Prevalence of dyslipidaemia among HIV-infected patients receiving combination antiretroviral therapy in North Shewa, Ethiopia.

BACKGROUND: Data on the burden of dyslipidaemia among people with HIV undergoing antiretroviral therapy (ART) in sub-Saharan Africa are limited and little is known about the factors contributing for poor lipid profiles. The aim of this study was to determine the prevalence of dyslipidaemia and factors associated with lipid levels among HIV-infected patients receiving first-line combination ART in North Shewa, Ethiopia. METHODS: A cross-sectional study was conducted between April and December 2018 among 392 HIV-infected adults receiving first-line ART for at least six months at the ART clinic of Mehal Meda Hospital in North Shewa, Ethiopia. Blood samples were collected for determination of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and CD4 counts. Logistic regression analysis was used to determine factors associated with lipid abnormalities. RESULTS: The prevalence of dyslipidaemia was 59.9% (95% CI 55.0-64.7%). High TC, high TG, low HDL-c, and high LDL-c were obtained in 47.3%, 30.9%, 19.4% and 29.6%, respectively. Fifty-four participants (13.8%) had high ratio of TC/HDL-c (TC/HDL-c ratio ≥ 5). Older age was independently associated with high TC (AOR = 2.51, 95% CI 1.64-3.84), high TG (AOR = 2.95, 95% CI 1.85-4.71), low HDL-c (AOR = 2.02, 95% CI 1.17-3.50), and high LDL-c (AOR = 3.37, 95% CI 2.08-5.47). Living in an urban area (AOR = 2.61, 95% CI 1.16-6.14) and smoking (AOR = 3.61, 95% CI 1.06-12.34) were associated with low HDL-c. Participants with longer duration of ART use were more likely to have high TG (AOR = 1.86, 95% CI: 1.13-3.07), low HDL-c (AOR = 3.47, 95% CI: 1.75-6.80), and high LDL-c (AOR = 2.20, 95% CI 1.30-3.71). High BMI was independently associated with higher TC (AOR = 2.43, 95% CI 1.19-4.97), high TG (AOR = 4.17, 95% CI 2.01-8.67) and high LDL-c (AOR = 6.53, 95% CI 3.05-13.98). CONCLUSIONS: We found a high prevalence of dyslipidaemia among HIV-infected patients receiving first-line ART in North Shewa, Ethiopia. There is a need for monitoring of blood lipid levels in patients with HIV on long term first-line ART with a special attention to be focused on older age, urban residents, longer duration of ART use, high BMI and smokers.

Serum YKL40: A novel potential link between inflammation and dyslipidemia in acne vulgaris.

BACKGROUND: Acne vulgaris (AV) is an inflammatory skin disorder that may be associated with metabolic disorders. The relation between lipid profile in acne is not widely investigated. Chitinase-3-like protein 1 (YKL-40) has been found to be implicated in different inflammatory conditions. AIMS: We aimed at investigating the role YKL-40 in acne pathogenesis and associated dyslipidemia in acne patients. PATIENTS/METHODS: This study included 50 acne vulgaris patients and 30 matched control subjects. Serum YKL-40 in addition to lipid profile were assessed in all studied subjects. RESULTS: Serum YKL-40 level was significantly elevated in acne patients than healthy controls (P < .001). We also found a significant positive correlations between serum YKL-40, serum TGs, TC, and LDL-C (P value: .022, .001, .017 respectively) while, a significant negative correlation between serum YKL-40 and HDL-c (P value: .036) was detected. CONCLUSION: Our study results suggest that YKL-40 might have a role in AV pathogenesis. In addition, it could provide a new potential link between inflammation and dyslipidemia observed in acne patients.

Antibodies towards high-density lipoprotein components in patients with psoriasis.

