Long-term Benefits and Harms Associated With Genetic Cholesteryl Ester Transfer Protein Deficiency in the General Population.

Importance: The balance between the potential long-term clinical benefits and harms associated with genetic cholesteryl ester transfer protein (CETP) deficiency, mimicking pharmacologic CETP inhibition, is unknown. Objective: To assess the relative benefits and harms associated with genetic CETP deficiency. Design, Setting, and Participants: This study examined 2 similar prospective cohorts of the Danish general population, with data on a total of 102 607 participants collected from October 10, 1991, through December 7, 2018. Exposures: Weighted CETP allele scores. Main Outcomes and Measures: Incident cardiovascular mortality, ischemic heart disease, myocardial infarction, ischemic stroke, peripheral arterial disease, vascular dementia, Alzheimer disease, all-cause mortality, and age-related macular degeneration (AMD). The study first tested whether a CETP allele score was associated with morbidity and mortality, when scaled to genetically lower levels of non-high-density lipoprotein (HDL) cholesterol (ie, 17 mg/dL), corresponding to the reduction observed for anacetrapib vs placebo in the Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial. Second, the study assessed how much of the change in morbidity and mortality was associated with genetically lower levels of non-HDL cholesterol. Finally, the balance between the potential long-term clinical benefits and harms associated with genetic CETP deficiency was quantified. For AMD, the analyses also included higher levels of HDL cholesterol associated with genetic CETP deficiency. Results: Of 102 607 individuals in the study, 56 559 (55%) were women (median age, 58 years [IQR, 47-67 years]). Multivariable adjusted hazard ratios showed that a genetically lower level of non-HDL cholesterol (ie, 17 mg/dL) was associated with a lower risk of cardiovascular mortality (hazard ratio [HR], 0.77 [95% CI, 0.62-0.95]), ischemic heart disease (HR, 0.80 [95% CI, 0.68-0.95]), myocardial infarction (HR, 0.72 [95% CI, 0.55-0.93]), peripheral arterial disease (HR, 0.80 [95% CI, 0.63-1.02]), and vascular dementia (HR, 0.38 [95% CI, 0.18-0.80]) and an increased risk of AMD (HR, 2.33 [95% CI, 1.63-3.30]) but was not associated with all-cause mortality (HR, 0.91 [95% CI, 0.81-1.02]), ischemic stroke (HR, 1.05 [95% CI, 0.81-1.36]), or Alzheimer disease (HR, 1.25 [95% CI, 0.89-1.76]). When scaled to a higher level of HDL cholesterol, the increased risk of AMD was even larger. A considerable fraction of the lower risk of cardiovascular end points was associated with genetically lower levels of non-HDL cholesterol, while the higher risk of AMD was associated with genetically higher levels of HDL cholesterol. Per 1 million person-years, the projected 1916 more AMD events associated with genetically higher levels of HDL cholesterol was similar to the 1962 fewer events of cardiovascular mortality and myocardial infarction combined associated with genetically lower levels of non-HDL cholesterol. Conclusions and Relevance: This study suggests that genetic CETP deficiency, mimicking pharmacologic CETP inhibition, was associated with a lower risk of cardiovascular morbidity and mortality, but with a markedly higher risk of AMD.

ANGPTL3 and ANGPTL8 in Thai subjects with hyperalphalipoproteinemia and severe hypertriglyceridemia.

BACKGROUND: The role of ANGPTL3 and ANGPTL8 in lipid regulation in patients with very high levels of HDL-cholesterol and triglyceride is unknown. OBJECTIVE: We examined plasma levels of ANGPTL3 and ANGPTL8 in subjects with hyperalphalipoproteinemia (HALP) and in those with severe hypertriglyceridemia (HTG). METHODS: Plasma ANGPTL3 and ANGPTL8 levels were measured by ELISA in 320 subjects, consisting of HALP subjects with HDL-cholesterol ≥100 mg/dl (n=90) and healthy controls (n=90) and subjects with triglyceride ≥886 mg/dl (n=89) and control subjects (n=51). RESULTS: The mean plasma ANGPTL3 level was significantly higher in the HALP group compared to that of the controls (297 ± 112 ng/mL vs. 230 ± 100 ng/mL, p<0.001). Similarly, the mean plasma ANGPTL8 level was also higher in the HALP group (30 ± 11 ng/mL vs. 20 ± 8 ng/mL, p<0.001). Both ANGPTL3 and ANGPTL8 levels positively correlated with HDL-cholesterol levels. In the severe HTG group, plasma ANGPTL3 level was significantly higher than those in the control group (223 ± 105 ng/mL vs. 151 ± 60 ng/mL, p<0.001), but not ANGPTL8 (23 ± 20 ng/mL vs. 31 ± 23 ng/mL in controls, p=0.028). Only ANGPTL3, but not ANGPTL8, levels positively correlated with triglyceride levels. CONCLUSION: Plasma level of ANGPTL3 was increased in both HALP and severe HTG whereas an increase in plasma level of ANGPTL8 was found only in HALP, and not in severe HTG, suggesting that both ANGPTL3 and ANGPTL8 might play distinct roles in lipid regulation on these two extremes of dyslipidemia.

