RESUMO
OBJECTIVE: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) and statins are known to lower plasma LDL (low-density lipoprotein)-cholesterol concentrations. However, the comparative effects of these treatments on the postprandial metabolism of TRLs (triglyceride-rich lipoproteins) remain to be investigated. APPROACH AND RESULTS: We performed a 2-by-2 factorial trial of the effects of 8 weeks of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on postprandial TRL metabolism in 80 healthy, normolipidemic men after ingestion of an oral fat load. We evaluated plasma total and incremental area under the curves for triglycerides, apo (apolipoprotein)B-48, and VLDL (very-LDL)-apoB-100. We also examined the kinetics of apoB-48 using intravenous D3-leucine administration, mass spectrometry, and multicompartmental modeling. Atorvastatin and evolocumab independently lowered postprandial VLDL-apoB-100 total area under the curves (P<0.001). Atorvastatin, but not evolocumab, reduced fasting plasma apoB-48, apoC-III, and angiopoietin-like 3 concentrations (P<0.01), as well as postprandial triglyceride and apoB-48 total area under the curves (P<0.001) and the incremental area under the curves for plasma triglycerides, apoB-48, and VLDL-apoB-100 (P<0.01). Atorvastatin also independently increased TRL apoB-48 fractional catabolic rate (P<0.001) and reduced the number of apoB-48-containing particles secreted in response to the fat load (P<0.01). In contrast, evolocumab did not significantly alter the kinetics of apoB-48. CONCLUSIONS: In healthy, normolipidemic men, atorvastatin decreased fasting and postprandial apoB-48 concentration by accelerating the catabolism of apoB-48 particles and reducing apoB-48 particle secretion in response to a fat load. Inhibition of PCSK9 with evolocumab had no significant effect on apoB-48 metabolism.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Gorduras na Dieta/sangue , Lipoproteínas/sangue , Inibidores de PCSK9 , Inibidores de Serina Proteinase/administração & dosagem , Triglicerídeos/sangue , Administração Oral , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Apolipoproteína B-100/sangue , Apolipoproteína B-48/sangue , Apolipoproteína C-III/sangue , Gorduras na Dieta/administração & dosagem , Método Duplo-Cego , Esquema de Medicação , Humanos , Injeções Subcutâneas , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Pró-Proteína Convertase 9/metabolismo , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Bempedoic acid (BemA; ETC-1002) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. In phase 2 studies, BemA lowers elevated low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients. In the present study, we tested the ability of BemA to decrease plasma cholesterol and LDL-C and attenuate atherosclerosis in a large animal model of familial hypercholesterolemia. APPROACH AND RESULTS: Gene targeting has been used to generate Yucatan miniature pigs heterozygous (LDLR+/-) or homozygous (LDLR-/-) for LDL receptor deficiency (ExeGen). LDLR+/- and LDLR-/- pigs were fed a high-fat, cholesterol-containing diet (34% kcal fat; 0.2% cholesterol) and orally administered placebo or BemA for 160 days. In LDLR+/- pigs, compared with placebo, BemA decreased plasma cholesterol and LDL-C up to 40% and 61%, respectively. In LDLR-/- pigs, in which plasma cholesterol and LDL-C were 5-fold higher than in LDLR+/- pigs, BemA decreased plasma cholesterol and LDL-C up to 27% and 29%, respectively. Plasma levels of triglycerides and high-density lipoprotein cholesterol, fasting glucose and insulin, and liver lipids were unaffected by treatment in either genotype. In the aorta of LDLR+/- pigs, BemA robustly attenuated en face raised lesion area (-58%) and left anterior descending coronary artery cross-sectional lesion area (-40%). In LDLR-/- pigs, in which lesions were substantially more advanced, BemA decreased aortic lesion area (-47%) and left anterior descending coronary artery lesion area (-48%). CONCLUSIONS: In a large animal model of LDLR deficiency and atherosclerosis, long-term treatment with BemA reduces LDL-C and attenuates the development of aortic and coronary atherosclerosis in both LDLR+/- and LDLR-/- miniature pigs.