Psoriasis is a chronic inflammatory immune disorder associated with an increased risk of atherosclerosis. This increased risk is not fully understood. High-density lipoproteins (HDL) play an important role in the prevention of atherosclerosis and any factors that may hamper HDL function such as anti-HDL antibodies (aHDL) might be associated with an increased cardiovascular risk. We aimed to determine whether anti-HDL antibodies (aHDL) are present in patients with psoriasis. Sixty-seven patients with psoriasis were compared with a healthy control group. Epidemiologic and clinical data were recorded. IgG and IgM aHDL, IgG anti-apolipoprotein A-I (aApoA-I), anti-apolipoprotein E (aApoE), and anti-paraoxonase 1 (aPON1) antibodies, as well as VCAM-1, IL-6, and TNF-α were assessed by ELISA. Apolipoprotein A-I (ApoA-I) and Apolipoprotein E (ApoE) were measured by immunoturbidimetric immunoassay. Patients with psoriasis had higher titers of IgG aHDL (p < 0.001), IgG aApoA-I (p = 0.001) and aApoE antibodies (p < 0.001). IgG aHDL and aApoE titers were higher in patients with severe psoriasis (p = 0.010 and p = 0.018, respectively). Multiple regression analysis, considering all clinical and biological variables, showed that aApoE, IL-6, and aPON1 are the biological variables that best explain aHDL variability. This is the first report showing the presence of aHDL, aApoA-I, and aApoE antibodies in patients with psoriasis. These antibodies were associated with increased disease severity and may contribute to the pathogenesis of atherosclerosis in psoriasis. They may fulfill the clinical need for biomarkers of cardiovascular risk associated with psoriasis that would help to stratify patients for prevention and therapeutic approaches.

Cholesterol membrane content has a ubiquitous evolutionary function in immune cell activation: the role of HDL.

PURPOSE OF REVIEW: Cellular cholesterol content influences the structure and function of lipid rafts, plasma membrane microdomains essential for cell signaling and activation. HDL modulate cellular cholesterol efflux, thus limiting cholesterol accumulation and controlling immune cell activation. Aim of this review is to discuss the link between HDL and cellular cholesterol metabolism in immune cells and the therapeutic potential of targeting cholesterol removal from cell membranes. RECENT FINDINGS: The inverse relationship between HDL-cholesterol (HDL-C) levels and the risk of cardiovascular disease has been recently challenged by observations linking elevated levels of HDL-C with increased risk of all-cause mortality, infections and autoimmune diseases, paralleled by the failure of clinical trials with HDL-C-raising therapies. These findings suggest that improving HDL function might be more important than merely raising HDL-C levels. New approaches aimed at increasing the ability of HDL to remove cellular cholesterol have been assessed for their effect on immune cells, and the results have suggested that this could be a new effective approach. SUMMARY: Cholesterol removal from plasma membrane by different means affects the activity of immune cells, suggesting that approaches aimed at increasing the ability of HDL to mobilize cholesterol from cells would represent the next step in HDL biology.

Metabolic syndrome mediates inflammatory and oxidative stress responses in patients with recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) is defined as three or more consecutive pregnancy losses prior to the 20th week of gestation. Exaggerated maternal immune response and oxidative stress status have been proposed as one of the main underlying mechanisms for RPL. The aim of this study was to evaluate the role of inflammatory pathway and oxidative stress imbalance in RPL patients with or without metabolic syndrome (MetS). 21 and 28 RPL patients with (RPL-MS) and without (RPL-NMS) metabolic syndrome were enrolled in this clinical study. 42 healthy women also were considered as the control group. The levels of IL1ß, IL6, IL17, TNFα, CCL2, CXCL8 were evaluated by ELISA method. Additionally, the oxidative stress biomarkers including TAS, TOS, NO, CAT, SOD, AOPP, MPO were analyzed by spectrophotometry. The expression levels of IL1ß, IL6, IL17, TNFα, CCL2, CXCL8, NFĸB, AP1, miR-21, miR-146-a, miR-223 were also assessed by real time PCR. The frequency of Th17 and T-reg cells was also measured by flow cytometry. Significant increase in the expression levels of IL1ß, IL6, IL17, TNFα, CCL2, CXCL8, NFĸB, AP1 and miR-21 was observed in RPL-MS patients. Furthermore, significant decreased expression levels of FoxP3, miR-146-a and miR-223 was also observed in RPL-MS group. The levels of IL1ß, IL6, IL17, TNFα, CCL2, CXCL8, NO, MPO and TOS were found to be higher in RPL-MS group compared to the RPL-NMS and healthy controls. In contrast, the level of CAT and SOD in RPL-MS patients was decreased. The frequency of Th17 and Treg cells was also higher and lower in RPL-MS patients compared to the other groups, respectively. Our results support the concept that subclinical inflammatory state, oxidative stress and metabolic syndrome play a crucial role in the etiopathogenesis of RPL assisting clinicians for pregnancy consequences prediction.

