·4%, respectively. Interference from plasma glucose at concentrations up to 55·1 mmol/L was eliminated by gel filtration. Labile glycated apolipoprotein A-I did not interfere with the measurement of glycated apolipoprotein A-I. Reference values for glycated apolipoprotein A-I were determined to be 2·4–4·0% (n = 140), with no significant difference between men and women. The mean concentration of plasma glycated apolipoprotein A-I in patients with uncontrolled diabetes mellitus (5·11%) was significantly higher than in normal subjects (3·12%, P < 0·001). The method is simple, rapid and highly sensitive for determination of the glycation level of plasma apolipoprotein A-I.

Vitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemia

There is growing evidence of the capacity of vitamin A to regulate the expression of the genetic region that encodes apolipoproteins (apo) A-I, C-III, and A-IV. This region in turn has been proposed to modulate the expression of hyperlipidemia in the commonest genetic form of dyslipidemia, familial combined hyperlipidemia (FCHL). The hypothesis tested here was whether vitamin A (retinol), by controlling the expression of the AI-CIII-AIV gene cluster, plays a role in modulating the hyperlipidemic phenotype in FCHL. We approached the subject by studying three genetic variants of this region: a C1100–T transition in exon 3 of the apoC-III gene, a G3206–T transversion in exon 4 of the apoC-III gene, and a G–75–A substitution in the promoter region of the apoA-I gene. The association between plasma vitamin A concentrations and differences in the plasma concentrations of apolipoproteins A-I and C-III based on the different genotypes was assessed in 48 FCHL patients and 74 of their normolipidemic relatives. The results indicated that the subjects carrying genetic variants associated with increased concentrations of apoA-I and C-III (C1100–T and G–75–A) also presented increased plasma concentrations of vitamin A. This was only observed among the FCHL patients, which suggested that certain characteristics of these patients contributed to this association. The G3206–T was not associated with changes in either apolipoprotein concentrations or in vitamin A. In summary, we report a relationship between genetically determined elevations of proteins of the AI-CIII-AIV gene cluster and vitamin A in FCHL patients. More studies will be needed to confirm that vitamin A plays a role in FCHL which might also be important for its potential application to therapeutical approaches. —Ribalta, J., J. Girona, J. C. Vallvé, A. E. La Ville, M. Heras, and L. Masana. Vitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemia. J. Lipid Res. 1999. 40: 426–431.

Metabolism of lipoproteins containing apolipoprotein B in hepatic lipase-deficient mice

Mice lacking hepatic lipase have been reported to express mild hyperlipidemia characterized by increased concentrations of large high density lipoproteins, but normal concentrations of lipoproteins containing apolipoprotein B. Whereas hepatic lipase has been implicated in the clearance and processing of chylomicron remnants in rats, no such defect was found in these mice. We have further characterized the abnormal lipoprotein phenotype in young hepatic lipase-deficient mice and have found more pronounced elevations of high density lipoproteins associated in particular with a 5-fold increase in plasma concentrations of apolipoprotein E. In addition, there was a reduction in the concentration of low density lipoproteins containing apolipoprotein B-100 and B-48 relative to precursor lipoproteins of lower density and a pronounced deficiency of apolipoprotein B-containing low density lipoproteins with density exceeding 1.029 g/mL. Conversion of radiolabeled rabbit intermediate density lipoproteins to low density lipoproteins was reduced by 6-fold as compared with wild-type mice. Although clearance of cholesteryl ester-labeled chylomicrons from the blood was unimpaired in the deficient mice, that of chylomicron remnants was reduced. Furthermore, endocytosis of chylomicron cholesteryl esters into liver cells occurred more rapidly than in wild-type mice. The unimpaired hepatic clearance of injected chylomicron particles in hepatic lipase-deficient mice may be the result of greater acquisition of apoE from high density lipoproteins during remnant formation.▪ These studies thus demonstrate a critical role for mouse hepatic lipase in the formation of small, dense low density lipoproteins, as well as participation in the normal clearance and processing of chylomicron remnants.—Qiu, S., N. Bergeron, L. Kotite, R. M. Krauss, A. Bensadoun, and R. J. Havel. Metabolism of lipoproteins containing apolipoprotein B in hepatic lipase-deficient mice.

Hypobetalipoproteinemia is associated with low levels of hemostatic risk factors in the Framingham offspring population.