Efficacy of erzhu jiedu recipe on hepatitis B cirrhosis with hyperalphafetoproteinemia: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Hepatitis B cirrhosis with hyperalphafetoproteinemia is the intermediate stage of liver cirrhosis progressing to hepatocellular carcinoma (HCC), there is no effective way to treat precancerous lesions of liver in modern medicine. In recent decades, clinical and experimental evidence shows that Chinese medicine (CM) has a certain beneficial effect on Hepatitis B Cirrhosis. Therefore, this trial aims to evaluate the efficacy and safety of a CM erzhu jiedu recipe (EZJDR) for the treatment of Hepatitis B Cirrhosis with Hyperalphafetoproteinemia. METHODS: We designed a randomized, double blind, placebo-controlled clinical trial. A total of 72 patients of Hepatitis B Cirrhosis with hyperalphafetoproteinemia were randomized in 2 parallel groups. Patients in the control group received placebo granules similar to the EZJDR. In the EZJDR group, patients received EZJDR twice a day, after meals, for 48 weeks. The primary efficacy measures were changes in serum alpha-fetoprotein (AFP) and alpha-fetoprotein alloplasm (AFP-L3); The secondary indicators of efficacy are changes in liver function indicators, HBV-DNA level; Liver stiffness measurement (LSM); Hepatic portal vein diameter; T lymphocyte subgroup indexes during treatment. All data will be recorded in case report forms and analyzed by Statistical Analysis System software. Adverse events will also be evaluated. RESULTS: The results showed that EZJDR can significantly inhibit the levels of AFP and AFP-L3 in patients with hepatitis B cirrhosis and hyperalphafetoproteinemia and have good security. ETHICS AND DISSEMINATION: The study protocol was approved by the Medical Ethics Committee of Shuguang Hospital, affiliated with University of Traditional Chinese Medicine, Shanghai (NO.2018-579-08-01). TRIAL REGISTRATION: This trial was registered on Chinese Clinical Trial Center (NO.ChiCTR1800017165).

Cholesterol-Ester Transfer Protein Alters M1 and M2 Macrophage Polarization and Worsens Experimental Elastase-Induced Pulmonary Emphysema.

Cholesterol-ester transfer protein (CETP) plays a role in atherosclerosis, the inflammatory response to endotoxemia and in experimental and human sepsis. Functional alterations in lipoprotein (LP) metabolism and immune cell populations, including macrophages, occur during sepsis and may be related to comorbidities such as chronic obstructive pulmonary disease (COPD). Macrophages are significantly associated with pulmonary emphysema, and depending on the microenvironment, might exhibit an M1 or M2 phenotype. Macrophages derived from the peritoneum and bone marrow reveal CETP that contributes to its plasma concentration. Here, we evaluated the role of CETP in macrophage polarization and elastase-induced pulmonary emphysema (ELA) in human CETP-expressing transgenic (huCETP) (line 5203, C57BL6/J background) male mice and compared it to their wild type littermates. We showed that bone marrow-derived macrophages from huCETP mice reduce polarization toward the M1 phenotype, but with increased IL-10. Compared to WT, huCETP mice exposed to elastase showed worsened lung function with an increased mean linear intercept (Lm), reflecting airspace enlargement resulting from parenchymal destruction with increased expression of arginase-1 and IL-10, which are M2 markers. The cytokine profile revealed increased IL-6 in plasma and TNF, and IL-10 in bronchoalveolar lavage (BAL), corroborating with the lung immunohistochemistry in the huCETP-ELA group compared to WT-ELA. Elastase treatment in the huCETP group increased VLDL-C and reduced HDL-C. Elastase-induced pulmonary emphysema in huCETP mice promotes lung M2-like phenotype with a deleterious effect in experimental COPD, corroborating the in vitro result in which CETP promoted M2 macrophage polarization. Our results suggest that CETP is associated with inflammatory response and influences the role of macrophages in COPD.