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.

Akkermansia muciniphila can reduce the damage of gluco/lipotoxicity, oxidative stress and inflammation, and normalize intestine microbiota in streptozotocin-induced diabetic rats.

This study aimed to investigate how Akkermansia muciniphila can implicate type 2 diabetes mellitus and the mechanisms underlying the effects A. muciniphila on type 2 diabetes mellitus. Normal and streptozotocin-induced diabetic Sprague-Dawley rats were orally administered with A. muciniphila and solvent. After 4 weeks of treatment, diabetic rats orally administered with live or pasteurized A. muciniphila exhibited significant increase in the blood concentration of high-density lipoprotein, and decrease in the hepatic glycogen, serum plasminogen activator inhibitor-1, tumor necrosis factor-α, lipopolysaccharide, malondialdehyde and total glucagon-like peptide-1. Moreover, diabetic rats orally administered with A. muciniphila showed significantly increased species alpha diversity and gene function in gut microbes. These results indicated that A. muciniphila can improve liver function, reduce gluco/lipotoxicity, alleviate oxidative stress, suppress inflammation and normalize intestine microbiota of the host animal, thereby ameliorating type 2 diabetes mellitus. Akkermansia muciniphila might be considered as one of the ideal new probiotics used in the management of type 2 diabetes mellitus in future.

Reduced mitochondrial DNA content in lymphocytes is associated with insulin resistance and inflammation in patients with impaired fasting glucose.

Altered mitochondrial DNA (mtDNA) is the most common denominator to numerous metabolic diseases. The present study sought to investigate the correlation between mtDNA content in lymphocytes and associated clinical risk factors for impaired fasting glucose (IFG). We included 23 healthy control and 42 IFG participants in this cross-sectional study. The measurements of mtDNA content in lymphocytes and pro-inflammatory markers derived from both normal and diseased individuals were quantified. Spearman partial correlation and multivariate statistical analyses were employed to evaluate the association between mtDNA content and other metabolic covariates in IFG. Reduced mtDNA content was observed in the IFG group with microvascular complications than those without complications. The IFG patients with lowest median of mtDNA content had considerably elevated hyperglycemia, insulin resistance and inflammation. The adjusted partial correlation analysis showed that mtDNA content was positively correlated with HDL-cholesterol and IL-10 (P < 0.005 for all). Further, multiple linear regression analyses verified that reduced mtDNA content in lymphocytes was independently associated with HOMA-IR (ß = 0.027, P = 0.003), HbA1c (ß = 0.652, P = 0.002), HDL-cholesterol (ß = - 1.056, P = 0.021), IL-6 (ß = 0.423, P = 0.002), IL-10 (ß = - 1.234, P = 0.043) and TNF-α (ß = 0.542, P < 0.001) after adjustment for confounding factors. Our data show that reduced mtDNA content in lymphocytes was associated with insulin resistance and inflammation in individuals with IFG.

Extended-release niacin increases anti-apolipoprotein A-I antibodies that block the antioxidant effect of high-density lipoprotein-cholesterol: the EXPLORE clinical trial.

