Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 13 de 13
Filter
1.
Int J Infect Dis ; 101: 49-51, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32987182

ABSTRACT

INTRODUCTION: An acute respiratory disease caused by a novel coronavirus (SARSCOV2) is spreading from China since January 2020. Surprisingly, few cases of Covid-19 have been reported in people living with HIV (PLWHIV). METHODS: Here we present a series of 30 PLWHIV diagnosed for SARS-COV2 infection. The principal outcome was to describe clinical characteristics of this population. RESULTS: Eighteen (60%) patients were men, 10/30 (33,3%) women and 2/30 (6,7%) transgender women. Median age was 53,7 years (range 30-80 years) and 23/30 patients (76,7%) were born in a foreign country (out of France). The most common comorbidities were cardiovascular disease (11/30, 36,7%), hypertension (11/30, 36,7%), diabetes (9/30,30%) obesity (7/30, 23%) and chronic renal disease (5/30, 16,7%). Twenty (66,7%) patients presented overweight. Five patients (16,7%) had a Charlson comorbidity (Quan et al., 2011) score ≥3. Twenty-seven (90%) patients were virologically suppressed.CD4 count was >500cell/mm 3 in 23/30 (76,6%) patients. An antiviral treatment for SARS-COV2 was administered, in addition to HIV treatment, in 5/30 patients (16,3%). Twenty-four patients (80%) recovered from covid-19, 3/30 (10%) required invasive mechanical ventilation, 2/30 (6,7%) patients died and 4/30 (13,3%) patients were still hospitalized. CONCLUSIONS: Most of the patients were virologically suppressed with CD4>500 mm3. Risk factors were the same as those described in other SARS-COV2 series, suggesting that HIV infection is probably not an independent risk factor for covid-19.


Subject(s)
COVID-19/etiology , HIV Infections/complications , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Hospitals, University , Humans , Male , Middle Aged
2.
AIDS ; 33(5): 855-865, 2019 04 01.
Article in English | MEDLINE | ID: mdl-30664006

ABSTRACT

BACKGROUND: HIV-infected transwomen face multiple specific issues. Economic and social marginalization, sex work, substance abuse, hormonal consumption and silicone injection may affect the course of HIV infection and lead to metabolic and endocrine complications. METHODS: A matched case-control study was performed between 2013 and 2015 in a University Hospital and compared metabolic syndrome (MetS), thyroid and adrenal functions in HIV-infected transwomen (i.e. cases) and cisgender HIV-infected men (i.e. controls) matched for age and antiretroviral therapy. The interaction between hormonal consumption, the course of HIV infection and antiretroviral therapy was also studied. Clinical and biological data (CD4 cell count, HIV RNA load, antiretroviral plasma drug concentration, HDL, triglycerides, glucose, cortisol, thyroid stimulating hormone, free thyroxine, prolactine) were measured. RESULTS: A total of 292 HIV-infected patients (100 cases and 192 controls) were prospectively included. There was no difference between the two populations in terms of frequency of MetS, but subclinical hypothyroidism and adrenal insufficiency were more frequent in cases than in controls with, respectively, 12 vs. 3% (P < 0.002) for hypothyroidism and 20 vs. 8% (P < 0.001) for adrenal insufficiency. Prolactinemia, only performed in transwomen, was often elevated (21%) but rarely confirmed as true active hyperprolactinemia (monomeric form) (3%). Although hormonal intake was frequent among transwomen (31%), no impact on antiretroviral bioavailability and efficacy was detected. CONCLUSION: In this study, no increase in the prevalence of MetS was detected in HIV-infected transwomen patients. In contrast, adrenal and thyroid functions abnormalities were frequent and should be systematically assessed in this population. No impact of hormonal intake on antiretroviral bioavailability and efficacy was detected.