Atherosclerotic cardiovascular disease in hyperalphalipoproteinemia due to LIPG variants.

BACKGROUND: High density lipoprotein cholesterol (HDL-C) concentration correlates inversely with atherosclerotic cardiovascular disease (ASCVD) risk and is included in risk calculations. Endothelial lipase (EL) is a phospholipase that remodels HDL. Deficiency of EL due to mutations in its gene, LIPG, is associated with hyperalphalipoproteinemia. The effects of EL on HDL function and ASCVD risk remain poorly understood. OBJECTIVES: To determine whether hyperalphalipoproteinemia due to EL deficiency is protective against ASCVD. METHODS: We identified LIPG variants amongst patients with severe hyperalphalipoproteinemia (HDL-C >2.5 mmol/L) attending a referral lipid clinic in the Western Cape Province of South Africa. We analysed the clinical and biochemical phenotypes amongst primary hyperalphalipoproteinemia cases (males HDL-C >1.6 mmol/L; females HDL-C >1.8 mmol/L) due to LIPG variants, and the distribution of variants in normal and hyperalphalipoproteinemia ranges of HDL-C. RESULTS: 1007 patients with HDL-C concentration ranging from 1.2 to 4.5 mmol/L were included. Seventeen females had primary hyperalphalipoproteinemia. Vascular disease was prominent, but not associated with HDL-C concentration, LDL-C concentration or carotid artery intima media thickness. Two novel and three known LIPG variants were identified in severe hyperalphalipoproteinemia. Four additional variants were identified in the extended cohort. Two common variants appeared normally distributed across the HDL-C concentration range, while six less-common variants were found only at higher HDL-C concentrations. One rare variant had a moderate effect. CONCLUSION: Hyperalphalipoproteinemia due to LIPG variants is commoner in females and may not protect against ASCVD. Use of current risk calculations may be inappropriate in patients with hyperalphalipoproteinemia due to EL deficiency. Our study cautions targeting EL to reduce risk.

Hyperalphalipoproteinemic scavenger receptor BI knockout mice exhibit a disrupted epidermal lipid barrier.

Scavenger receptor class B type I (SR-BI) mediates the selective uptake of cholesteryl esters (CE) from high-density lipoproteins (HDL). An impaired SR-BI function leads to hyperalphalipoproteinemia with elevated levels of cholesterol transported in the HDL fraction. Accumulation of cholesterol in apolipoprotein B (apoB)-containing lipoproteins has been shown to alter skin lipid composition and barrier function in mice. To investigate whether these hypercholesterolemic effects on the skin also occur in hyperalphalipoproteinemia, we compared skins of wild-type and SR-BI knockout (SR-BI-/-) mice. SR-BI deficiency did not affect the epidermal cholesterol content and induced only minor changes in the ceramide subclasses. The epidermal free fatty acid (FFA) pool was, however, enriched in short and unsaturated chains. Plasma CE levels strongly correlated with epidermal FFA C18:1 content. The increase in epidermal FFA coincided with downregulation of cholesterol and FFA synthesis genes, suggesting a compensatory response to increased flux of plasma cholesterol and FFAs into the skin. Importantly, the SR-BI-/- epidermal lipid barrier showed increased permeability to ethyl-paraminobenzoic acid, indicating an impairment of the barrier function. In conclusion, increased HDL-cholesterol levels in SR-BI-/- mice can alter the epidermal lipid composition and lipid barrier function similarly as observed in hypercholesterolemia due to elevated levels of apoB-containing lipoproteins.

Shotgun proteomic analysis reveals proteome alterations in HDL of patients with cholesteryl ester transfer protein deficiency.