AIMS: Extended-release niacin (ERN) is the most effective agent for increasing high-density lipoprotein-cholesterol (HDL-C). Having previously identified anti-HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A-I (aApoA-I). METHODS: Twenty-one patients older than 18 years, with HDL-C ≤40 mg dl-1 (men) or ≤50 mg dl-1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12-week periods, with 4 weeks of wash-out before cross-over. Primary outcome was change of paraoxonase-1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA-I antibodies. Clinical Trial Unique Identifier: EudraCT 2006-006889-42. RESULTS: The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l-1 , 95% confidence interval [CI] -9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL-C levels (coefficient estimate 5.21 mg dl-1 , 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl-1 , 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl-1 , 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA-I antibodies (coefficient estimate 0.25 µg ml-1 , 95% CI 0.09-0.40; P = 0.001). aApoA-I titres at baseline were correlated with decreased PON activity. CONCLUSIONS: The rise in HDL-C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA-I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk.

Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism.

Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouse(TM) platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease.

FISH OIL AND VITAMIN E CHANGE LIPID PROFILES AND ANTI-LDL-ANTIBODIES IN TWO DIFFERENT ETHNIC GROUPS OF WOMEN TRANSITIONING THROUGH MENOPAUSE.

BACKGROUND: studies have investigated the relationship between the transition through menopause and cardiovascular diseases. White population, generally, have lower levels of traditional coronary heart risk factors, particularly dyslipidemia, hypertension, obesity, and diabetes, and lower rates of coronary heart disease mortality, than black population. Furthermore many studies have shown the cardioprotective and anti-inflammatory effects of omega-3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) of marine origin. The aim of this study was to investigate the effect of omega-3 supplementation, combined or not with vitamin E, on oxidative biomarkers and lipid profiles in nonwhite and white women with dyslipidemia transitioning through menopause. METHODS: a randomized, double-blind, placebo-controlled trial was conducted. Seventy-four eligible women were assigned to receive: fish oil, fish oil plus vitamin E and placebo for three months. At baseline, 45 and 90 days blood sample for biochemical variables and biomarkers of oxidative stress were taken. Socioeconomic and lifestyle variables were collected with standardized questionnaires. RESULTS: after 90 days the fish oil plus vitamin E treated group had a significant decrease in total cholesterol and LDL-C. Furthermore, there was a decrease in anti- LDL- autoantibodies after 45 days. Plasma TBARS concentrations were increased after 90 days in the group receiving only fish oil when compared to the placebo and fish oil-vitamin E groups. All of the effects observed were independent of ethnic group. CONCLUSION: supplementation with fish oil and vitamin E reduced total cholesterol and LDL-C, but had opposite effects on oxidative stress compared to supplementation with fish oil alone.

Introducción: diversos estudios han investigado la relación entre la transición a la menopausia y las enfermedades cardiovasculares. Generalmente, la población de etnia blanca posee bajos niveles de factores de riesgo coronarios, particularmente dislipidemia, hipertensión, obesidad, diabetes y bajas tasas de mortalidad por enfermedades del corazón en comparación con la población de etnia negra. Además, varios estudios demostraron efectos cardioprotectores y antiinflamatorios provenientes de ácidos grasos poliinsaturados omega-3 (ácido eicosapentaenoico y ácido docosahexaenoico) de origen marino. El objetivo del estudio fue investigar el efecto de la suplementación de omega-3 combinado o no con vitamina E en biomarcadores oxidativos y perfiles lipídicos en mujeres blancas y no blancas con dislipidemia en transición hacia la menopausia. Métodos: fue realizado un estudio randomizado, duplo- ciego, placebo-controlado. Setenta y cuatro mujeres elegibles fueron escogidas para recibir: aceite de pescado, aceite de pescado con vitamina E y placebo durante tres meses. Fueron recogidas muestras de sangre en de referencia, 45 y 90 días para realizar exámenes bioquímicos y de biomarcadores para estrés oxidativo. Las variables socioeconómicas y de estilo de vida fueron recogidas por medio de cuestionarios estandarizados. Resultados: después de 90 días, el grupo tratado con aceite de pescado con vitamina E tuvo una disminución significativa para colesterol total y LDL-C. Además, hubo una disminución de anticuerpos anti-LDL después de 45 días. La concentración de plasma TBARS aumentó después de 90 días en el grupo que recibió solamente aceite de pescado, comparado con los grupos placebo y aceite de pescado con vitamina E. Todos los efectos observados fueron independientes del grupo étnico. Conclusión: la suplementación con aceite de pescado y vitamina E redujo el colesterol total y LDL-C, pero tuvo un efecto opuesto en el estrés oxidativo comparado con la suplementación solamente con aceite de pescado.

