Plasma Lipoprotein Subfractions Research Articles

Identification of genetic drivers of plasma lipoprotein size in the Diversity Outbred mouse population

Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred mice maintained on a Western-style diet. We identified 21 quantitative trait loci (QTL) affecting lipoprotein abundance. To refine the QTL and link them to disease risk in humans, we asked if the human homologs of genes located at each QTL were associated with lipid traits in human genome-wide association studies. Integration of mouse QTL with human genome-wide association studies yielded candidate gene drivers for 18 of the 21 QTL. This approach enabled us to nominate the gene encoding the neutral ceramidase, Asah2, as a novel candidate driver at a QTL on chromosome 19 for large HDL particles (HDL-2b). To experimentally validate Asah2, we surveyed lipoproteins in Asah2−/− mice. Compared to wild-type mice, female Asah2−/− mice showed an increase in several lipoproteins, including HDL. Our results provide insights into the genetic regulation of circulating lipoproteins, as well as mechanisms by which lipoprotein subfractions may affect cardiovascular disease risk in humans.

Milk intake, lactase persistence genotype, plasma proteins and risks of cardiovascular events in the Swedish general population

To investigate the associations of milk intake (non-fermented and fermented milk), lactase persistence (LCT-13910 C/T) genotype (a proxy for long-term non-fermented milk intake), and gene-milk interaction with risks of cardiovascular disease (CVD) and CVD mortality. Also, to identify the CVD-related plasma proteins and lipoprotein subfractions associated with milk intake and LCT-13910 C/T genotype. The prospective cohort study included 20,499 participants who were followed up for a mean of 21 years. Dietary intake was assessed using a modified diet history method. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). After adjusting for sociodemographic and lifestyle factors, higher non-fermented milk intake was significantly associated with higher risks of coronary heart disease (CHD) and CVD mortality, whereas higher fermented milk intake was significantly associated with lower risks of CVD and CVD mortality. The genotype associated with higher milk (mainly non-fermented) intake was positively associated with CHD (CT/TT vs. CC HR = 1.27; 95% CI: 1.03, 1.55) and CVD (HR = 1.22; 95% CI: 1.05, 1.42). The association between rs4988235 genotype and CVD mortality was stronger in participants with higher milk intake than among participants with lower intake (P for interaction < 0.05). Furthermore, leptin, HDL, and large HDL were associated with non-fermented milk intake, while no plasma proteins or lipoprotein subfractions associated with fermented milk intake and LCT-13910 C/T genotype were identified. In conclusion, non-fermented milk intake was associated with higher risks of CHD and CVD mortality, as well as leptin and HDL, whereas fermented milk intake was associated with lower risks of CVD and CVD mortality.

A Randomized Trial of ω-3 Fatty Acid Supplementation and Circulating Lipoprotein Subclasses in Healthy Older Adults

Omega-3 (n-3) PUFAs are recognized for triglyceride-lowering effects in people with dyslipidemia, but it remains unclear if n-3-PUFA intake influences lipoprotein profiles in older adults without hypertriglyceridemia. The objective was to determine the effect of n-3-PUFA supplementation on plasma lipoprotein subfractions in healthy older men and women in the absence of cardiovascular disease (CVD) or hypertriglyceridemia. This was a secondary analysis and considered exploratory. Thirty young (20-35 y old) and 54 older (65-85 y old) men and women were enrolled in the study. Fasting plasma samples were collected. After baseline sample collection, 44 older adults were randomly assigned to receive either n-3-PUFA ethyl esters (3.9g/d) or placebo (corn oil) for 6 mo. Pre- and postintervention plasma samples were used for quantitative lipoprotein subclass analysis using high-resolution proton NMR spectroscopy. The number of large, least-dense LDL particles decreased 17%-18% with n-3 PUFAs compared with placebo (<1% change; P<0.01). The number of small, dense LDL particles increased 26%-44% with n-3 PUFAs compared with placebo (∼11% decrease; P<0.01). The cholesterol content of large HDL particles increased by 32% with n-3 PUFAs and by 2% in placebo (P<0.01). The cholesterol content of small HDL particles decreased by 23% with n-3 PUFAs and by 2% in placebo (P<0.01). Despite increasing abundance of small, dense LDL particles that are associated with CVD risk, n-3 PUFAs reduced total triglycerides, maintained HDL, reduced systolic blood pressure, and shifted the HDL particle distribution toward a favorable cardioprotective profile in healthy older adults without dyslipidemia. This study suggests potential benefits of n-3-PUFA supplementation to lipoprotein profiles in healthy older adults without dyslipidemia, which should be considered when weighing the potential health benefits against the cost and ecological impact of widespread use of n-3-PUFA supplements.This trial was registered at clinicaltrials.gov as NCT03350906.