BACKGROUND: We previously reported that the patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) show marked changes in the size and lipid compositions of high-density lipoprotein (HDL) and that they are not protected from atherosclerotic cardiovascular diseases, despite increased serum HDL-cholesterol (HDL-C) levels. HDL particles carry a variety of proteins, some of which are known to have antiatherogenic functions. OBJECTIVE: This study aimed to investigate the protein composition of HDL particles in patients with CETP-D. METHODS: Eight patients with complete deficiency of CETP and 8 normolipidemic healthy subjects were enrolled. We performed shotgun proteomic analysis to investigate the proteome of ultracentrifugally isolated HDL. RESULTS: We identified 79 HDL-associated proteins involved in lipid metabolism, protease inhibition, complement regulation, and acute-phase response, including 5 potential newly identified HDL-associated proteins such as angiopoietin-like3 (ANGPTL3). Spectral counts of apolipoprotein (apo) E were increased in patients with CETP-D compared with controls (60.3 ± 6.9 vs 43.7 ± 2.5, P < .001), which is concordant with our previous report. Complement regulatory proteins such as C3, C4a, C4b, and C9 were also significantly enriched in HDL from patients with CETP-D. Furthermore, apoC-III and ANGPTL3, both of which are now known to associate with increased atherosclerotic cardiovascular diseases, were enriched in patients with CETP-D compared with normolipidemic subjects (35.9 ± 5.3 vs 27.1 ± 3.7, 2.3 ± 1.1 vs 0.4 ± 1.1, respectively; P < .01). CONCLUSION: We have characterized HDL-associated proteins in patients with CETP-D. We identified a significant increase in the amount of apoE, apoC-III, ANGPTL3, and complement regulatory proteins. These proteomic changes might be partly responsible for the enhanced atherogenicity of patients with CETP-D.

ADCY9 (Adenylate Cyclase Type 9) Inactivation Protects From Atherosclerosis Only in the Absence of CETP (Cholesteryl Ester Transfer Protein).

BACKGROUND: Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined. METHODS: Adcy9-inactivated ( Adcy9Gt/Gt) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETPtg Adcy9Gt/Gt and CETPtg Adcy9WT), were submitted to an atherogenic protocol (injection of an AAV8 [adeno-associated virus serotype 8] expressing a PCSK9 [proprotein convertase subtilisin/kexin type 9] gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, vasorelaxation, telemetry, and adipose tissue magnetic resonance imaging were evaluated. RESULTS: Adcy9Gt/Gt mice had a 65% reduction in aortic atherosclerosis compared to WT ( P<0.01). CD68 (cluster of differentiation 68)-positive macrophage accumulation and proliferation in plaques were reduced in Adcy9Gt/Gt mice compared to WT animals ( P<0.05 for both). Femoral artery endothelial-dependent vasorelaxation was improved in Adcy9Gt/Gt mice (versus WT, P<0.01). Selective pharmacological blockade showed that the nitric oxide, cyclooxygenase, and endothelial-dependent hyperpolarization pathways were all responsible for the improvement of vasodilatation in Adcy9Gt/Gt ( P<0.01 for all). Aortic endothelium from Adcy9Gt/Gt mice allowed significantly less adhesion of splenocytes compared to WT ( P<0.05). Adcy9Gt/Gt mice gained more weight than WT with the atherogenic diet; this was associated with an increase in whole body adipose tissue volume ( P<0.01 for both). Feed efficiency was increased in Adcy9Gt/Gt compared to WT mice ( P<0.01), which was accompanied by prolonged cardiac RR interval ( P<0.05) and improved nocturnal heart rate variability ( P=0.0572). Adcy9 inactivation-induced effects on atherosclerosis, endothelial function, weight gain, adipose tissue volume, and feed efficiency were lost in CETPtg Adcy9Gt/Gt mice ( P>0.05 versus CETPtg Adcy9WT). CONCLUSIONS: Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone.

Particle number analysis of lipoprotein subclasses by gel permeation HPLC in patients with cholesteryl ester transfer protein deficiency.