The pleiotropic role of HDL in autoimmune diseases.

As is widely known, the classic function of HDL is reverse cholesterol transport (RCT), thus removing cholesterol from peripheral tissues. Early epidemiological studies, such as Framingham's, stated that increased HDL levels were associated with a significant decrease in relative risk for cardiovascular disease (CVD) mortality. However, those with heightened expectations in recent years for the development of therapeutic targets to increase HDL levels have been disappointed, because efforts have demonstrated the opposite effect on cardiovascular and global mortality. However, in contrast, studies have highlighted the complexity and the intriguing role of HDL in different pathological conditions, such as infections, neoplasms, and autoimmune diseases. In this review an attempt is made to summarize some biological pathways that link HDL function with the immune system, and its possible clinical repercussions in autoimmune diseases.

HDL in innate and adaptive immunity.

During infections or acute conditions high-density lipoproteins cholesterol (HDL-C) levels decrease very rapidly and HDL particles undergo profound changes in their composition and function. These changes are associated with poor prognosis following endotoxemia or sepsis and data from genetically modified animal models support a protective role for HDL. The same is true for some parasitic infections, where the key player appears to be a specific and minor component of HDL, namely apoL-1. The ability of HDL to influence cholesterol availability in lipid rafts in immune cells results in the modulation of toll-like receptors, MHC-II complex, as well as B- and T-cell receptors, while specific molecules shuttled by HDL such as sphingosine-1-phosphate (S1P) contribute to immune cells trafficking. Animal models with defects associated with HDL metabolism and/or influencing cell cholesterol efflux present features related to immune disorders. All these functions point to HDL as a platform integrating innate and adaptive immunity. The aim of this review is to provide an overview of the connection between HDL and immunity in atherosclerosis and beyond.

A panel of biomarkers is associated with increased risk of the presence and progression of atherosclerosis in women with systemic lupus erythematosus.

OBJECTIVE: An increased frequency of atherosclerosis (ATH) in systemic lupus erythematosus (SLE) is well-documented but not fully explained by the presence of traditional cardiac risk factors. Several nontraditional biomarkers, including proinflammatory high-density lipoprotein (piHDL) and leptin, have been individually associated with subclinical ATH in SLE. The aim of this study was to examine whether these and other biomarkers can be combined into a risk profile, the Predictors of Risk for Elevated Flares, Damage Progression, and Increased Cardiovascular Disease in Patients with SLE (PREDICTS), that could be used to better predict future progression of ATH. METHODS: In total, 210 patients with SLE and 100 age-matched healthy control subjects (all women) participated in this prospective cohort study. The longitudinal presence of carotid plaque and intima-media thickness (IMT) were measured at baseline and followup (mean ± SD 29.6 ± 9.7 months). RESULTS: At followup, carotid plaque was present in 29% of SLE patients. Factors significantly associated with plaque, determined using Salford Predictive Modeling and multivariate analysis, included age ≥48 years (odds ratio [OR] 4.1, P = 0.002), high piHDL function (OR 9.1, P < 0.001), leptin levels ≥34 ng/dl (OR 7.3, P = 0.001), plasma soluble TWEAK levels ≥373 pg/ml (OR 28.8, P = 0.004), and history of diabetes (OR 61.8, P < 0.001). Homocysteine levels ≥12 µmoles/liter were also a predictor. However, no single variable demonstrated an ideal combination of good negative predictive values (NPVs), positive predictive values (PPVs), sensitivity, and specificity. A high-risk PREDICTS profile was defined as ≥3 positive biomarkers or ≥1 positive biomarker plus a history of diabetes; for high-risk SLE patients, the PPV was 64%, NPV was 94%, sensitivity was 89%, and specificity was 79%. In multivariate analysis, SLE patients with the high-risk profile had 28-fold increased odds for the longitudinal presence of plaque (P < 0.001) and increased progression of IMT (P < 0.001). CONCLUSION: A high-risk PREDICTS score confers 28-fold increased odds of the presence of any current, progressive, or acquired carotid plaque, both in patients with SLE and in control subjects, and is significantly associated with higher rates of IMT progression.