Is There a Correlation between Dietary and Blood Cholesterol? Evidence from Epidemiological Data and Clinical Interventions.

Dietary cholesterol has been a topic of debate since the 1960s when the first dietary guidelines that limited cholesterol intake to no more than 300 mg/day were set. These recommendations were followed for several years, and it was not until the late 1990s when they were finally challenged by the newer information derived from epidemiological studies and meta-analysis, which confirmed the lack of correlation between dietary and blood cholesterol. Further, dietary interventions in which challenges of cholesterol intake were evaluated in diverse populations not only confirmed these findings but also reported beneficial effects on plasma lipoprotein subfractions and size as well as increases in HDL cholesterol and in the functionality of HDL. In this review, we evaluate the evidence from recent epidemiological analysis and meta-analysis as well as clinical trials to have a better understanding of the lack of correlation between dietary and blood cholesterol.

Validation by HPLC analyses of new equations for estimating cholesterol in plasma lipoprotein subfractions

• New equation to calculate sdLDL cholesterol is validated by HPLC analysis. • Ultracentrifugal preparation underestimates VLDL comparing to HPLC. • Homogeneous HDL cholesterol assay is validated by HPLC analysis.

Effect of the Fat Eaten at Breakfast on Lipid Metabolism: A Crossover Trial in Women with Cardiovascular Risk.

Recent studies point out that not only the daily intake of energy and nutrients but the time of day when they are ingested notably regulates lipid metabolism and cardiovascular risk (CVR). Therefore, the aim of the study was to assess if the type of fat ingested at breakfast can modify lipid metabolism in women with CVR. A randomized, crossover clinical trial was performed. Sixty volunteers were randomly assigned to a (A) polyunsaturated fatty acid (PUFA)-rich breakfast, (B) saturated fatty acid (SFA)-rich breakfast, or (C) monounsaturated fatty acid (MUFA)-rich breakfast. Plasma lipoprotein and apolipoprotein subfractions were determined. Our data showed that the PUFA-rich breakfast decreased lipoprotein (a) (Lp(a)), very low-density lipoproteins (VLDL), and intermediate-density lipoproteins (IDL), and increased high-density lipoproteins (HDL). A similar trend was observed for the MUFA-rich breakfast, whereas the SFA-rich breakfast, although it decreased VLDL, also increased IDL and reduced HDL. The PUFA-rich breakfast also decreased β-lipoproteins and apolipoprotein-B. In summary, varying the type of fat eaten at breakfast is enough to significantly modify the lipid metabolism of women with CVR, which can be of great relevance to establish new therapeutic strategies for the treatment of these subjects.

Effects of a Low-Carbohydrate Diet on Cardiometabolic Risk Factors During Weight-Loss Maintenance: A Randomized Controlled Feeding Trial