Subject(s)
HIV Infections/physiopathology , Hormone Replacement Therapy/adverse effects , Hypothyroidism/physiopathology , Metabolic Syndrome/physiopathology , Substance-Related Disorders/complications , Transgender Persons , Adult , Case-Control Studies , Female , HIV Infections/blood , Hospitals, University , Humans , Hypothyroidism/blood , Hypothyroidism/etiology , Male , Metabolic Syndrome/blood , Metabolic Syndrome/etiology , Prospective Studies , Transgender Persons/statistics & numerical data
3.
AIDS Res Hum Retroviruses ; 33(1): 11-16, 2017 01.
Article in English | MEDLINE | ID: mdl-27476681

ABSTRACT

In attempt to identify the factors associated with delayed diagnosis during HIV infection, we studied retrospectively the epidemiological profile of HIV-infected patients diagnosed between January 1, 2012 and December 31, 2013 and followed in our clinical center in Paris. Data were compared to those obtained at the same site during the year 2003. One hundred eighty-six patients fulfilled the inclusion criteria: 49 (26%) had a CD4 count <200/mm3 at diagnosis. Compared to subjects with CD4 count ≥200/mm3, advanced patients were older, had a higher plasma viral load, had more often an AIDS-defining event at the time of HIV diagnosis (45% vs. 3%), had been infected more often through heterosexual contact (69% vs. 44%), had less frequently past HIV testing (23% vs. 63%), and tended to live in less favorable conditions. A higher proportion of these patients initiated antiretroviral therapy in the 3 months following diagnosis (93.9% vs. 48.1%). Compared to data obtained in 161 patients in 2003, the proportions of advanced patients were similar between the two periods (26% vs. 22%). There was a significant increase from year 2003 to the 2012-2013 period in the proportion of men who have sex with men (MSM) (50% vs. 27%) and in the percentage of patients infected with HIV-1 subtype B (48% vs. 27%) and with positive syphilis serology (22% vs. 8%). Our data show that (1) HIV screening should be extended to populations with the following characteristics: older age, heterosexuality, and low socioeconomic level, and (2) HIV transmission continues to progress in MSM, arguing for the value of preexposure prophylaxis.


Subject(s)
HIV Infections/diagnosis , HIV Infections/epidemiology , Adult , Anti-Retroviral Agents/therapeutic use , CD4 Lymphocyte Count , Female , Genotype , HIV Infections/drug therapy , HIV Infections/pathology , HIV-1/classification , HIV-1/genetics , HIV-1/isolation & purification , Humans , Male , Middle Aged , Paris/epidemiology , Plasma/virology , Retrospective Studies , Viral Load
4.
Atherosclerosis ; 223(2): 394-400, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22683120

ABSTRACT

BACKGROUND: The identification of mutations in PCSK9 (proprotein convertase subtilisin kexin9) in autosomal dominant hypercholesterolemia (ADH), has revealed the existence of a new player in cholesterol homeostasis. PCSK9 has been shown to enhance the degradation of the LDL receptor (LDLR) at the cell surface. Gain-of-function mutations of PCSK9 induce ADH and are very rare, but their identification is crucial in studying PCSK9's role in hypercholesterolemia, its detailed trafficking pathway and its impact on the LDLR. METHODS: In order to identify new mutations and understand the exact mechanisms of action of mutated PCSK9, PCSK9 was sequenced in 75 ADH patients with no mutations in the LDLR or APOB genes. Functional analyses in cell culture were conducted and the impact of novel PCSK9 mutations on the quantitative and qualitative features of lipoprotein particles and on the HDL-mediated cellular cholesterol efflux was studied. RESULTS: Among these 75 ADH probands with no mutations in the LDLR or APOB genes, four gain-of-function mutations of PCSK9 were identified, of which two were novel: the p.Leu108Arg and the p.Asp35Tyr substitutions. In vitro studies of their consequences on the activity of PCSK9 on cell surface levels of LDLR showed that the p.Leu108Arg mutation clearly results in a gain-of-function, while the p.Asp35Tyr mutation created a novel Tyr-sulfation site, which may enhance the intracellular activity of PCSK9. CONCLUSION: These data further contribute to the characterization of PCSK9 mutations and to better understanding of the impact on cholesterol metabolism of this new therapeutic target.