HDL does not influence the polarization of human monocytes toward an alternative phenotype.

BACKGROUND: Macrophages are crucial cells in the pathogenesis of atherosclerosis. Macrophages are plastic cells which can switch from a classical pro-inflammatory M1 to an alternative anti-inflammatory M2 macrophage phenotype, depending on the environmental stimuli. Because high-density lipoprotein (HDL) cholesterol levels are inversely correlated to cardiovascular disease and since HDL displays anti-inflammatory properties, we investigated whether HDL can affect alternative macrophage differentiation of primary human monocytes in the presence of interleukin (IL)-4, a M2 macrophage polarization driver, in vitro and ex vivo. METHODS AND RESULTS: M2 macrophages are highly responsive to HDL stimulation, since the expression of pentraxin 3 (PTX3), a well known HDL target gene, is induced by HDL more strongly in M2 macrophages than in control unpolarized resting macrophages (RM). As expected, the expression of M2 markers, such as Mannose Receptor (MR), CD200 Receptor (CD200R), Coagulation factor XIII A1 (F13A1), IL-1 receptor antagonist (IL-1RA) and IL10, was induced in IL-4 polarized M2 macrophages compared to RM. However, incubation with HDL added in vitro did not modulate the gene expression of M2 macrophage polarization markers. Moreover, monocytes isolated from subjects with genetically low HDL levels, carrying ABCA1 or LCAT mutations, differentiated ex vivo into M2 macrophages without any difference in the alternative macrophage marker expression profile. CONCLUSIONS: These in vitro and ex vivo results indicate that, contrary to mouse macrophages, HDL does not influence macrophage M2 polarization of human monocyte-derived macrophages. Thus, the anti-inflammatory properties of HDL in humans are probably not related to the enhancement of the M2 macrophage phenotype.

Analysis and modelling of cholesterol and high-density lipoprotein cholesterol changes across the range of C-reactive protein levels in clinical practice as an aid to better understanding of inflammation-lipid interactions.

OBJECTIVES: Raised total cholesterol (TC) and reduced high-density lipoprotein (HDL) cholesterol levels are established cardiovascular disease (CVD) risk factors. However, in autoimmune conditions the lipid-CVD association appears paradoxical, with inflammation as a potential confounding factor. We therefore sought to model the relationship between systemic inflammatory illness and lipid levels using C-reactive protein (CRP) as the prototypical marker of inflammation. Our hypothesis was that there would be an inverse association between raised CRP levels and both TC and HDL-cholesterol levels. METHODS: Results from samples analysed simultaneously for CRP and lipids in a 6-month period were collected retrospectively from a large city hospital laboratory database that collates results from both primary and secondary care. The relationships between CRP and lipids were determined using graphical techniques and empirical, non-parametric, best fit models. RESULTS: A total of 11 437 blood samples was included. We identified a significant (p<0.001) biphasic relationship between TC and CRP: TC increased within the healthy CRP range of less than 5 mg/l, but decreased with CRP levels above 10 mg/l. The two effects approximately cancelled each other out in the intermediate CRP range of 5-10 mg/l. There was an inverse relationship between HDL-cholesterol and CRP. CONCLUSIONS: Lipid levels change significantly during inflammatory illness in a population with both acute and chronic conditions. These results provide a strong epidemiological basis for the better understanding of lipid changes in inflammatory conditions and with anti-inflammatory therapies.

