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Mice have been used widely to define the mechanism of action of fibric acid derivatives. The fibrates are pharmacological agonists of the peroxisome proliferator-activated receptor alpha (PPARalpha), whose activation in human subjects promotes potent reduction in plasma levels of triglycerides (TG) with concomitant increase in those of HDL-cholesterol. The impact of PPARalpha agonists on gene expression in humans and rodents is however distinct; such distinctions include differential regulation of key genes of lipid metabolism. We evaluated the question as to whether the human and murine genes encoding apolipoprotein apoAV, a regulator of plasma concentrations of TG-rich lipoproteins, might be differentially regulated in response to fibrates. Fenofibrate, a classic PPARalpha agonist, repressed expression of mouse Apoa5 in vivo in a mouse model transgenic for the human APOA5 gene; by contrast, expression of the human ortholog was up-regulated. Our findings are consistent with the presence of a functional PPAR-binding element in the promoter of the human APOA5 gene; this element is however degenerate and non-functional in the corresponding mouse Apoa5 sequence, as demonstrated by reporter assays and gel shift analyses. These data further highlights the distinct mechanisms which are implicated in the metabolism of TG-rich lipoproteins in mice as compared to man. They equally emphasize the importance of the choice of a mouse model for investigation of the impact of pharmaceutical modifiers on hypertriglyceridemia.

The apolipoprotein AV gene (APOA5) is a key determinant of plasma triglyceride levels, a major risk factor for coronary artery disease and a biomarker for the metabolic syndrome. Since thyroid hormones influence very low density lipoprotein triglyceride metabolism and clinical studies have demonstrated an inverse correlation between thyroid status and plasma triglyceride levels, we examined whether APOA5 is regulated by thyroid hormone. Here we report that 3,5,3'-triiodo-L-thyronine (T3) and a synthetic thyroid receptor beta (TRbeta) ligand increase APOA5 mRNA and protein levels in hepatocytes. Our data revealed that T3-activated TR directly regulates APOA5 promoter through a functional direct repeat separated by four nucleotides (DR4). Interestingly, we show that upstream stimulatory factor 1, a transcription factor associated with familial combined hyperlipidemia and elevated triglyceride levels in humans, and upstream stimulatory factor 2 cooperate with TR, resulting in a synergistic activation of APOA5 promoter in a ligand-dependent manner via an adjacent E-box motif. In rats, we observed that apoAV levels declines with thyroid hormone depletion but returned to normal levels upon T3 administration. In addition, treatments with a TRbeta-selective agonist increased apoAV and diminished triglyceride levels. The identification of APOA5 as a T3 target gene provides a new potential mechanism whereby thyroid hormones can influence triglyceride homeostasis. Additionally, these data suggest that TRbeta may be a potential pharmacological target for the treatment of hypertriglyceridemia.

We have isolated a cDNA encoding an apo(a)-related protein designated HaRP-1 (Hedgehog apo(a) related protein-1). The HaRP-1 cDNA (2114 bp; corresponding to a 2.6 kb transcript) was isolated from a hedgehog liver cDNA library. The HaRP-1 clone corresponded to an open reading frame of 676 amino acids and contains a signal sequence followed by a preactivation domain and 7 kringle domains which exhibit an average of 57% amino acid identity with hedgehog plasminogen kringle III. We expressed HaRP-1 in human embryonic kidney cells; immunoprecipitation of metabolically-labeled conditioned medium from transfected cells showed the presence of a 74 kDa band corresponding to HaRP-1. Of note, we also observed an approximately 72 kDa species present in hedgehog plasma by western blotting using a human anti-apo(a) monoclonal antibody; we speculate that the 72 kDa plasma species corresponds to HaRP-1. Interestingly, although none of the 7 kringle domains contained a canonical lysine-binding site, we found that recombinant HaRP-1 bound specifically to lysine-Sepharose. It is likely that the evolution of the HaRP-1 gene is coincident with the evolution of hedgehog apo(a), both of which occurred by duplication of the plasminogen kringle III motif. The function of HaRP-1 remains unclear at present, but may constititute a member of the family of apo(a) proteins that functions in the regulation of lysine-dependent proteolysis.