Subject(s)
Hyperlipoproteinemia Type II/genetics , Mutation , Proprotein Convertases/genetics , Serine Endopeptidases/genetics , Apolipoproteins B/genetics , Apolipoproteins B/metabolism , Biomarkers/blood , Cholesterol, HDL/blood , DNA Mutational Analysis , Female , Genetic Predisposition to Disease , HEK293 Cells , Hep G2 Cells , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/metabolism , Male , Paris , Pedigree , Phenotype , Proprotein Convertase 9 , Proprotein Convertases/metabolism , Receptors, LDL/genetics , Receptors, LDL/metabolism , Serine Endopeptidases/metabolism , Transfection
5.
Atherosclerosis ; 221(1): 160-8, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22265126

ABSTRACT

OBJECTIVE: To evaluate the impact of CETP inhibition on the capacity of individual postprandial HDL subspecies to promote key steps of the reverse cholesterol transport pathway. METHODS: The capacity of HDL particles to mediate cellular free cholesterol efflux and selective hepatic uptake of cholesteryl esters was evaluated throughout postprandial phase (0-8 h) following consumption of a standardised mixed meal before and after treatment for 6 weeks with atorvastatin alone (10 mg/d) and subsequently with combination torcetrapib/atorvastatin (60/10 mg/d) in 16 patients displaying low HDL-C levels (<40 mg/dl). RESULTS: The larger HDL2b and HDL2a subfraction displayed a superior capacity to mediate cellular free cholesterol efflux via both SR-BI and ABCG1-dependent pathways than smaller HDL3 subspecies. CETP inhibition specifically enhanced the capacity of HDL2b subfraction for both SR-BI and ABCG1 dependent efflux. However, only the SR-BI-dependent efflux to HDL2b subspecies can be further enhanced during postprandial lipemia following CETP inhibition. Concomitantly, postprandial lipemia was associated with a reduced capacity of total HDL particles to deliver cholesteryl esters to hepatic cells in a drug independent manner. CONCLUSION: CETP inhibition specifically improves postprandial SR-BI and ABCG1-dependent efflux to larger HDL2b subspecies. In addition, CETP inhibition improves HDL-CE delivery to hepatic cells and maintains an efficient direct return of cholesteryl esters to the liver during postprandial lipemia.


Subject(s)
Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol, HDL/blood , Heptanoic Acids/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipidemias/drug therapy , Hypolipidemic Agents/therapeutic use , Lipoproteins, HDL2/blood , Postprandial Period , Pyrroles/therapeutic use , Quinolines/therapeutic use , ATP Binding Cassette Transporter, Subfamily G, Member 1 , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Adult , Animals , Apolipoprotein A-I/blood , Apolipoprotein A-II/blood , Atorvastatin , CD36 Antigens/metabolism , CHO Cells , Cholesterol Ester Transfer Proteins/metabolism , Cholesterol Esters/blood , Cricetinae , Cricetulus , Drug Therapy, Combination , Humans , Hyperlipidemias/blood , Liver/drug effects , Liver/metabolism , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Middle Aged , Paris , Particle Size , Time Factors , Transfection , Treatment Outcome
6.
Arterioscler Thromb Vasc Biol ; 31(7): 1675-81, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21527752

ABSTRACT

OBJECTIVE: Low high-density lipoprotein (HDL) cholesterol levels are frequently observed in familial hypercholesterolemia (FH) and might be associated with functional alterations of HDL particles that may influence their efficaciousness in the reverse cholesterol transport pathway. METHODS AND RESULTS: We evaluated key steps of the reverse cholesterol transport, ie, cellular free cholesterol efflux, cholesteryl ester transfer protein-mediated cholesteryl ester (CE) transfer from HDL to apolipoprotein B-containing lipoproteins, and hepatic HDL-CE uptake, in patients displaying FH (n = 12) and in healthy normolipidemic control subjects (n = 12). Large HDL2 particles isolated from FH patients displayed a reduced capacity to mediate free cholesterol efflux via both scavenger receptor-BI- and ABCG1-dependent pathways. A significant inverse relationship between scavenger receptor-BI-dependent HDL2 efflux capacity and carotid intima-media thickness (r = -0.473; P = 0.0186), as well as between ABCG1-dependent HDL2 efflux capacity and carotid intima-media thickness (r = -0.485; P = 0.0212), was detected. We also observed an elevated cholesteryl ester transfer protein-mediated CE transfer from HDL2 and HDL3 particles to low-density lipoprotein and a reduced capacity of HDL particles to deliver CEs to the liver. CONCLUSIONS: We demonstrated that the centripetal movement of cholesterol from peripheral tissues, including the vessel wall, to feces is defective in FH, thereby emphasizing its atherogenicity.