[Progress of anti-infection of high density lipoprotein].

Bacterial infection is likely to develop into sepsis, which is regarded as the main reason for high mortality rate. High-density lipoprotein cholesterol (HDL-C) and its associated apolipoprotein can combine with lipopolysaccharide, regulate the body's inflammatory response and reduce the mortality, which can provide a new method for treatment of bacterial infection.

Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein.

Interleukin (IL)-15 effects on CD8 T and natural killer (NK) lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Rα) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I (Apo A-I), IL-15, and IL-15Rα's sushi domain. Apo A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Rα's sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10 µg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (<2.5 µg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen, and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Rα(-/-) mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL-15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL, and displayed immunotherapeutic effects against metastatic disease.

HDL functionality.

PURPOSE OF REVIEW: HDL cholesterol concentration is inversely correlated with cardiovascular disease and has a wide range of functions involved in many systems. The purpose of this review is to summarize HDL functionality, its relevance to atherosclerosis and factors affecting HDL functions. RECENT FINDINGS: The contribution of HDL to reverse cholesterol transport may not be as great as first envisaged. However, it still plays an important role in cholesterol efflux from peripheral tissues. The capacity of HDL to promote cellular cholesterol efflux in an ex-vivo model has been reported to correlate more closely with carotid intima-media thickness than HDL cholesterol concentration. Recently, a variety of other functions of HDL have been described including antimicrobial, antioxidant, antiglycation, anti-inflammatory, nitric oxide--inducing, antithrombotic and antiatherogenic activity and immune modulation as well as a potential role in glucose homeostasis, diabetes pathophysiology and complications. SUMMARY: HDL has a wide range of functions some of which are independent of its cholesterol content. Its cargo of apolipoproteins, various proteins and phospholipids contributes most to its various functions. These functions are affected by a number of genetic, physiological and pathological factors.

Statin-induced immunomodulation alters peripheral invariant natural killer T-cell prevalence in hyperlipidemic patients.

PURPOSE: To assess the difference in the prevalence of invariant Natural Killer T (iNKT) lymphocytes between hyperlipidemic and control individuals and to evaluate changes in iNKT cell levels after 6 months lipid lowering therapy. METHODS: A total of 77 hyperlipidemic individuals (54 ± 5 years) were assigned to simvastatin 40 mg or ezetimibe 10 mg daily for 6 months. Fifty individuals with normal cholesterol levels were used as control. iNKT cells were measured by flow cytometry in peripheral blood. RESULTS: Patients with hypercholesterolemia had significantly lower iNKT cell levels (percentage on the lymphocyte population) compared to control group (0.16 ± 0.04% vs 0.39 ± 0.08%, p = 0.03). iNKT cells significantly increased after 6 months treatment with simvastatin (from 0.15 ± 0.04% to 0.28 ± 0.11%, p = 0.03) but not with ezetimibe (from 0.16 ± 0.05% to 0.17 ± 0.06%, p = 0.55). Simvastatin treatment did not alter the activation status of iNKT cells as measured by HLA-DR expression. Changes of iNKT cells were independent from changes in total (r(2) = 0.009, p = 0.76) or LDL cholesterol (r(2) = 0.008, p = 0.78) reached by simvastatin. CONCLUSIONS: Hyperlipidemic patients have reduced numbers of iNKT in peripheral circulation compared to individuals with normal cholesterol levels. Their number is increasing after long term administration of simvastatin 40 mg but not after ezetimibe.