Assuntos
Anticolesterolemiantes/farmacologia , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Doença da Artéria Coronariana/prevenção & controle , Ácidos Dicarboxílicos/farmacologia , Ácidos Graxos/farmacologia , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Receptores de LDL/deficiência , Animais , Animais Geneticamente Modificados , Anticolesterolemiantes/farmacocinética , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Ácidos Dicarboxílicos/farmacocinética , Modelos Animais de Doenças , Regulação para Baixo , Ácidos Graxos/farmacocinética , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Masculino , Fenótipo , Placa Aterosclerótica , Receptores de LDL/genética , Suínos , Porco MiniaturaRESUMO
Aims: Lipoprotein(a) [Lp(a)], a low-density lipoprotein (LDL) particle covalently bound to apolipoprotein(a) [apo(a)], is a potentially potent heritable risk factor for cardiovascular disease. We investigated the mechanism whereby evolocumab, a monoclonal antibody against proprotein convertase subtilisin-kexin type 9 (PCSK9), lowers Lp(a). Methods and results: We studied the kinetics of Lp(a) particles in 63 healthy men, with plasma apo(a) concentration >5 nmol/L, participating in an 8-week factorial trial of the effects of evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on lipoprotein metabolism. Lipoprotein(a)-apo(a) kinetics were studied using intravenous D3-leucine administration, mass spectrometry, and compartmental modelling; Lp(a)-apoB kinetics were also determined in 16 subjects randomly selected from the treatment groups. Evolocumab, but not atorvastatin, significantly decreased the plasma pool size of Lp(a)-apo(a) (-36%, P < 0.001 for main effect). As monotherapy, evolocumab significantly decreased the production of Lp(a)-apo(a) (-36%, P < 0.001). In contrast, in combination with atorvastatin, evolocumab significantly increased the fractional catabolism of Lp(a)-apo(a) (+59%, P < 0.001), but had no effect on the production of Lp(a)-apo(a). There was a highly significant association between the changes in the fractional catabolism of Lp(a)-apo(a) and Lp(a)-apoB in the substudy of 16 subjects (r = 0.966, P < 0.001). Conclusions: Evolocumab monotherapy lowered the plasma Lp(a) pool size by decreasing the production of Lp(a) particles. In combination with atorvastatin, evolocumab lowered the plasma Lp(a) pool size by accelerating the catabolism of Lp(a) particles. This dual mechanism may relate to an effect of PCSK9 inhibition on Lp(a)-apo(a) production and to marked up-regulation of LDL receptor activity on Lp(a) holoparticle clearance. Clinical Trial Registration Information: NCT02189837.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/farmacologia , Atorvastatina/farmacologia , Lipoproteína(a)/efeitos dos fármacos , Lipoproteína(a)/metabolismo , Inibidores de PCSK9 , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Humanos , Cinética , Lipoproteína(a)/sangue , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Small dense LDL (sdLDL) has been reported to be more atherogenic than large buoyant LDL (lbLDL). We examined the metabolism and protein composition of sdLDL and lbLDL in six subjects with combined hyperlipidemia on placebo and rosuvastatin 40 mg/day. ApoB-100 kinetics in triglyceride-rich lipoproteins (TRLs), lbLDL (density [d] = 1.019-1.044 g/ml), and sdLDL (d = 1.044-1.063 g/ml) were determined in the fed state by using stable isotope tracers, mass spectrometry, and compartmental modeling. Compared with placebo, rosuvastatin decreased LDL cholesterol and apoB-100 levels in TRL, lbLDL, and sdLDL by significantly increasing the fractional catabolic rate of apoB-100 (TRL, +45%; lbLDL, +131%; and sdLDL, +97%), without a change in production. On placebo, 25% of TRL apoB-100 was catabolized directly, 37% was converted to lbLDL, and 38% went directly to sdLDL; rosuvastatin did not alter these distributions. During both phases, sdLDL apoB-100 was catabolized more slowly than lbLDL apoB-100 (P < 0.01). Proteomic analysis indicated that rosuvastatin decreased apoC-III and apoM content within the density range of lbLDL (P < 0.05). In our view, sdLDL is more atherogenic than lbLDL because of its longer plasma residence time, potentially resulting in more particle oxidation, modification, and reduction in size, with increased arterial wall uptake. Rosuvastatin enhances the catabolism of apoB-100 in both lbLDL and sdLDL.