Abstract Objectives To compare effects of diets varying in carbohydrate (carb) and fat on plasma lipids and lipoprotein subfractions. Methods Participants (N = 164, 70% female, 18–65 y, BMI ≥ 25 kg/m2) achieved 10–14% weight loss on a run-in diet and then were randomized to 3 test diets for 20 weeks of weight-loss maintenance. Percentages of total energy from carb-fat-protein for high-, moderate-, and low-carb diets were 60-20-20 (HI), 40-40-20 (MOD), and 20–60-20 (LO). Relative amounts of added sugar (15% total carb) and saturated fat (35% total fat) were fixed across diets. Plasma was collected at START (post-weight loss) and END of trial. The primary outcome for this ancillary study was lipoprotein insulin resistance (LPIR) – a 6-component weighted score of triglyceride-rich, high-density, and low-density lipoprotein particle (TRL-P, HDL-P, LDL-P) sizes and subfraction concentrations (large/very large TRL-P, large HDL-P, small LDL-P) (NMR spectroscopy, LabCorp). Other outcomes included large LDL-P concentration, triglycerides (TG), and cholesterol (HDL-C, LDL-C). Means (±SE) and END–START changes (mean [95% CI]) were constructed and compared from repeated measures ANOVA. Results Retention was 90% and 147 participants provided evaluable data, with no difference in body weight by diet after randomization. LPIR was 32.6 ± 1.5 at START. Change in LPIR differed by diet (P = 0.009): LO (−5.3 [−9.2, −1.5]), MOD (−0.02 [−4.1, 4.1]), HI (3.6 [−0.6, 7.7]). Diet effects favoring LO compared to HI were observed for large/very large TRL-P (P = 0.005), large HDL-P (P = 0.045), TG (P = 0.006), and HDL-C (P = 0.04). There were no mean differences between diets for particle sizes, LDL-P subfraction concentrations, and LDL-C (START: 79.3 ± 1.8 mg/dL; END–START: HI, 8.2 [4.2, 12.2]; MOD, 11.7 [7.8, 15.7]; LO, 10.0 [6.3, 13.7]). Conclusions With 3-fold higher saturated fat content (21% vs 7% total energy), a low- vs high-carb diet improved LPIR, a biomarker of diabetes risk, and several other components of the metabolic syndrome, with no adverse effects on LDL-P or LDL-C. These results from a large feeding study suggest that carb restriction may help prevent cardiometabolic disease independent of body weight. Funding Sources Nutrition Science Initiative (gifts from Arnold Ventures and Robert Lloyd Corkin Charitable Foundation), New Balance Foundation, Many Voices Foundation, Blue Cross Blue Shield.

Gender differences in LDL and HDL subfractions in atherogenic and nonatherogenic phenotypes

ObjectivesThe aim of our study was to examine the role of low density lipoprotein (LDL)-subfractions in individuals with the atherogenic and non-atherogenic phenotype and the gender differences in lipoprotein subfractions including small dense LDL (sdLDL) and small high density lipoprotein (sHDL) subfractions representing the most atherogenic lipoprotein subfractions. Design & methods35 persons in the atherogenic group (AG) (with sdLDL3–7 subfractions ≥6 mg/dl) and 104 individuals in the non-atherogenic group (NAG) (sdLDL3–7 subfractions <6 mg/dl) were included in our study. To analyze plasma lipoprotein subfractions, a polyacrylamide gel electrophoresis–the Lipoprint system was used. ResultsMales compared to females in the AG had significantly higher levels of atherogenic lipoprotein subfractions such as HDL8, HDL9 and HDL10. All participants in AG had significantly lower levels of intermediate density lipoprotein IDL-A than those in NAG but significantly higher levels of IDL-B and IDL-C. Males in the AG compared to NAG had significantly lower levels of LDL1 and higher levels of LDL2 and LDL3–7 subfractions. In the NAG LDL2 positively correlated with sHDL subfractions while in the AG with the large HDL subfraction. ConclusionResults of our study demonstrate more atherogenic profile in males compared to females and a double role of LDL2 subfraction in the atherogenic process depending on the phenotype (atherogenic/non-atherogenic) of individuals.

Elevated Plasminogen Activator Inhibitor-1 Level Correlates With Low-Density Lipoprotein Subfractions In Obesity

Background and Aims: Plasminogen activator inhibitor-1 (PAI-1) is the primary regulator of fibrinolysis breaking down fibrin in the intravascular compartment and may influence the development of atherosclerotic plaque formation. Circulating lipoproteins represent heterogeneous subpopulations with different size, density and chemical composition. To date, association of plasma PAI-1 and lipoprotein subfractions are still unclear. The aim of the present study was to determine the relationship between plasma PAI-1 levels and the distribution of lipoprotein subfractions in obesity.

Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension

BackgroundAberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive.ObjectiveTo investigate the relationship between circulating lipoprotein subclasses and...

Molecular Fingerprints of Iron Parameters among a Population-Based Sample.

Iron deficiency is the most frequent deficiency disease and parameters of iron metabolism appear to be linked to major metabolic and cardiovascular diseases. We screened a large set of small molecules in plasma for associations with iron status among apparently healthy subjects to elucidate subclinical profiles which may provide a link between iron status and onset of diseases. Based on mass spectrometry and nuclear magnetic resonance spectroscopy we determined 613 plasma metabolites and lipoprotein subfractions among 820 apparently healthy individuals. Associations between ferritin, transferrin, haemoglobin and myoglobin and metabolite levels were tested by sex-specific linear regression analyses controlling for common confounders. Far more significant associations in women (82 out of 102) compared to men became obvious. The majority of the metabolites associated with serum ferritin and haemoglobin in women comprising fatty acid species, branched-chain amino acid catabolites and catabolites of heme. The latter was also obvious among men. Positive associations between serum transferrin and VLDL and IDL particle measures seen in women were observed in men with respect to serum ferritin. We observed a sexual-dimorphic fingerprint of surrogates of iron metabolism which may provide a link for the associations between those parameters and major metabolic and cardiovascular disease.

Novel findings in relation to multiple anti-atherosclerotic effects of XueZhiKang in humans

BackgroundPrevious studies have clearly demonstrated that XueZhiKang (XZK), an extract of cholestin, can decrease low-density lipoprotein cholesterol (LDL-C) and cardiovascular events. However, the mechanism of the effects of XZK on atherosclerosis (AS) in humans has been reported less frequently. In the present study, we investigated the impact of XZK on lipoprotein subfractions, oxidized LDL (oxLDL), and interleukin-6 (IL-6). MethodsFrom October 2015 to July 2016, 40 subjects were enrolled in this study. Of them, 20 subjects with dyslipidemia received XZK 1200 mg/day for 8 weeks (XZK group); 20 additional healthy subjects who did not receive therapy acted as controls. The plasma lipoprotein subfractions, oxLDL, and IL-6 were examined at baseline and again at 8 weeks. ResultsData showed that XZK could significantly decrease not only plasma LDL-C levels (87.26 ± 24.45 vs. 123.34 ± 23.99, P < 0.001), total cholesterol (4.14 ± 0.87 vs. 5.08 ± 1.03, P < 0.001), triglycerides (0.95 ± 0.38 vs. 1.55 ± 0.61, P < 0.05), and apolipoprotein B (1.70 ± 0.35 vs. 1.81 ± 0.72, P < 0.05), but also oxLDL (36.36 ± 5.31 vs. 49.20 ± 15.01, P < 0.05) and IL-6 (8.50 ± 7.40 vs. 10.40 ± 9.49, P < 0.05). At the same time, XZK reduced the concentration of small LDL-C (1.78 ± 2.17 vs. 6.33 ± 7.78, P < 0.05) and the percentage of the small LDL subfraction (1.09 ± 1.12 vs. 3.07 ± 3.09, P < 0.05). ConclusionsTreatment with 1200 mg/day XZK for 8 weeks significantly decreased the atherogenic small LDL subfraction and reduced oxidative stress and inflammatory markers, in addition to affecting the lipid profile, suggesting multiple beneficial effects in coronary artery disease.