Subject(s)
Atherosclerosis/prevention & control , Cholesterol/blood , Hyperlipoproteinemia Type II/blood , ATP Binding Cassette Transporter 1 , ATP Binding Cassette Transporter, Subfamily G, Member 1 , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Adolescent , Adult , Animals , Apolipoproteins B/blood , Atherosclerosis/blood , Atherosclerosis/diagnostic imaging , Atherosclerosis/etiology , Atherosclerosis/genetics , Biological Transport , CHO Cells , Carotid Arteries/diagnostic imaging , Carotid Arteries/metabolism , Case-Control Studies , Cholesterol Ester Transfer Proteins/blood , Cholesterol, HDL/blood , Cricetinae , Cricetulus , Feces/chemistry , Female , Femoral Artery/diagnostic imaging , Femoral Artery/metabolism , France , Hep G2 Cells , Humans , Hyperlipoproteinemia Type II/complications , Hyperlipoproteinemia Type II/diagnostic imaging , Hyperlipoproteinemia Type II/genetics , Liver/metabolism , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Phospholipid Transfer Proteins/blood , Receptors, LDL/deficiency , Receptors, LDL/genetics , Scavenger Receptors, Class B/metabolism , Transfection , Tunica Intima/diagnostic imaging , Tunica Intima/metabolism , Tunica Media/diagnostic imaging , Tunica Media/metabolism , Ultrasonography , Young Adult
7.
Atherosclerosis ; 216(2): 370-3, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21354572

ABSTRACT

OBJECTIVES: To identify the genetic variant in the CETP gene of the proband with high HDL-C and low CETP activity and to investigate whether HDL from the CETP-deficient subject was dysfunctional in the reverse cholesterol transport (RCT) pathway. METHODS: We sequenced the CETP gene and assessed its promoter activity. Cholesterol efflux and hepatic cholesteryl ester delivery studies were also performed using the proband's HDL. RESULTS: A proband was a compound heterozygote for a known D459G variant and a novel 18-bp deletion mutation in the CETP promoter. This promoter mutation markedly reduced the transcriptional activity in HepG2 cells. HDL2 from this subject increased SR-BI-mediated cholesterol efflux, whereas cholesteryl ester delivery into hepatocytes was maintained. CONCLUSION: A novel deletion mutation in the CETP promoter is associated with high HDL-C and decreased promoter activity. HDL from this CETP-deficient subject was not dysfunctional in mediating two main steps of RCT assessed in vitro.


Subject(s)
Cholesterol Ester Transfer Proteins/genetics , Cholesterol Ester Transfer Proteins/physiology , ATP Binding Cassette Transporter, Subfamily G, Member 1 , ATP-Binding Cassette Transporters/metabolism , Animals , Base Sequence , CD36 Antigens/metabolism , Cell Line , Cholesterol/metabolism , Cholesterol Ester Transfer Proteins/deficiency , Cholesterol, HDL/metabolism , Gene Deletion , Hepatocytes/cytology , Heterozygote , Humans , Mice , Models, Biological , Molecular Sequence Data , Promoter Regions, Genetic
8.
J Clin Endocrinol Metab ; 96(4): 1151-9, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21289254

ABSTRACT

AIM: We tested the hypothesis that quantitative changes in high-density lipoprotein (HDL) particles weight loss induced by Roux-en-Y bypass (RYGBP) in morbidly obese subjects might be associated with improved functionality of these particles in the reverse cholesterol transport pathway. METHODS AND RESULTS: Thirty-four morbidly obese women were recruited and followed up before and 6 months after RYGBP. After surgery, along with a major weight loss (-20%; P < 0.0001), we observed a significant increase in HDL mass concentration (+14%; P < 0.04), reflecting a specific increase in large HDL2 subfraction levels (+42%; P < 0.01), whereas those of HDL3 remained unchanged. Cholesterol ester transfer protein activity decreased significantly (-15%; P < 0.0001). Efflux capacity of total plasma increased significantly via both scavenger receptor class B type I (SR-BI) (+58%; P < 0.0001) and ATP binding cassette G1 (ABCG1) (+26%; P < 0.0001) pathways. Such enhanced capacity resulted from increased capacity of HDL2 particles to mediate cholesterol efflux through the SR-BI pathway (+56%, P < 0.001) and from the increase plasma level of cholesteryl ester-rich HDL2 particles for the ABCG1 pathway. CONCLUSION: RYGBP-induced weight loss results in improvement in atherogenic lipid profile including a shift toward a more cardioprotective HDL subfraction profile. In addition, our in vitro studies demonstrated an increased in plasma efflux capacity via both SR-BI and ABCG1 after surgery.