Given the importance of thrombosis in causation of acute coronary syndromes, it is possible that the beneficial effect of low lipid levels on the risk of coronary events is achieved by lowering thrombotic potential of the blood. Hypobetalipoproteinemia is characterized by plasma concentrations of apolipoprotein B and LDL cholesterol that are one third of those observed in the general population. The aim of this study was to utilize subjects with hypobetalipoproteinemia to examine the relation between thrombotic potential and low levels of LDL cholesterol. Hemostatic risk factors were measured in 1878 individuals (1003 women and 875 men) participating in cycle 5 of the Framingham Offspring Study. The subjects were divided into five groups on the basis of LDL cholesterol level. Subjects with hypobetalipoproteinemia (LDL cholesterol < 70 mg/dL) had the lowest levels of fibrinogen, plasminogen activator inhibitor-1 antigen, and tissue plasminogen activator antigen. As LDL cholesterol increased, there was a significant increase in the levels of the hemostatic risk factors, with the exception of von Willebrand factor antigen. Adjustment with multivariate regression analyses for the covariates age, sex, body mass index, diabetes mellitus, smoking, alcohol intake, triglyceride level, and use of antihypertensive medication did not materially alter the results. Decreasing levels of LDL cholesterol are associated with decreasing levels of hemostatic risk factors. Subjects with hypobetalipoproteinemia have the lowest levels of hemostatic risk factors and may be protected against thrombotic complications of atherosclerotic cardiovascular disease because of reduced thrombotic potential. One mechanism by which lipid-lowering therapy may decrease clinical cardiac events is through a reduction in thrombotic tendency.

A Major Locus Influencing Plasma High-Density Lipoprotein Cholesterol Levels in the San Antonio Family Heart Study

To detect and measure the effects of a single locus on quantitative variation in plasma concentrations of HDL cholesterol (HDL-C), we conducted statistical genetic analyses on data from 526 Mexican American individuals in 25 randomly ascertained pedigrees. By using maximum-likelihood complex segregation analysis, we found evidence for a major locus with a codominant mixture model that included the phenotypic means, standard deviations, relative frequency of a low HDL-C allele, and heritability for plasma HDL-C levels, plus the effects of sex (genotype specific), age-by-sex, age2-by-sex, plasma concentrations of apolipoprotein (apo)AI and triglycerides (genotype specific), exogenous sex hormone use, and menopausal status under an unrestricted general model. Inclusion of the four covariates (in addition to the sex and age-by-sex effects) accounted for nearly 79% of the variance in total plasma HDL-C levels. Of the remaining 21% of the variance, the detected major locus accounted for approximately 55% in men and 21% in women; the total genetic contributions to the variance by genes were approximately 82% in men and 69% in women. Linkage analyses with penetrance parameter estimates from the segregation analysis excluded tight linkage between the detected major locus and markers for the following candidate loci: the apoAI/apoCIII genomic region (P < .05), apoB (P < .01), hepatic lipase (P < .001), lipoprotein lipase (P < .001), and the LDL receptor (P < .001). While not excluding the apoE locus (LOD = -0.348, P < .21), the analysis provided no support for tight linkage between it and the detected major locus.

ACAT inhibitors CL 283,546 and CL 283,796 reduce LDL cholesterol without affecting cholesterol absorption in African green monkeys.

Previous studies with a number of selective acylcoenzyme A:cholesterol acyltransferase (ACAT) inhibitors in several animal models have demonstrated significant reductions in plasma cholesterol and, in some studies, triglyceride levels. This study was conducted to examine the effects of two ACAT inhibitors, CL 283,546 and CL 283,796, in cholesterol-high fat diet fed African green monkeys, a relevant primate model of hyperlipidemia and coronary artery atherosclerosis. Treatment with CL 283,546 or CL 283,796 resulted in significant reductions (ca. 25-30%) in total plasma cholesterol at both 10 and 30 mg/kg per day doses. This reduction in plasma cholesterol was due almost entirely to reduction in low density lipoprotein (LDL) cholesterol (ca. 45%) without significantly affecting high density lipoprotein (HDL) cholesterol, very low density lipoprotein + intermediate density lipoprotein (VLDL + IDL) cholesterol, or triglyceride concentrations. There were no significant effects on plasma concentrations of apolipoproteins A-I, E, or B and, thus, the reduction seen in LDL cholesterol appears to be due to a diminished cholesterol content of LDL particles. Our studies revealed that treatment with these compounds did not reduce cholesterol absorption, which was somewhat surprising as ACAT inhibitors are generally thought to exert their hypolipidemic effects, at least in part, by inhibition of intestinal cholesterol absorption. Our data are consistent with a principal activity of these drugs on the liver to reduce cholesteryl ester secretion in VLDL, leading to a diminished LDL-cholesterol content, and, presumably, enhanced biliary cholesterol-bile acid excretion.