Platelet-activating factor-acetylhydrolase (PAF-AH) is a lipoprotein-associated phospholipase A2 capable of hydrolyzing platelet-activating factor (PAF) and oxidatively modified phospholipids. We studied the plasma- and lipoprotein-associated PAF-AH activity in patients with primary hypercholesterolemia. Thirty-eight unrelated patients with heterozygous familial hypercholesterolemia (HeteroFH), five patients with homozygous FH (HomoFH), and 33 patients with primary non-FH hypercholesterolemia (NonFH) participated in the study. In all patient groups the plasma PAF-AH activity was significantly elevated compared with 33 normolipidemic controls, the HomoFH having the highest and the NonFH patients showing the lowest enzyme activity. Gradient ultracentrifugation studies showed that this increase is not only due to the elevation in the plasma LDL but also to the increase in the PAF-AH activity associated with each LDL subfraction, being more profound in the small-dense LDL-5. Unlike LDL, no difference in the HDL-associated PAF-AH activity was observed among all groups. Consequently, an altered distribution of enzyme activity among apolipoprotein B (apoB)- and apolipoprotein A-I (apoA-I)-containing lipoproteins is observed in hypercholesterolemic patients, resulting in a significant decrease in the ratio of the HDL-associated PAF-AH to the total plasma enzyme activity compared with controls. This reduction is proportional to the increase of the plasma LDL-cholesterol (LDL-C) levels and consequently to the severity of the hypercholesterolemia. Thus, the ratio of HDL-associated PAF-AH-total plasma enzyme activity may be useful as a potential marker of atherogenicity in subjects with primary hypercholesterolemia.

Importance: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels.Objective: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB.Design, Setting, and Participants: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017.Exposures: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores.Main Outcomes and Measures: Odds ratio (OR) for coronary heart disease (CHD)-defined as coronary death, myocardial infarction, or coronary revascularization-per 10-mg/dL lower concentration of ApoB-containing lipoproteins.Results: A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10-1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10-465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10-38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10-46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10-20).Conclusions and Relevance: Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB. [ABSTRACT FROM AUTHOR]

Importance: Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered.Objective: To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene.Design, Setting, and Participants: Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015.Exposures: Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median.Main Outcomes and Measures: Odds ratio (OR) for major cardiovascular events.Results: The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB.Conclusions and Relevance: Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles. [ABSTRACT FROM AUTHOR]

Background Familial hypercholesterolemia (FH) features elevated oxidative stress and accelerated atherosclerosis driven by elevated levels of atherogenic lipoproteins relative to subnormal levels of atheroprotective high-density lipoprotein (HDL). Small, dense HDL3 potently protects low-density lipoprotein (LDL) against proinflammatory oxidative damage. OBJECTIVE To determine whether antioxidative and/or anti-inflammatory activities of HDL are defective in FH and whether such defects are corrected by LDL apheresis. Methods Antioxidative and antiinflammatory activities of HDL were evaluated as protection of reference LDL from oxidative stress and capacity to prevent accumulation of proinflammatory oxidised lipids, respectively. Lipid surface rigidity of HDL was assessed using a fluorescent probe. HDL components were measured by analytical approaches. Systemic oxidative stress was characterized as plasma 8-isoprostanes. Results Pre-LDL-apheresis, FH patients (n = 10) exhibited elevated systemic oxidative stress (3.3-fold, P < 0.001) vs. sex- and age-matched normolipidemic controls (n = 10). Both antioxidative and antiinflammatory activity of HDL3 were impaired (up to −91%, P < 0.01) in FH. Sphingomyelin and saturated fatty acid contents were elevated in FH HDL3, resulting in enhanced lipid surface rigidity. The surface lipid content (phospholipids, free cholesterol) was reduced in FH (up to −15%, P < 0.001), whereas content of core lipids (cholesteryl esters, triglycerides) was elevated (up to +17%, P < 0.001). Molar apolipoprotein A-I content of HDL3 was subnormal in FH. A single LDL-apheresis session partially corrected (by up to 76%) deficient HDL antiatherogenic activities, attenuated systemic oxidative stress and partially normalised both the lipid composition and surface rigidity of HDL particles. Conclusions FH features elevated oxidative stress and deficient antioxidative and anti-inflammatory activities of small, dense HDL3; such functional deficiency is intimately linked to anomalies in lipid and protein composition, which may impair the capacity of HDL to acquire and inactivate oxidized lipids. [ABSTRACT FROM AUTHOR]