Assuntos
LDL-Colesterol/química , LDL-Colesterol/metabolismo , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipidemia Familiar Combinada/metabolismo , Tamanho da Partícula , Proteômica , Rosuvastatina Cálcica/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rosuvastatina Cálcica/uso terapêuticoRESUMO
PURPOSE OF REVIEW: Dysregulated lipoprotein metabolism leads to increased plasma concentrations of atherogenic lipoproteins. We highlight the findings from recent studies of the effect of lipid-regulating therapies on apolipoprotein metabolism in humans employing endogenous labelling with stable isotopically labelled isotopomers. RECENT FINDINGS: Fish oil supplementation and niacin treatment both reduce fasting and postprandial triglyceride levels by decreasing the hepatic secretion of VLDL-apoB-100 (apoB) and apoB-48-containing chylomicron particles in obese and/or type 2 diabetes. Niacin also lowers plasma LDL-apoB and Lp(a) levels by increasing catabolism of LDL-apoB and decreasing secretion of Lp(a), respectively. In subjects with hypercholesterolaemia, inhibition of cholesteryl ester transfer protein raises apoA-I and lowers apoB by decreasing and increasing the catabolism of HDL-apoA-I and LDL-apoB, respectively. Antisense oligonucleotides directed at apoB mRNA lowers plasma LDL-cholesterol and apoB chiefly by increasing the catabolism and decreasing the secretion of LDL-apoB in healthy subjects. That apoB ASO treatment does not lower hepatic secretion in humans is unexpected and merits further investigation. SUMMARY: Kinetic studies provide mechanistic insight into the mode of action of lipid lowering therapies and lipoprotein disorders. Understanding the mode of action of new drugs in vivo is important to establish their effective use in clinical practice.
Assuntos
Ensaios Clínicos como Assunto/métodos , Tratamento Farmacológico/métodos , Lipoproteínas/metabolismo , Humanos , CinéticaRESUMO
BACKGROUND: Experimental data suggest that apolipoprotein (apo) C-II and C-III regulate triglyceride-rich lipoprotein (TRL) metabolism, but there are limited studies in humans. We investigated the metabolic associations of TRLs with apoC-II and apoC-III concentrations and kinetics in women. MATERIAL AND METHODS: The kinetics of plasma apoC-II, apoC-III and very low-density lipoprotein (VLDL) apoB-100 and triglycerides were measured in the postabsorptive state using stable isotopic techniques and compartmental modelling in 60 women with wide-ranging body mass index (19·5-32·9 kg/m(2) ). RESULTS: Plasma apoC-II and apoC-III concentrations were positively associated with the concentrations of plasma triglycerides, VLDL1 - and VLDL2 -apoB-100 and triglyceride (all P < 0·05). ApoC-II production rate (PR) was positively associated with VLDL1 -apoB-100 concentration, VLDL1 triglyceride concentration and VLDL1 triglyceride PR, while apoC-II fractional catabolic rate (FCR) was positively associated with VLDL1 triglyceride FCR (all P < 0·05). No significant associations were observed between apoC-II and VLDL2 apoB-100 or triglyceride kinetics. ApoC-III PR, but not FCR, was positively associated with VLDL1 triglyceride, and VLDL2 -apoB-100 and triglyceride concentrations (all P < 0·05). No significant associations were observed between apoC-III and VLDL-apoB-100 and triglyceride kinetics. In multivariable analysis, including homoeostasis model assessment score, menopausal status and obesity, apoC-II concentration was significantly associated with plasma triglyceride, VLDL1 -apoB-100 and VLDL1 triglyceride concentrations and PR. Using the same multivariable analysis, apoC-III was significantly associated with plasma triglyceride and VLDL1 - and VLDL2 -apoB-100 and triglyceride concentrations and FCR. CONCLUSIONS: In women, plasma apoC-II and apoC-III concentrations are regulated by their respective PR and are significant, independent determinants of the kinetics and plasma concentrations of TRLs.