Subject(s)
ATP-Binding Cassette Transporters/physiology , Bariatric Surgery , Cholesterol/metabolism , Obesity, Morbid/surgery , Scavenger Receptors, Class B/physiology , Weight Loss/physiology , ATP Binding Cassette Transporter 1 , ATP Binding Cassette Transporter, Subfamily G, Member 1 , ATP-Binding Cassette Transporters/genetics , Adolescent , Adult , Animals , Bariatric Surgery/rehabilitation , CHO Cells , Cells, Cultured , Cholesterol/blood , Cricetinae , Cricetulus , Female , Follow-Up Studies , Humans , Mice , Middle Aged , Obesity, Morbid/blood , Obesity, Morbid/metabolism , Rats , Scavenger Receptors, Class B/genetics , Young Adult
9.
J Lipid Res ; 51(11): 3350-8, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20713650

ABSTRACT

Lipid and cholesterol metabolism in the postprandial phase is associated with both quantitative and qualitative remodeling of HDL particle subspecies that may influence their anti-atherogenic functions in the reverse cholesterol transport pathway. We evaluated the capacity of whole plasma or isolated HDL particles to mediate cellular free cholesterol (FC) efflux, cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester (CE) transfer, and selective hepatic CE uptake during the postprandial phase in subjects displaying type IIB hyperlipidemia (n = 16). Postprandial, large HDL2 displayed an enhanced capacity to mediate FC efflux via both scavenger receptor class B type I (SR-BI)-dependent (+12%; P < 0.02) and ATP binding cassette transporter G1 (ABCG1)-dependent (+31%; P < 0.008) pathways in in vitro cell systems. In addition, the capacity of whole postprandial plasma (4 h and 8 h postprandially) to mediate cellular FC efflux via the ABCA1-dependent pathway was significantly increased (+19%; P < 0.0003). Concomitantly, postprandial lipemia was associated with elevated endogenous CE transfer rates from HDL2 to apoB lipoproteins and with attenuated capacity (-17%; P < 0.02) of total HDL to deliver CE to hepatic cells. Postprandial lipemia enhanced SR-BI and ABCG1-dependent efflux to large HDL2 particles. However, postprandial lipemia is equally associated with deleterious features by enhancing formation of CE-enriched, triglyceride-rich lipoprotein particles through the action of CETP and by reducing the direct return of HDL-CE to the liver.


Subject(s)
ATP-Binding Cassette Transporters/metabolism , CD36 Antigens/metabolism , Cholesterol/metabolism , Hyperlipidemias/metabolism , Lipoproteins, HDL2/metabolism , Particle Size , Postprandial Period , ATP Binding Cassette Transporter, Subfamily G, Member 1 , Adult , Biological Transport , Cholesterol Esters/metabolism , Female , Humans , Hyperlipidemias/blood , Hyperlipidemias/pathology , Hyperlipidemias/physiopathology , Kinetics , Lipoproteins, HDL2/blood , Lipoproteins, HDL2/chemistry , Liver/cytology , Liver/metabolism , Male , Middle Aged , Triglycerides/blood
10.
PLoS Pathog ; 5(2): e1000310, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19229312