OBJECTIVE: We previously reported that patients with cholesteryl ester transfer protein (CETP) deficiency (CETP-D) have a higher prevalence of atherosclerotic cardiovascular disease, in spite of increased HDL-C levels. However, characterization of HDL in CETP-D has not been well described. Therefore, we examined HDL particle number (PN) rather than HDL-C level. APPROACH AND RESULTS: Nine patients with CETP-D and 9 normolipidemic subjects were enrolled. We performed gel permeation high-performance liquid chromatography (GP-HPLC) analysis, determined the cholesterol and triglyceride composition of all lipoprotein subclasses, and calculated the PN of each subclass, which consisted of 3 VLDL (large, medium, and small), 4 LDL (large, medium, small, and very small), and 5 HDL (very large, large, medium, small, and very small) subclasses. The PNs of large and medium LDL were significantly lower in CETP-D than that in healthy subjects (0.66- and 0.63-fold decrease, respectively; p<0.001), whereas the PN of very small LDL, which is known to be atherogenic, was significantly higher (1.36-fold increase, p = 0.016). The PNs of very large and large HDL in CETP-D were markedly higher than that in healthy subjects (19.9- and 4.5-fold increase, respectively; p<0.001), whereas the PNs of small and very small HDL, which have more potent anti-atherogenic functions, were significantly lower (0.76- and 0.61-fold decrease, respectively; p<0.001). CONCLUSION: We have assessed the PNs of detailed subclasses of patients with CETP-D for the first time. The PN of larger HDL was markedly increased, that of smaller HDL was decreased, and that of very small LDL was increased, suggesting that CETP-D has pro-atherogenic lipoprotein properties.

Paradoxical coronary artery disease in humans with hyperalphalipoproteinemia is associated with distinct differences in the high-density lipoprotein phosphosphingolipidome.

BACKGROUND: Plasma high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with risk of coronary artery disease (CAD) in epidemiologic studies. Despite this, the directionality of this relationship and the underlying biology behind it remain to be firmly established, especially at the extremes of HDL-C levels. OBJECTIVE: We investigated differences in the HDL phosphosphingolipidome in a rare population of subjects with premature CAD despite high HDL-C levels to gain insight into the association between the HDL lipidome and CAD disease status in this unusual phenotype. We sought to assess differences in HDL composition that are associated with CAD in subjects with HDL-C >90th percentile. We predicted that quantitative lipidomic analysis of HDL particles would reveal novel differences between CAD patients and healthy subjects with matched HDL-C levels. METHODS: We collected plasma samples from 25 subjects with HDL-C >90th percentile and clinically manifest CAD and healthy controls with HDL-C >90th percentile and without self-reported CAD. More than 140 individual HDL phospholipid and sphingolipid species were analyzed by LC/MS/MS. RESULTS: Significant reductions in HDL phosphatidylcholine (-2.41%, Q value = 0.025) and phosphatidylinositol (-10.7%, Q value = 0.047) content, as well as elevated sphingomyelin (+10.0%, Q value = 0.025) content, and sphingomyelin/phosphatidylcholine ratio (+12.8%, P value = .005) were associated with CAD status in subjects with high HDL-C. CONCLUSIONS: These differences may lay the groundwork for further analysis of the relationship between the HDL lipidome and disease states, as well as for the development of biomarkers of CAD status and HDL function.

Deficiency of Cholesteryl Ester Transfer Protein Protects Against Atherosclerosis in Rabbits.

OBJECTIVE: CETP (cholesteryl ester transfer protein) plays an important role in lipoprotein metabolism; however, whether inhibition of CETP activity can prevent cardiovascular disease remains controversial. APPROACH AND RESULTS: We generated CETP knockout (KO) rabbits by zinc finger nuclease gene editing and compared their susceptibility to cholesterol diet-induced atherosclerosis to that of wild-type (WT) rabbits. On a chow diet, KO rabbits showed higher plasma levels of high-density lipoprotein (HDL) cholesterol than WT controls, and HDL particles of KO rabbits were essentially rich in apolipoprotein AI and apolipoprotein E contents. When challenged with a cholesterol-rich diet for 18 weeks, KO rabbits not only had higher HDL cholesterol levels but also lower total cholesterol levels than WT rabbits. Analysis of plasma lipoproteins revealed that reduced plasma total cholesterol in KO rabbits was attributable to decreased apolipoprotein B-containing particles, while HDLs remained higher than that in WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. Apolipoprotein B-depleted plasma isolated from CETP KO rabbits showed significantly higher capacity for cholesterol efflux from macrophages than that from WT rabbits. Furthermore, HDLs isolated from CETP KO rabbits suppressed tumor necrosis factor-α-induced vascular cell adhesion molecule 1 and E-selectin expression in cultured endothelial cells. CONCLUSIONS: These results provide evidence that genetic ablation of CETP activity protects against cholesterol diet-induced atherosclerosis in rabbits.