Aims To evaluate the effect of long-term maximally intensive statin therapy on indices of coronary atheroma composition in a randomized trial, and how these changes relate to modifications of serum lipoproteins and systemic inflammation. Methods and results The Study of coronary Atheroma by inTravascular Ultrasound: the effect of Rosuvastatin vs. atorvastatiN (SATURN) employed serial intravascular ultrasound (IVUS) measures of coronary atheroma in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg daily for 24 months. Seventy-one patients underwent serial assessment of indices of plaque composition by spectral analysis of the radiofrequency IVUS signal. Changes in low-density lipoprotein cholesterol [LDL-C; −52 (−72, −33) mg/dL, P < 0.001], C-reactive protein [CRP −0.2 (−1, 0.1) mg/L, P = 0.01], and high-density lipoprotein cholesterol [HDL-C; +2.8 (−0.3, 7.8) mg/dL, P < 0.001] were associated with regression of percent atheroma volume (PAV: −1.6 ± 3.6%, P < 0.001). A reduction in estimated fibro-fatty tissue volume accompanied atheroma regression (P < 0.001), while dense calcium tissue volume increased (P = 0.002). There were no changes in fibrous or necrotic core tissue volumes. Volumetric changes in necrotic core tissue correlated with on-treatment HDL-C (r = −0.27, P = 0.03) and CRP (r = 0.25, P = 0.03) levels. A per-lesion analysis showed a reduction in the number of pathological intimal thickening lesions (defined by ≥3 consecutive IVUS frames containing PAV of ≥40%, predominantly fibro-fatty plaque, with <10% confluent necrotic core and <10% confluent dense calcium) at follow-up (67 vs. 38, P = 0.001). Fibroatheromas and fibrotic lesions remained static in number. Conclusions Changes in indices of atheroma composition accompany regression of coronary atheroma with maximally intensive statin therapy, and associate with anti-inflammatory effects of statins. ClinicalTrails.gov number NCT000620542. [ABSTRACT FROM PUBLISHER]

This article presents a review of data in literature that deals with the impact of high-density lipoprotein (HDL) infusion therapies on the clinical management and prognosis of atherosclerotic vascular disease. It discusses the need for outcome trials and of the relevance of the individual biological activities of HDL particles to the pathophysiology of vascular disease.

High-density lipoproteins (HDLs) mediate cholesterol transport and protection from cardiovascular disease. Although synthetic HDLs have been studied for 30 years, the structures of human plasma-derived HDL and its major protein apolipoprotein apoA-I are unknown. We separated normal human HDL into five density subfractions and then further isolated those containing predominantly apoA-I (LpA-I). Using cross-linking chemistry and mass spectrometry, we found that apoA-I adopts a structural framework in these particles that closely mirrors that in synthetic HDL. We adapted established structures for synthetic HDL to generate the first detailed models of authentic human plasma HDL in which apoA-I adopts a symmetrical cage-like structure. The models suggest that HDL particle size is modulated by means of a twisting motion of the resident apoA-I molecules. This understanding offers insights into how apoA-I structure modulates HDL function and its interactions with other apolipoproteins. [ABSTRACT FROM AUTHOR]

Plasma high-density lipoproteins (HDLs) protect endothelial cells against apoptosis induced by oxidized low-density lipoprotein (oxLDL). The specific component(s) of HDLs implicated in such cytoprotection remain(s) to be identified. Human microvascular endothelial cells (HMEC-1) were incubated with mildly oxLDL in the presence or absence of each of five physicochemically distinct HDL subpopulations fractionated from normolipidemic human plasma ( n= 7) by isopycnic density gradient ultracentrifugation. All HDL subfractions protected HMEC-1 against oxLDL-induced primary apoptosis as revealed by nucleic acid staining, annexin V binding, quantitative DNA fragmentation, inhibition of caspase-3 activity and reduction of cytoplasmic release of cytochrome c and apoptosis-inducing factor. Small, dense HDL 3c displayed twofold superior intrinsic cytoprotective activity (as determined by mitochondrial dehydrogenase activity) relative to large, light HDL 2b on a per particle basis ( P < 0.05). Equally, all HDL subfractions attenuated intracellular generation of reactive oxygen species (ROS); such anti-oxidative activity diminished from HDL 3c to HDL 2b. The HDL protein moiety, in which apolipoprotein A-I (apoA-I) predominated, accounted for ∼70% of HDL anti-apoptotic activity. Furthermore, HDL reconstituted with apoA-I, cholesterol and phospholipid potently protected HMEC-1 from apoptosis. By contrast, modification of the content of sphingosine-1-phosphate in HDL did not significantly alter cytoprotection. We conclude that small, dense, lipid-poor HDL 3 potently protects endothelial cells from primary apoptosis and intracellular ROS generation induced by mildly oxLDL, and that apoA-I is pivotal to such protection. [ABSTRACT FROM AUTHOR]