ABSTRACT

HCV entry into cells is a multi-step and slow process. It is believed that the initial capture of HCV particles by glycosaminoglycans and/or lipoprotein receptors is followed by coordinated interactions with the scavenger receptor class B type I (SR-BI), a major receptor of high-density lipoprotein (HDL), the CD81 tetraspanin, and the tight junction protein Claudin-1, ultimately leading to uptake and cellular penetration of HCV via low-pH endosomes. Several reports have indicated that HDL promotes HCV entry through interaction with SR-BI. This pathway remains largely elusive, although it was shown that HDL neither associates with HCV particles nor modulates HCV binding to SR-BI. In contrast to CD81 and Claudin-1, the importance of SR-BI has only been addressed indirectly because of lack of cells in which functional complementation assays with mutant receptors could be performed. Here we identified for the first time two cell types that supported HCVpp and HCVcc entry upon ectopic SR-BI expression. Remarkably, the undetectable expression of SR-BI in rat hepatoma cells allowed unambiguous investigation of human SR-BI functions during HCV entry. By expressing different SR-BI mutants in either cell line, our results revealed features of SR-BI intracellular domains that influence HCV infectivity without affecting receptor binding and stimulation of HCV entry induced by HDL/SR-BI interaction. Conversely, we identified positions of SR-BI ectodomain that, by altering HCV binding, inhibit entry. Finally, we characterized alternative ectodomain determinants that, by reducing SR-BI cholesterol uptake and efflux functions, abolish HDL-mediated infection-enhancement. Altogether, we demonstrate that SR-BI is an essential HCV entry factor. Moreover, our results highlight specific SR-BI determinants required during HCV entry and physiological lipid transfer functions hijacked by HCV to favor infection.


Subject(s)
Hepacivirus/metabolism , Scavenger Receptors, Class B/genetics , Virus Internalization , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , CHO Cells , Cell Line , Cell Line, Tumor , Claudin-1 , Cricetinae , Cricetulus , Dogs , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mutagenesis , Protein Structure, Tertiary , Rats , Receptors, Virus/genetics , Receptors, Virus/metabolism , Recombinant Fusion Proteins , Scavenger Receptors, Class B/metabolism , Tetraspanin 28
11.
Arterioscler Thromb Vasc Biol ; 29(2): 268-75, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19038848

ABSTRACT

OBJECTIVE: Therapeutic strategies to raise low plasma HDL-cholesterol levels, with concomitant normalization of the intravascular metabolism, physicochemical properties, and antiatherogenic function of HDL particles, are a major focus in atherosclerosis prevention. METHODS AND RESULTS: Patients displaying Type IIB hyperlipidemia (n=14) and healthy controls (n=11) were recruited. After drug washout, dyslipidemic patients first received atorvastatin (10 mg/d) for 6 weeks and subsequently torcetrapib/atorvastatin (60/10 mg/d) for the same period. Partial CETP inhibition markedly reduced supranormal CE transfer rates to normal levels from HDL3 (-58%; P<0.0001) to apoB-lipoproteins; endogenous CE transfer rates from HDL2 to apoB-lipoproteins were markedly subnormal as compared to those in control subjects (10.7+/-0.9 versus 29.3+/-4.8 microg CE/h/mL plasma, respectively). Torcetrapib enhanced the subnormal capacity of HDL2 particles from dyslipidemic patients to mediate free cholesterol efflux via both SR-BI and ABCG1 pathways (+38%; P<0.003 and +35%; P<0.03, respectively) as compared to baseline. In vitro observations and in vivo studies in mice demonstrated that CETP inhibition was associated with an enhanced selective hepatic uptake of CE from HDL particles (1.7-fold; P<0.0003). CONCLUSIONS: CETP inhibition partially corrected the abnormal physicochemical and functional properties of HDL2 and HDL3 particles in type IIB hyperlipidemia. Enhanced hepatic selective uptake of HDL-CE may compensate for attenuated indirect CE transfer to apoB-containing lipoproteins via CETP attributable to torcetrapib.


Subject(s)
Anticholesteremic Agents/therapeutic use , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol, HDL/blood , Hyperlipoproteinemia Type II/drug therapy , Lipoproteins, HDL2/blood , Lipoproteins, HDL3/blood , Liver/drug effects , Quinolines/therapeutic use , ATP Binding Cassette Transporter, Subfamily G, Member 1 , ATP-Binding Cassette Transporters/blood , Adult , Animals , Apolipoproteins B/blood , Atorvastatin , Cell Line, Tumor , Cholesterol Ester Transfer Proteins/blood , Cholesterol Esters/blood , Drug Therapy, Combination , Heptanoic Acids/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type II/blood , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Middle Aged , Pyrroles/therapeutic use , Scavenger Receptors, Class B/blood , Time Factors , Treatment Outcome
12.
J Lipid Res ; 49(3): 635-43, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18057374