Assuntos
Apolipoproteína C-III/metabolismo , Apolipoproteína C-II/metabolismo , Resistência à Insulina/fisiologia , Lipoproteínas/metabolismo , Obesidade/metabolismo , Triglicerídeos/metabolismo , Adulto , VLDL-Colesterol/metabolismo , Feminino , Humanos , Menopausa/metabolismo , Pessoa de Meia-Idade , Análise de RegressãoRESUMO
OBJECTIVE: The effects of extended-release niacin (ERN; 1-2 g/d) on the metabolism of lipoprotein(a) (Lp(a)) and apolipoprotein (apo) B-100-containing lipoproteins were investigated in 11 statin-treated white men with type 2 diabetes mellitus in a randomized, crossover trial of 12-weeks duration. APPROACH AND RESULTS: The kinetics of Lp(a) and very low-density lipoprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL) apoB-100 were determined following a standardized oral fat load (87% fat) using intravenous administration of D3-leucine, gas chromatography-mass spectrometry, and compartmental modeling. ERN significantly decreased fasting plasma total cholesterol, LDL cholesterol, and triglyceride concentrations. These effects were achieved without significant changes in body weight or insulin resistance. ERN significantly decreased plasma Lp(a) concentration (-26.5%) and the production rates of apo(a) (-41.5%) and Lp(a)-apoB-100 (-32.1%); the effect was greater in individuals with elevated Lp(a) concentration. ERN significantly decreased VLDL (-58.7%), intermediate-density lipoprotein (-33.6%), and LDL (-18.3%) apoB-100 concentrations and the corresponding production rates (VLDL, -49.8%; intermediate-density lipoprotein, -44.7%; LDL, -46.1%). The number of VLDL apoB-100 particles secreted increased in response to the oral fat load. Despite this, total VLDL apoB-100 production over the 10-hour postprandial period was significantly decreased with ERN (-21.9%). CONCLUSIONS: In statin-treated men with type 2 diabetes mellitus, ERN decreased plasma Lp(a) concentrations by decreasing the production of apo(a) and Lp(a)-apoB-100. ERN also decreased the concentrations of apoB-100-containing lipoproteins by decreasing VLDL production and the transport of these particles down the VLDL to LDL cascade. Our study provides further mechanistic insights into the lipid-regulating effects of ERN.
Assuntos
Apolipoproteína B-100/sangue , Diabetes Mellitus Tipo 2/complicações , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteína(a)/sangue , Niacina/uso terapêutico , Período Pós-Prandial , Rosuvastatina Cálcica/uso terapêutico , Idoso , Apolipoproteínas A/sangue , Biomarcadores/sangue , Estudos Cross-Over , Preparações de Ação Retardada , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Gorduras na Dieta/sangue , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/diagnóstico , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Lipoproteínas LDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: Patients with obesity and diabetes mellitus have increased risk of cardiovascular disease. A major cause is an atherogenic dyslipidemia related primarily to elevated plasma concentrations of triglyceride-rich lipoproteins. The aim of this study was to clarify determinants of plasma triglyceride concentration. We focused on factors that predict the kinetics of very-low density lipoprotein 1 (VLDL1) triglycerides. APPROACH AND RESULTS: A multicenter study using dual stable isotopes (deuterated leucine and glycerol) and multicompartmental modeling was performed to elucidate the kinetics of triglycerides and apoB in VLDL1 in 46 subjects with abdominal obesity and additional cardiometabolic risk factors. Results showed that plasma triglyceride concentrations were dependent on both the secretion rate (r=0.44, P<0.01; r=0.45, P<0.01) and fractional catabolism (r=0.49, P<0.001; r=0.55, P<0.001) of VLDL1-triglycerides and VLDL1-apoB. Liver fat mass was independently and directly associated with secretion rates of VLDL1-triglycerides (r=0.56, P<0.001) and VLDL1-apoB (r=0.53, P<0.001). Plasma apoC-III concentration was independently and inversely associated with the fractional catabolisms of VLDL1-triglycerides (r=0.48, P<0.001) and VLDL1-apoB (r=0.51, P<0.001). CONCLUSIONS: Plasma triglyceride concentrations in abdominal obesity are determined by the kinetics of VLDL1 subspecies, catabolism being mainly dependent on apoC-III concentration and secretion on liver fat content. Reduction in liver fat and targeting apoC-III may be an effective approach for correcting triglyceride metabolism atherogenic dyslipidemia in obesity.