The apolipoprotein APOA5 gene, a member of the gene cluster on chromosome 11q23 that includes APOA1, APOC3 and APOA4, has gained considerable interest as it encodes ApoAV, a key determinant of circulating levels of potentially atherogenic triglyceride-rich lipoproteins (TRL). Indeed, strong associations between genetic variants of the APOA5 gene sequence and elevated triglyceride (TG) levels have been established. This apolipoprotein may potentiate lipolysis of TRL through facilitation of lipoprotein interaction with lipoprotein lipase. In addition, ApoAV may enhance clearance of remnant lipoproteins by mediating their interaction with the LDL receptor-related protein (LRP)1. The implication of ApoAV in intravascular TRL metabolism is further supported by studies that have demonstrated upregulation of APOA5 gene expression by nuclear receptors (PPARα, FXR and HNF4α) and hormones (thyroxine) involved in hypotriglyceridemic pathways. APOA4 expression may equally be modulated by nutritional status and, more specifically, by stimulation of lipogenesis through transcriptional regulation mediated by insulin and SREBP-1c. However, despite the fact that studies in mice have clearly revealed that plasma levels of ApoAV are inversely correlated with plasma TG levels, the relationship between ApoAV and metabolism of TRL remains controversial in man. Indeed, positive correlations between ApoAV and TG levels have recently been observed in patients with hypertriglyceridemia and Type 2 diabetes. The question as to whether ApoAV is a key determinant of TG levels in humans therefore remains conjectural. [ABSTRACT FROM AUTHOR]

The article discusses the coexistence of foam cells and hypocholesterolemia in mice lacking the ABC transporters A1 and G1. It explains the relation of targeted disruption of both ABCA1 and ABCG1 in mice, despite severe plasma hypocholesterolemia, to massive lipid accumulation and foam cell formation of tissue macrophages. It was stated that ABCA1 and ABCG1 was important in the prevention of foam cell formation.

The laying hen represents a physiological model in which the mechanisms of action of estrogens on lipid transport can be evaluated. The plasma lipoproteins in the laying hen were subfractionated into discrete particle species by isopycnic density gradient ultracentrifugation and the physicochemical properties and apolipoprotein contents of individual subfractions evaluated. The qualitative and quantitative aspects of this estrogen-specific profile were then compared to those of the immature chicken. As observed earlier, estrogens induced dramatic elevation in very-low-density lipoproteins (VLDL) (up to 900 mg/dl). Indeed, triglyceride-rich lipoproteins with densities up to 1.035 g/ml, i.e. VLDL and their remnants, behaved as a continuum which displayed little variation in size (20.5-21 nm), electrophoretic mobility (β-like) and apolipoprotein content; apo B-100 (540 kDa) predominated while apo A-I (27 kDa), apo VLDL-II (19 kDa) and an apo-C- like protein (13 kDa) were present as minor components. The typical high-density lipoproteins (HDL) in the immature chicken were replaced by a lipoprotein population whose physicochemical properties were quite distinct. Thus these particles were distributed as a single, asymmetric peak over the density range 1.030-1.158 g/ml, a wide interval which overlapped that of apo-B-rich particles at its lower limit. The ρ 1.030-1.158 g/ml lipoproteins were present at concentrations (≈ to 200 mg/dl) some twofold to threefold lower than those of HDL in immature birds. Furthermore, they displayed physical and chemical properties in common with both low-density lipoproteins (LDL) and HDL and were LDL-like in exhibiting β mobility but HDL- like in size (9-15 nm diameter). Their protein moiety was also HDL-like in its predominant content of apo A-I; small amounts of apo VLDL-II and the apo-C-like protein were also detected. Substantial amounts of lipid were found at ρ > 1.195 g/ml: such substances are absent in the immature chicken and may reflect the presence of vitellogenins. The hyperestrogenic state in the laying hen is therefore associated with major modifications in lipoprotein and apolipoprotein profile. Such modifications may be of relevance to clinical disorders involving estrogen-induced hyperlipidemia. [ABSTRACT FROM AUTHOR]