Plasma lipoprotein subfraction concentrations are associated with lipid metabolism and age-related macular degeneration

Disturbance in lipid metabolism has been suggested as a major pathogenic factor for age-related macular degeneration (AMD). Conventional lipid measures have been inconsistently associated with AMD. Other factors that can alter lipid metabolism include lipoprotein phenotype and genetic mutations. We performed a case-control study to examine the association between lipoprotein profile and neovascular AMD (nAMD) and whether the cholesterylester transfer protein (CETP) D442G mutation modulates these associations. Patients with nAMD had significantly higher concentrations of HDL and IDL compared with controls. The increase in HDL particles in nAMD patients was driven by an excess of medium-sized particles. Concurrently, patients with nAMD also had lower Apo A-1, lower VLDL and chylomicron lipoprotein. Many of these associations showed a dose-dependent association between controls, early AMD cases, and nAMD cases. Adjustment for the presence of the D442G mutation at the CETP locus did not significantly alter the increased AMD risk associated with HDL particle concentration. AMD is associated with variation in many lipoprotein subclasses, including increased HDL and IDL particles and decreased Apo A-1, VLDL, and chylomicron particles. These data suggest widespread systemic disturbance in lipid metabolism in the pathogenesis of AMD, including possible alterations in lipoprotein carrier capacity.

TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD

Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic β-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.

Changes in plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypercholesterolemia after atorvastatin

Changes in plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypercholesterolemia after atorvastatin

Low normal thyroid function as a determinant of increased large very low density lipoprotein particles

Aim: Increased susceptibility for atherosclerotic cardiovascular disease attributable to low-normal thyroidfunction is likely to be in part be due to effects on plasma lipoproteins. Associations of changes in lipoprotein metabolism with thyroid function could be enhanced in the context of chronic hyperglycemia. We determined relationships of plasma lipids and lipoprotein subfractions with thyroid stimulating hormone (TSH) and free thyroxine (free T4) in euthyroid subjects with and without Type 2 diabetes mellitus (T2DM).

Relationship between plasma phospholipase A2 concentrations and lipoprotein subfractions in patients with stable coronary artery disease

BackgroundBoth increased lipoprotein-associated phospholipase A2 (Lp-PLA2) concentrations and atherogenic lipoprotein subfractions have been shown to reflect unfavourable cardiovascular risk. However, the correlation between Lp-PLA2 and lipoprotein subfractions in patients with coronary artery disease (CAD) has not been assessed yet. MethodsA total of 324 consecutive subjects who were not treated with lipid-lowering drugs were enrolled (angiographically proven CAD: n=253; non-CAD: n=71). Plasma Lp-PLA2 concentrations were measured using ELISA. The low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions were determined by Lipoprint System. ResultsPlasma Lp-PLA2 concentrations were higher in patients with CAD compared with those without CAD (153.61±78.73 vs. 131.41±65.49ng/ml, p=0.028). The univariable correlation analysis revealed that Lp-PLA2 concentrations were positively correlated with the cholesterol concentrations of each LDL subfractions and the intermediate as well as small HDL subfractions, while negatively linked with the LDL particle size and large HDL-cholesterol (HDL-C) concentrations in CAD group. However, no similar results were observed in the non-CAD group. Furthermore, multivariable regression analysis was performed in patients with CAD and showed that plasma Lp-PLA2 concentrations were independently correlated with the cholesterol concentrations of each LDL subfractions [large LDL-cholesterol (LDL-C): β=0.263, p<0.001; intermediate LDL-C: β=0.327, p<0.001; small LDL-C: β=0.135, p=0.033] and small HDL-C (β=0.133, p=0.034). ConclusionLp-PLA2 concentrations were positively associated with all LDL subfractions and small HDL subfraction, suggesting an interaction between Lp-PLA2 and lipoprotein subfraction phenotypes in the status of CAD.

Low normal thyroid function as a determinant of increased large very low density lipoprotein particles