Involvement of CETP (Cholesteryl Ester Transfer Protein) in the Shift of Sphingosine-1-Phosphate Among Lipoproteins and in the Modulation of its Functions.

OBJECTIVE: Sphingosine-1-phosphate (S1P) is a vasoprotective lipid mediator. About two thirds of plasma S1P rides on high-density lipoprotein (HDL), and several pleiotropic properties of HDL have been ascribed to S1P. In human subjects, CETP (cholesteryl ester transfer protein) greatly influences HDL quantities. In this study, we attempted to elucidate the roles of CETP in the metabolism of S1P. APPROACH AND RESULTS: We overexpressed CETP in mice that lacked CETP and found that CETP overexpression decreased the HDL level but failed to modulate the levels of S1P and apolipoprotein M (apoM), a carrier of S1P, in the total plasma. We observed, however, that the distribution of S1P and apoM shifted from HDL to apoB-containing lipoproteins. When we administered C17S1P bound to apoM-containing lipoprotein, C17S1P and apoM were rapidly transferred to apoB-containing lipoproteins in CETP-overexpressing mice. When HDL containing C17S1P was mixed with low-density lipoprotein ex vivo, C17S1P shifted to the low-density lipoprotein fraction independent of the presence of CETP. Concordant with these results, apoM was distributed mainly to the same fraction as apo AI in a CETP-deficient subject, although apoM was also detected in apo AI-poor fractions in a corresponding hypercholesterolemia subject. About the bioactivities of S1P carried on each lipoprotein, S1P riding on apoB-containing lipoproteins induced the phosphorylation of Akt (AKT8 virus oncogene cellular homolog) and eNOS (endothelial nitric oxide synthase) in human umbilical vein endothelial cells, and CETP overexpression increased insulin secretion and sensitivity, which was inhibited by an S1P receptor 1 or 3 antagonist. CONCLUSIONS: CETP modulates the distribution of S1P among lipoproteins, which affects the bioactivities of S1P.

Bioinformatic Analysis of Plasma Apolipoproteins A-I and A-II Revealed Unique Features of A-I/A-II HDL Particles in Human Plasma.

Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated.

Re-evaluation of cholesteryl ester transfer protein function in atherosclerosis based upon genetics and pharmacological manipulation.

PURPOSE OF REVIEW: To re-evaluate the functions of plasma cholesteryl ester transfer protein (CETP) in atherosclerosis based upon recent findings from human genetics and pharmacological CETP manipulation. RECENT FINDINGS: CETP is involved in the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins, a key step of reverse cholesterol transport (RCT). CETP inhibitors have been developed to raise serum HDL-cholesterol (HDL-C) levels and reduce cardiovascular events. However, outcome studies of three CETP inhibitors (torcetrapib, dalcetrapib and evacetrapib) were prematurely terminated because of increased mortality or futility despite marked increases in HDL-cholesterol and decreases in LDL-cholesterol except for dalcetrapib. Patients with CETP deficiency show remarkable changes in HDL and LDL and are sometimes accompanied by atherosclerotic cardiovascular diseases. Recent prospective epidemiological studies demonstrated atheroprotective roles of CETP. CETP inhibition induces formation of small dense LDL and possibly dysfunctional HDL and downregulates hepatic scavenger receptor class B type I (SR-BI). Therefore, CETP inhibitors may interrupt LDL receptor and SR-BI-mediated cholesterol delivery back to the liver. SUMMARY: For future drug development, the opposite strategy, namely enhancers of RCT via CETP and SR-BI activation as well as the inducers of apolipoprotein A-I or HDL production might be a better approach rather than delaying HDL metabolism by inhibiting a main stream of RCT in vivo.

Limitations of a Cardiac Risk (QRISK2) Calculator in Patients with High Density Lipoprotein (HDL).

INTRODUCTION: There is existing debate as to the relationship between blood concentration of HDL (high density lipoprotein) and cardiovascular outcomes. Patients with hyperalphalipoproteinaemia (HALP) have high HDL levels and this can be attributed to a variety of factors. AIM AND METHODS: This study aims for the first time to examine the HALP cohort and understand demographics, relationship with cardiovascular disease (CVD) risk and scoring with a cardiac risk calculator (QRISK 2 calculator). RESULTS: The study found 42 patients had a statistically significant difference (p = 0.001) between CVD risk estimated using actual measured HDL (Score 1) versus CVD risk calculated using standard population mean HDL values (Score 2). Furthermore, in the CVD event group (n = 6) a significant difference was also seen between Score 1 and Score 2 (p = 0.027). CONCLUSION: The study highlights issues with underestimation of CVD risk in this population and strongly advocates use of standard population mean values in assessment of CVD risk.