Assuntos
Apolipoproteína C-III/sangue , Doenças Cardiovasculares/sangue , Dislipidemias/sangue , Lipoproteínas VLDL/sangue , Lipoproteínas/sangue , Obesidade Abdominal/sangue , Triglicerídeos/sangue , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Índice de Massa Corporal , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Dislipidemias/complicações , Feminino , Humanos , Cinética , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Obesidade Abdominal/complicações , Tamanho do Órgão , Traçadores Radioativos , Valores de Referência , Medição de RiscoRESUMO
BACKGROUND: Atherosclerosis is a lipid-driven inflammatory disease of the arterial wall involving complex and multifactorial processes. Proprotein convertase subtilisin kexin type 9 (PCSK9) may play a role in the development of atherosclerosis. METHODS: We investigated the associations between serum PCSK9 and carotid intima-medial wall thickness (IMT), a measure of subclinical atherosclerosis that predicts cardiovascular events, in 295 asymptomatic subjects from community. Carotid IMT was determined by high-resolution B-mode carotid ultrasonography and serum PCSK9 was measured by immunoassay. RESULTS: In univariate analysis, serum PCSK9 concentration was positively (P<0.05 in all) associated with age (r=0.204), BMI (r=0.149), waist circumference (r=0.139), systolic blood pressures (r=0.116), glucose (r=0.211), insulin (r=0.178), HOMA score (r=0.195), plasma triglyceride (r=0.285), total cholesterol (r=0.241) and LDL-cholesterol concentrations (r=0.172). In multivariate regression including male gender, hypertension, smoking status, HOMA score, obesity, LDL-cholesterol, lipoprotein (a) or markers of inflammation, serum PCSK9 remained an independent predictor of mean carotid IMT (P<0.001). CONCLUSIONS: These data suggest that serum levels of PCSK9 may contribute to increased risk of subclinical carotid atherosclerosis independent of conventional risk factors. Whether PCSK9 inhibition improves cardiovascular outcomes remains to be demonstrated in large, ongoing clinical trials.
Assuntos
Doenças das Artérias Carótidas , Espessura Intima-Media Carotídea , Pró-Proteína Convertase 9/sangue , Adulto , Idoso , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco , Fatores SexuaisRESUMO
Postprandial lipaemia, due to elevated plasma apolipoprotein (apo) B-48 concentrations, contributes to increased cardiovascular (CV) risk in obesity. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and apoC-III may play a role in regulating triacylglycerol-rich lipoprotein (TRL)-apoB-48 metabolism. We investigated the associations between plasma PCSK9 and apoC-III concentrations and the kinetics of apoB-48 in obese subjects. Seventeen obese subjects were given an oral fat load. ApoB-48 tracer/tracee ratios were measured after an intravenous 2H3-leucine administration using GC-MS. Kinetic parameters, including secretion and fractional catabolic rates (FCRs), were derived using a multi-compartmental model. Plasma PCSK9 and apoC-III concentrations were significantly and positively (P<0.05 in all) associated with the total area-under-curve (AUC) and incremental AUC for apoB-48 and inversely with TRL-apoB-48 FCR. Plasma PCSK9 and apoC-III concentrations were not correlated (P>0.05 in all) with basal secretion or the number of TRL-apoB-48 secreted over the postprandial period. In the stepwise regression analysis, plasma PCSK9 was the best predictor of the total and incremental AUCs for plasma apoB-48 and the FCR of TRL-apoB-48. The association between plasma PCSK9 and apoC-III and TRL-apoB-48 FCR remained significant (P<0.05 in all) after adjusting for age, homoeostasis model assessment (HOMA) score, hepatic lipase or lipoprotein lipase (LPL). In a multiple regression model, 31% of variance in TRL-apoB-48 FCR was accounted for by plasma PCSK9 and apoC-III concentrations (adjusted R2=0.306, P<0.05). However, their associations with TRL-apoB-48 FCR were not independent of each other. Our results suggest that the catabolism of TRL-apoB-48 in the postprandial state may be co-ordinated by PCSK9 and apoC-III in obese individuals.