Familial apolipoprotein A-I (apoA-I) deficiency (FAID) involving low levels of both apoA-I and high-density lipoprotein (HDL) cholesterol is associated with accelerated atherosclerosis. The objective of this study was to define distinctive patterns in the lipidome of HDL subpopulations in FAID in relationship to antiatherogenic activities. Five HDL subfractions were isolated by ultracentrifugation from plasma of FAID Caucasian patients (n = 5) and age-matched healthy normolipidemic Caucasian controls (n = 8), and the HDL lipidome (160 molecular species of 9 classes of phospholipids and sphingolipids) was quantitatively evaluated. Increased concentrations of numerous molecular species of lysophosphatidylcholine (up to 12-fold), ceramides (up to 3-fold), phosphatidylserine (up to 34-fold), phosphatidic acid (up to 71-fold), and phosphatidylglycerol (up to 20-fold) were detected throughout all five HDL subpopulations as compared with their counterparts from controls, whereas concentrations of phosphatidylethanolamine species were decreased (up to 5-fold). Moderately to highly abundant, within their lipid class, species of phosphatidylcholine, sphingomyelin, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, and ceramide featuring multiple unsaturations were primarily affected by apoA-I deficiency; their HDL content, particularly that of phosphatidylcholine (34:2), was strongly correlated with HDL function, impaired in FAID. Metabolic pathway analysis revealed that sphingolipid, glycerophospholipid, and linoleic acid metabolism was significantly affected by FAID. These data reveal that altered content of specific phospholipid and sphingolipid species is linked to deficient antiatherogenic properties of HDL in FAID. • High-density lipoprotein lipidome was markedly altered in a family with a nonsense mutation in APOA1. • Unsaturated lipid species, primarily phosphatidylcholine(34:2), were most strongly affected. • Lipids altered by apoA-I deficiency were typically moderately to highly abundant. • ApoA-I deficiency strongly affected linoleic acid metabolism. [ABSTRACT FROM AUTHOR]

Background Niacin as an adjunct to statin treatment to reduce cardiovascular risk is questioned. Objective To evaluate interrelationships between the effects of niacin on mixed dyslipidemia and a spectrum of metabolic and inflammatory biomarkers. Methods Obese, nondiabetic, hypertriglyceridemic males ( n = 19) with low high-density lipoprotein–cholesterol levels received extended-release nicotinic acid for 8 weeks. Multiple biomarkers were measured using enzyme-linked immunosorbent assay, enzymatic/absorptiometric, or multiplex biochip assays. Treatment effects were determined for each variable and a differential correlation network created on the basis of univariate correlations between baseline and response to niacin treatment for all pairs of variables. Results Extended-release niacin treatment favoured normalization of plasma lipid and apolipoprotein profile. Plasma markers of inflammation, hepatic function, cellular adhesion and proliferation, and macrophage phenotype were attenuated; however, insulin resistance increased. Differential network analysis revealed that changes in triglycerides and high-density lipoprotein–cholesterol were closely linked; equally, niacin mediated reductions in total cholesterol, apolipoprotein B, low-density lipoprotein–cholesterol and lipoprotein(a) clustered together, as did homeostatic model assessment of insulin resistance, insulin, and interleukin-6 levels. Two clusters of inflammatory markers were identified, involving (1) intercellular adhesion molecule 1 and high-sensitive C-reactive protein and (2) soluble tumor necrosis factor receptors; and novel clusters involving matrix metallopeptidase 9 and apolipoprotein E, and adiponectin and cystatin C, respectively, were equally revealed. At lower stringency, lipid and insulin resistance clusters were linked; a C-reactive protein-centered cluster linked reduction in apolipoprotein CIII to intercellular adhesion molecule 1, gamma-glutamyltransferase, soluble tumor necrosis factor receptors, and E-selectin. Conclusion A niacin-mediated trend to normalize atherogenic mixed dyslipidemia was intimately linked to attenuation of biomarkers of inflammation, cell adhesion, hepatic dysfunction and cell proliferation, but to enhanced insulin resistance and plasma homocysteine elevation. [ABSTRACT FROM AUTHOR]