ABSTRACT

We evaluated the impact of gender differences in both the quantitative and qualitative features of HDL subspecies on cellular free cholesterol efflux through the scavenger receptor class B type I (SR-BI), ABCA1, and ABCG1 pathways. For that purpose, healthy subjects (30 men and 26 women) matched for age, body mass index, triglyceride, apolipoprotein A-I, and high density lipoprotein-cholesterol (HDL-C) levels were recruited. We observed a significant increase (+14%; P < 0.03) in the capacity of whole sera from women to mediate cellular free cholesterol efflux via the SR-BI-dependent pathway compared with sera from men. Such enhanced efflux capacity resulted from a significant increase in plasma levels of large cholesteryl ester-rich HDL2 particles (+20%; P < 0.04) as well as from an enhanced capacity (+14%; P < 0.03) of these particles to mediate cellular free cholesterol efflux via SR-BI. By contrast, plasma from men displayed an enhanced free cholesterol efflux capacity (+31%; P < 0.001) via the ABCA1 transporter pathway compared with that from women, which resulted from a 2.4-fold increase in the plasma level of prebeta particles (P < 0.008). Moreover, in women, SR-BI-mediated cellular free cholesterol efflux was significantly correlated with plasma HDL-C (r = 0.72, P < 0.0001), whereas this relationship was not observed in men. In conclusion, HDL-C level may not represent the absolute indicator of the efficiency of the initial step of the reverse cholesterol transport.


Subject(s)
ATP-Binding Cassette Transporters/metabolism , Cholesterol/metabolism , Scavenger Receptors, Class B/metabolism , ATP Binding Cassette Transporter 1 , ATP Binding Cassette Transporter, Subfamily G, Member 1 , Female , Humans , Lipoproteins, HDL/metabolism , Lipoproteins, HDL2/metabolism , Male , Sex Factors
13.
Arterioscler Thromb Vasc Biol ; 28(1): 148-54, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17951324

ABSTRACT

OBJECTIVE: The purpose of this study was to evaluate the impact of torcetrapib on atherogenic TG-rich lipoprotein subfractions in the postprandial phase in Type IIB hyperlipidemia. METHODS AND RESULTS: The quantitative and qualitative features of the postprandial profile of TG-rich lipoproteins were determined at baseline, after treatment for 6 weeks with 10 mg/d atorvastatin, and subsequently with an atorvastatin/torcetrapib combination (10/60 mg/d) in Type IIB patients (n=18). After ingestion of a standardized mixed meal, TG-rich lipoprotein subfractions were evaluated over 8 hours after each experimental period. On a background of atorvastatin, torcetrapib significantly attenuated the incremental postprandial area under the curve (iAUC 0 to 8 hours) for VLDL-1 (-40%), and the AUC 0 to 8 hours for VLDL-2 (-53%), with minor effect on chylomicron iAUC (-24%); concomitantly, the CE/TG ratio in both VLDL-1 and VLDL-2 was significantly reduced (-27% to -42%). Such reduction was attributable to torcetrapib-mediated attenuation of postprandial CE transfer to Chylomicrons (-17%) and VLDL-1 (-33%). Marked reduction in postprandial VLDL-1 levels was associated with apoE enrichment. CONCLUSIONS: On a background of atorvastatin, torcetrapib attenuated the quantitative and qualitative features of the atherogenic postprandial profile of chylomicrons, VLDL-1 and VLDL-2. Such changes reflect the sum of torcetrapib-mediated effects on TG-rich lipoprotein production, intravascular remodeling, and catabolism.


Subject(s)
Anticholesteremic Agents/pharmacology , Hyperlipoproteinemia Type II/drug therapy , Postprandial Period/drug effects , Quinolines/pharmacology , Adult , Atorvastatin , Cholesterol Ester Transfer Proteins/drug effects , Chylomicrons/drug effects , Dietary Fats/metabolism , Dietary Proteins/metabolism , Drug Therapy, Combination , Heptanoic Acids/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Lipoproteins, VLDL/drug effects , Male , Middle Aged , Pyrroles/therapeutic use
SELECTION OF CITATIONS
SEARCH DETAIL
...