Defective triglyceride biosynthesis in CETP-deficient SW872 cells.

We previously reported that reducing the expression of cholesteryl ester transfer protein (CETP) disrupts cholesterol homeostasis in SW872 cells and causes an ∼50% reduction in TG. The causes of this reduced TG content, investigated here, could not be attributed to changes in the differentiation status of CETP-deficient cells, nor was there evidence of endoplasmic reticulum (ER) stress. In short-term studies, the total flux of oleate through the TG biosynthetic pathway was not altered in CETP-deficient cells, although mRNA levels of some pathway enzymes were different. However, the conversion of diglyceride (DG) to TG was impaired. In longer-term studies, newly synthesized TG was not effectively transported to lipid droplets, yet this lipid did not accumulate in the ER, apparently due to elevated lipase activity in this organelle. DG, shown to be a novel CETP substrate, was also inefficiently transferred to lipid droplets. This may reduce TG synthesis on droplets by resident diacylglycerol acyltransferase. Overall, these data suggest that the decreased TG content of CETP-deficient cells arises from the reduced conversion of DG to TG in the ER and/or on the lipid droplet surface, and enhanced TG degradation in the ER due to its ineffective transport from this organelle.

Unique features of high-density lipoproteins in the Japanese: in population and in genetic factors.

Despite its gradual increase in the past several decades, the prevalence of atherosclerotic vascular disease is low in Japan. This is largely attributed to difference in lifestyle, especially food and dietary habits, and it may be reflected in certain clinical parameters. Plasma high-density lipoprotein (HDL) levels, a strong counter risk for atherosclerosis, are indeed high among the Japanese. Accordingly, lower HDL seems to contribute more to the development of coronary heart disease (CHD) than an increase in non-HDL lipoproteins at a population level in Japan. Interestingly, average HDL levels in Japan have increased further in the past two decades, and are markedly higher than in Western populations. The reasons and consequences for public health of this increase are still unknown. Simulation for the efficacy of raising HDL cholesterol predicts a decrease in CHD of 70% in Japan, greater than the extent by reducing low-density lipoprotein cholesterol predicted by simulation or achieved in a statin trial. On the other hand, a substantial portion of hyperalphalipoproteinemic population in Japan is accounted for by genetic deficiency of cholesteryl ester transfer protein (CETP), which is also commonly unique in East Asian populations. It is still controversial whether CETP mutations are antiatherogenic. Hepatic Schistosomiasis is proposed as a potential screening factor for historic accumulation of CETP deficiency in East Asia.

Multiple symmetric lipomatosis: a rare disease and its possible links to brown adipose tissue.

AIM: Aim of this study is an updated review of our case series (72 patients) as well as available literature on the Multiple Symmetric Lipomatosis (MSL), a rare disease primarily involving adipose tissue, characterized by the presence of not encapsulated fat masses, symmetrically disposed at characteristic body sites (neck, trunk, proximal parts of upper and lower limbs). DATA SYNTHESIS: The disease is more frequent in males, associated to an elevated chronic alcohol consumption, mainly in form of red wine. Familiarity has been reported and MSL is considered an autosomic dominant inherited disease. MSL is associated to severe clinical complications, represented by occupation of the mediastinum by lipomatous tissue with a mediastinal syndrome and by the presence of a somatic and autonomic neuropathies. Hyper-alphalipoproteinemia with an increased adipose tissue lipoprotein-lipase activity, a defect of adrenergic stimulated lipolysis and a reduction of mitochondrial enzymes have been described. The localization of lipomatous masses suggests that MSL lipomas could originate from brown adipose tissue (BAT). Moreover, studies on cultured pre-adipocytes demonstrate that these cells synthetize the mitochondrial inner membrane protein UCP-1, the selective marker of BAT. Surgical removal of lipomatous tissue is to date the only validated therapeutic approach. CONCLUSIONS: MSL is supposed to be the result of a disorder of the proliferation and differentiation of human BAT cells.