Background Statins impact the metabolism, concentrations, composition, and function of circulating lipoproteins. Objective We evaluated time course relationships between statin-mediated reduction in atherogenic apolipoprotein B (ApoB)–containing particles and dynamic intravascular remodeling of ApoAI-containing lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome. Methods Insulin-resistant, hypertriglyceridemic, hypercholesterolemic, obese males (n = 12) were treated with pitavastatin (4 mg/d) and response evaluated at 6, 42, and 180 days. Results Reduction in low-density lipoprotein (LDL) cholesterol, ApoB, and triglycerides (TGs) was essentially complete at 42 days (–38%, –32%, and –35%, respectively); rapid reduction equally occurred in remnant cholesterol, ApoCII, CIII, and E levels (day 6; –35%, –50%, –23%, and –26%, respectively). Small dense LDLs (LDL4 and LDL5 subpopulations) predominated at baseline and were markedly reduced on treatment (–29% vs total LDL mass). Cholesteryl ester (CE) transfer protein activity and mass decreased progressively (–18% and –16%, respectively); concomitantly, TG depletion (up to –49%) and CE enrichment occurred in all high-density lipoprotein (HDL) particle subpopulations with normalization of CE/TG mass ratio at 180 days. ApoAI was redistributed from LpAI to LpAI:AII particles in HDL2a and HDL3a subpopulations; ApoCIII was preferentially depleted from LpAI:AII–rich particles on treatment. Conclusion Overall, statin action exhibits duality in mixed dyslipidemia, as CE transfer protein–mediated normalization of the HDL CE/TG core lags markedly behind subacute reduction in elevated levels of atherogenic ApoB-containing lipoproteins. Normalization of the HDL neutral lipid core is consistent with enhanced atheroprotective function. The HDL CE/TG ratio constitutes a metabolomic marker of perturbed HDL metabolism in insulin-resistant states, equally allowing monitoring of statin impact on HDL metabolism, structure, and function. [ABSTRACT FROM AUTHOR]

The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and calculated non-HDL cholesterol (=total – HDL cholesterol) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDL cholesterol is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDL cholesterol shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a)-cholesterol is part of measured or calculated LDL cholesterol and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDL cholesterol decline poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDL cholesterol or apolipoprotein B, especially in patients with mild-to-moderate hypertriglyceridemia (2–10 mmol/L). Non-HDL cholesterol includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apolipoprotein B measurement can detect elevated LDL particle numbers often unidentified on the basis of LDL cholesterol alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20–100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds. Image 1 • Total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and calculated non-HDL cholesterol (=total – HDL cholesterol) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. • LDL cholesterol is the primary target of lipid-lowering therapies. • Lipoprotein(a)-cholesterol is part of measured or calculated LDL cholesterol and lipoprotein(a) should be measured at least once in all patients. • Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDL cholesterol or apolipoprotein B, especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). • Non-HDL cholesterol includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. • Laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds. [ABSTRACT FROM AUTHOR]

High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract: The heme protein myeloperoxidase (MPO) functions as a catalyst for lipoprotein oxidation. Hypochlorous acid (HOCl), a potent two-electron oxidant formed by the MPO–H2O2–chloride system of activated phagocytes, modifies antiatherogenic high-density lipoprotein (HDL). The structural heterogeneity and oxidative susceptibility of HDL particle subfractions were probed with HOCl. All distinct five HDL subfraction were modified by HOCl as demonstrated by the consumption of tryptophan residues and free amino groups, cross-linking of apolipoprotein AI, formation of HOCl-modified epitopes, increased electrophoretic mobility and altered content of unsaturated fatty acids in HDL subclasses. Small, dense HDL3 were less susceptible to oxidative modification than large, light HDL2 on a total mass basis at a fixed HOCl:HDL mass ratio of 1:32, but in contrast not on a particle number basis at a fixed HOCl:HDL molar ratio of 97:1. We conclude that structural and physicochemical differences between HDL subclasses do not influence their intrinsic susceptibility to oxidative attack by HOCl. [Copyright &y& Elsevier]