Assuntos
Apolipoproteína B-48/sangue , Apolipoproteína C-III/sangue , Obesidade/sangue , Período Pós-Prandial/fisiologia , Pró-Proteína Convertases/sangue , Serina Endopeptidases/sangue , Idoso , Apolipoproteína C-III/fisiologia , Transporte Biológico/fisiologia , Deutério , Gorduras na Dieta/administração & dosagem , Feminino , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Obesidade/fisiopatologia , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/fisiologia , Serina Endopeptidases/fisiologiaRESUMO
OBJECTIVE: To investigate the effect of extended-release (ER) niacin on the metabolism of high-density lipoprotein (HDL) apolipoprotein A-I (apoA-I) in men with type 2 diabetes mellitus on a background of optimal statin therapy. APPROACH AND RESULTS: Twelve men with type 2 diabetes mellitus were recruited for a randomized, crossover design trial. Patients were randomized to rosuvastatin or rosuvastatin plus ER niacin for 12 weeks and then crossed over to the alternate therapy after a 3-week washout period. Metabolic studies were performed at the end of each treatment period. HDL apoA-I kinetics were measured after a standardized liquid mixed meal and a bolus injection of d3-leucine for 96 hours. Compartmental analysis was used to model the data. ER niacin significantly decreased plasma triglyceride, plasma cholesterol, non-HDL cholesterol, low-density lipoprotein cholesterol, and apoB (all P<0.05) and significantly increased HDL cholesterol and apoA-I concentrations (P<0.005 and P<0.05, respectively). ER niacin also significantly increased HDL apoA-I pool size (6,088 ± 292 versus 5,675 ± 305 mg; P<0.001), and this was attributed to a lower HDL apoA-I fractional catabolic rate (0.33 ± 0.01 versus 0.37 ± 0.02 pools/d; P<0.005), with no significant changes in HDL apoA-I production (20.93 ± 0.63 versus 21.72 ± 0.85 mg/kg per day; P=0.28). CONCLUSIONS: ER niacin increases HDL apoA-I concentration in statin-treated subjects with type 2 diabetes mellitus by lowering apoA-I fractional catabolic rate. The effect on HDL metabolism was independent of the reduction in plasma triglyceride with ER niacin treatment. Whether this finding applies to other dyslipidemic populations remains to be investigated.