ObjectivesLow-normal thyroid function may relate to increases in plasma cholesterol and triglycerides, but effects on lipoprotein subfractions are largely unknown. Associations of alterations in lipoprotein metabolism and functionality with low-normal thyroid function could be more pronounced in Type 2 diabetes mellitus (T2DM). We determined relationships of plasma lipids and lipoprotein subfractions with thyroid-stimulating hormone (TSH) and free thyroxine (free T4) in euthyroid subjects, and assessed whether such relationships are modified in the context of T2DM. Design and methodsTSH, free T4, (apo)lipoproteins and lipoprotein subfractions (nuclear magnetic resonance spectroscopy) were measured after an overnight fast in 61 T2DM subjects and 52 non-diabetic subjects. ResultsTSH and free T4 were similar in T2DM and non-diabetic subjects. Plasma triglycerides, large very low density (VLDL) particles, VLDL size and small low density lipoprotein (LDL) particles were increased, whereas high density lipoprotein (HDL) cholesterol was decreased in T2DM subjects (p≤0.05 for each). Age-, sex-, and diabetes status-adjusted multivariable linear regression analysis demonstrated that plasma triglycerides were associated positively with TSH (β=0.196, p=0.039). Large VLDL particles (β=−0.215, p=0.020) and VLDL size were inversely associated with free T4 (β=−0.285, p<0.001). These relationships were not significantly modified by diabetes status (interaction terms: p>0.10 for each). In all subjects combined, LDL and HDL subfraction characteristics were not significantly related to thyroid function status. ConclusionsLow-normal thyroid function may confer increased plasma triglycerides, large VLDL particles and increased VLDL particle size. These relationships are not to a major extent modified in the context of T2DM.

Plasma apoE is Elevated in Metabolic Syndrome: Importance of Large Very Low Density and Low Density Lipoprotein Particles

Background: Apolipoprotein E (apoE) is carried by all major lipoprotein classes in plasma and is likely to contribute to the development of atherosclerosis. We set out to determine the extent to which plasma apoE is related to various VLDL, LDL and HDL subfractions in subjects with and without metabolic syndrome (MetS). Methods: Plasma lipids, lipoprotein subfractions (nuclear magnetic resonance spectroscopy) and plasma apoE were determined in 60 subjects with and 62 subjects without MetS (APOE e2/e2 carriers excluded). Results: Plasma apoE was higher in MetS, coinciding with increased total and large VLDL particles, as well as total LDL particles (p 0.30). Plasma apoE was unrelated to HDL particle concentration (p=0.88). Conclusions: Plasma apoE is elevated in MetS in conjunction with increased concentrations of (large) VLDL and LDL particles. These novel findings provide a rationale to explore whether preferential association of apoE with (large) VLDL and LDL could modify its influence on atherosclerosis development.

Changes in ultracentrifugally separated plasma lipoprotein subfractions in patients with polygenic hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypercholesterolemia after treatment with atorvastatin

Plasma levels of low-density lipoproteins (LDLs) are decreased through stimulation of their hepatic uptake by statins via an LDL receptor. However, it is unclear whether statins equally stimulate the hepatic uptake of all LDL subfractions. We compared the effects of atorvastatin on 3 LDL subfractions, and their associations with LDL-receptor activities, in Japanese patients with polygenic hypercholesterolemia (PHC), familial combined hyperlipoproteinemia (FCHL), and familial hypercholesterolemia (FH). Atorvastatin was administered to patients with PHC (n=11), FCHL (n=16), and FH (n=13). We measured plasma levels of lipids, remnant-like particle cholesterol, apoproteins, and cholesterol in lipoprotein fractions. Sequential ultracentrifugation was performed to subfractionate the plasma lipoproteins, and lymphocyte LDL-receptor activities were estimated using flow cytometry. The average daily dosage of atorvastatin was 10, 27, and 40mg in patients with PHC, FCHL, and FH, respectively; after 12months of atorvastatin treatment, LDL cholesterol (LDL-C) plasma levels decreased by 44%, 50%, and 53%, respectively (all, P<.0001). Atorvastatin reduced low-density LDL-C plasma levels in patients with PHC (48% reduction), FCHL (53%), and FH (46%) (all, P<.0001). Plasma levels of medium-density and high-density LDL-C were also significantly reduced in the 3 patient groups (all, P≤.0147). LDL-receptor activity was negatively correlated with baseline levels of medium-density LDL-C and with the decreases in plasma md-LDL-C levels. Atorvastatin decreased the levels of the 3 LDL fractions. The md-LDL decrease appeared to be mainly because of stimulation of LDL-receptor activity.