Scavenger receptor SR-BI has been implicated in HDL-dependent atheroprotective mechanisms. We report the generation of an SR-BI conditional knockout mouse model in which SR-BI gene targeting by loxP site insertion produced a hypomorphic allele (hypomSR-BI). Attenuated SR-BI expression in hypomSR-BI mice resulted in 2-fold elevation in plasma total cholesterol (TC) levels. Cre-mediated SR-BI gene inactivation of the hypomorphic SR-BI allele in hepatocytes (hypomSR-BI-KO(liver)) was associated with high plasma TC concentrations, increased plasma free cholesterol/TC (FC/TC) ratio, and a lipoprotein-cholesterol profile typical of SR-BI-/- mice. Plasma TC levels were increased 2-fold in hypomSR-BI and control mice fed an atherogenic diet, whereas hypomSR-BI-KO(liver) and SR-BI-/- mice developed severe hypercholesterolemia due to accumulation of FC-rich, VLDL-sized particles. Atherosclerosis in hypomSR-BI mice was enhanced (2.5-fold) compared with that in controls, but to a much lower degree than in hypomSR-BI-KO(liver) (32-fold) and SR-BI-/- (48-fold) mice. The latter models did not differ in either plasma lipid levels or in the capacity of VLDL-sized lipoproteins to induce macrophage cholesterol loading. However, reduced atherosclerosis in hypomSR-BI-KO(liver) mice was associated with decreased lesional macrophage content as compared with that in SR-BI-/- mice. These data imply that, in addition to its major atheroprotective role in liver, SR-BI may exert an antiatherogenic role in extrahepatic tissues. [ABSTRACT FROM AUTHOR]

This randomised, double-blind, placebo-controlled crossover study evaluated the effects of rosuvastatin (40 mg/day for 8 weeks) on atherogenic apolipoprotein B-containing lipoprotein subfractions. Subjects, recruited based on raised plasma triglyceride (TG) or low-density lipoprotein cholesterol (LDL-C), were divided into normotriglyceridaemic (NTG, n=13; TG<2.0 mmol/l) and hypertriglyceridaemic (HTG, n=16; TG≥2.0 mmol/l) groups. Similar reductions on rosuvastatin were observed for both groups in LDL-C (NTG −60%; HTG −56%), apoB (both −49%), intermediate-density lipoprotein (NTG −57%; HTG −54%) and LDL circulating mass (NTG −52%, HTG −58%) (all P<0.001 versus placebo), i.e., these changes were phenotype independent. Phenotype dependency in response was observed in HTG relative to NTG in concentration of small dense LDL (LDL-III) (NTG −44%, P=NS; HTG −69%, P<0.001), very-low-density lipoprotein1 (NTG −18%, P=NS; HTG 46%, P<0.01), and remnant-like particle cholesterol (NTG −31%, P=NS; HTG −48%, P<0.05). Rosuvastatin reduced cholesteryl ester transfer protein (CETP) by 33% in NTG and 37% in HTG (both P<0.001); a reduction in cholesteryl ester transfer activity (−59%, P<0.001) was observed in HTG only. Rosuvastatin therefore, in addition to lowering LDL and apoB-concentrations, largely corrected the TG and LDL abnormalities in subjects who had the propensity to develop the atherogenic lipoprotein phenotype. [Copyright &y& Elsevier]

Compares the lipoprotein metabolism in three transgenic lines displaying plasma concentrations of human apolipoprotein A-II (apo A-II). Increase of the level of plasma concentrations of high-density lipoproteins (HDL) in all genotypes; Presence of pre-beta migrating HDL transporting apo A-II; Impact of fasting in control and transgenic mice on HDL.

Presents a study which contends that at early stages of oxidation the thermal stability of apolipoprotein B100 in low-density lipoprotein is disrupted while neutral lipid core organization is conserved. Evaluation of the time course of unfolding characteristics of protein moiety; Research methods employed in this study; Results of this research.