Assuntos
Apolipoproteína A-I/sangue , Diabetes Mellitus Tipo 2/complicações , Dislipidemias/tratamento farmacológico , Fluorbenzenos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/uso terapêutico , Niacina/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Apolipoproteínas B/sangue , Biomarcadores/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos Cross-Over , Preparações de Ação Retardada , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/diagnóstico , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Rosuvastatina Cálcica , Resultado do Tratamento , Triglicerídeos/sangue , Regulação para Cima , Austrália OcidentalRESUMO
PURPOSE OF REVIEW: Dyslipidemia is a powerful risk factor for cardiovascular disease (CVD). Dietary fatty acid composition regulates lipids and lipoprotein metabolism and may confer CVD benefit. This review updates understanding of the effect of dietary fatty acids on lipoprotein metabolism in humans. RECENT FINDINGS: High dietary fish-derived n-3 polyunsaturated fatty acid (PUFA) consumption diminished hepatic triglyceride-rich lipoprotein (TRL) secretion and enhanced TRL to LDL conversion. n-3 PUFA also decreased TRL-apoB-48 concentration by decreasing TRL-apoB-48 secretion. High n-6 PUFA intake decreased liver fat, and plasma proprotein convertase subtilisin/kexin type 9, triglycerides, total-cholesterol and LDL-cholesterol concentrations. Intake of saturated fatty acids with increased palmitic acid at the sn-2 position was associated with decreased postprandial lipemia, which might be due to decreased triglyceride absorption. Replacing carbohydrate with monounsaturated fatty acids increased TRL catabolism. Ruminant trans-fatty acid decreased HDL cholesterol, but the mechanisms are unknown. A new role for APOE genotype in regulating lipid responses was also described. SUMMARY: The major advances in understanding the effect of dietary fatty acids on lipoprotein metabolism have focused on n-3 PUFA. This knowledge provides insights into the importance of regulating lipoprotein metabolism as a mode to improve plasma lipids and potential CVD risk. Further studies are required to better understand the cardiometabolic effects of other dietary fatty acids.
Assuntos
Doenças Cardiovasculares/metabolismo , Dislipidemias/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Fígado/metabolismo , Animais , Apolipoproteína B-48/sangue , Apolipoproteína B-48/genética , Doenças Cardiovasculares/dietoterapia , Doenças Cardiovasculares/etiologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/complicações , Dislipidemias/dietoterapia , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas/sangue , Lipoproteínas/genética , Fígado/efeitos dos fármacos , Triglicerídeos/sangue , Triglicerídeos/genéticaRESUMO
Increased arterial stiffness is associated with enhanced risk of cardiovascular disease in obese individuals. Whether n3 fatty acid ethyl ester (FAEE) supplementation improves arterial stiffness in obese participants on a weight loss diet has not yet been investigated. The objective of the study was to carry out a 12-wk randomized, single-blind trial to test the effect of a 25% energy deficit weight loss diet alone (WL) (n = 12) or WL plus 4 g/d Omacor (46% EPA and 38% DHA) supplementation (WL+FAEE) (n = 13) on arterial elasticity in obese adults. Large (C1) and small artery elasticity (C2) were measured by pulse contour analysis of the radial artery. WL alone reduced (P < 0.05 in all) body weight (-3%), waist circumference (-4%), systolic (-3%) and diastolic (-3%) blood pressures, cardiac output (-4%), plasma TG concentration (-25%), and the homeostasis model assessment (HOMA) score (-12%) and increased plasma HDL cholesterol (+9%) and adiponectin (+18%) concentrations. However, WL alone did not alter C1 and C2. The WL+FAEE intervention significantly reduced body weight (-4%), waist circumference (-4%), systolic (-8%) and diastolic (-5%) blood pressures, pulse pressure (-5%), heart rate (-8%), plasma TG concentration (-36%), and HOMA score (-12%) and increased stroke volume (+3%), plasma HDL cholesterol (+6%) and adiponectin concentrations (+28%), and C1 (+20%) and C2 (+22%) artery elasticity. The changes in systolic blood pressure, heart rate, plasma TGs, C1, and C2 were significantly greater in the WL+FAEE group than in the WL group. Supplementation with n3 FAEEs improves C1 and C2 independently of weight loss in obese adults.
Assuntos
Dieta Redutora , Ácidos Graxos Ômega-3/administração & dosagem , Obesidade/dietoterapia , Obesidade/fisiopatologia , Rigidez Vascular/efeitos dos fármacos , Adiponectina/sangue , Adolescente , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Restrição Calórica , HDL-Colesterol/sangue , Suplementos Nutricionais , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Artéria Radial , Método Simples-Cego , Volume Sistólico/efeitos dos fármacos , Triglicerídeos/sangue , Circunferência da Cintura/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos , Redução de Peso/fisiologiaRESUMO
Dysregulated VLDL-TAG (very-low-density lipoprotein triacylglycerol) metabolism in obesity may account for hypertriacylglycerolaemia and increased cardiovascular disease. ω-3 FAEEs (omega-3 fatty acid ethyl esters) decrease plasma TAG and VLDL concentrations, but the mechanisms are not fully understood. In the present study, we carried out a 6-week randomized, placebo-controlled study to examine the effect of high-dose ω-3 FAEE supplementation (3.2 g/day) on the metabolism of VLDL-TAG in obese men using intravenous administration of d5-glycerol. We also explored the relationship of VLDL-TAG kinetics with the metabolism of VLDL-apo (apolipoprotein) B-100 and HDL (high-density lipoprotein)-apoA-I. VLDL-TAG isotopic enrichment was measured using gas chromatography-mass spectrometry. Kinetic parameters were derived using a multicompartmental model. Compared with placebo, ω-3 FAEE supplementation significantly lowered plasma concentrations of total (-14%, P<0.05) and VLDL-TAG (-32%, P<0.05), as well as hepatic secretion of VLDL-TAG (-32%, P<0.03). The FCR (fractional catabolic rate) of VLDL-TAG was not altered by ω-3 FAEEs. There was a significant association between the change in secretion rates of VLDL-TAG and VLDL-apoB-100 (r=0.706, P<0.05). However, the change in VLDL-TAG secretion rate was not associated with change in HDL-apoA-I FCR (r=0.139, P>0.05). Our results suggest that the TAG-lowering effect of ω-3 FAEEs is associated with the decreased VLDL-TAG secretion rate and hence lower plasma VLDL-TAG concentration in obesity. The changes in VLDL-TAG and apoB-100 kinetics are closely coupled.
Assuntos
Ácidos Graxos Ômega-3/uso terapêutico , Lipoproteínas VLDL/metabolismo , Obesidade Abdominal/dietoterapia , Triglicerídeos/sangue , Apolipoproteínas/metabolismo , Suplementos Nutricionais , Ésteres , Humanos , Lipoproteínas HDL/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/sangue , Triglicerídeos/metabolismoRESUMO
OBJECTIVE: We investigated the impact of lipoprotein lipase (LPL) gene mutations on apolipoprotein B (apoB)-100 metabolism. METHODS AND RESULTS: We studied 3 subjects with familial LPL deficiency; 14 subjects heterozygous for the LPL gene mutations Gly188Glu, Trp64Stop, and Ile194Thr; and 10 control subjects. Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL)-apoB-100 kinetics were determined in the fed state using stable isotope methods and compartmental modeling. Compared with controls, familial LPL deficiency had markedly elevated plasma triglycerides and lower VLDL-apoB-100 fractional catabolic rate (FCR), IDL-apoB-100 FCR, VLDL-to-IDL conversion, and VLDL-apoB-100 production rate (P<0.01). Compared with controls, Gly188Glu had higher plasma triglyceride and VLDL- and IDL-apoB-100 concentrations and lower VLDL- and IDL-apoB-100 FCR (P<0.05). Plasma triglycerides were not different, but IDL-apoB-100 concentration and production rate and VLDL-to-IDL conversion were lower in Trp64Stop compared with controls (P<0.05). No differences between controls and Ile194Thr were observed. CONCLUSIONS: Our results confirm that hypertriglyceridemia is a key feature of familial LPL deficiency. This is due to impaired VLDL- and IDL-apoB-100 catabolism and VLDL-to-IDL conversion. Single-allele mutations of the LPL gene result in modest to elevated plasma triglycerides. The changes in plasma triglycerides and apoB-100 kinetics are attributable to the effects of the LPL genotype.
Assuntos
Apolipoproteína B-100/metabolismo , Heterozigoto , Homozigoto , Lipase Lipoproteica/genética , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Mutação/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/metabolismo , Lipase Lipoproteica/deficiência , Lipoproteínas IDL/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas VLDL/metabolismo , Masculino , Doenças Metabólicas/complicações , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
PURPOSE OF REVIEW: There has been a resurgence of interest in the role of triglyceride-rich lipoproteins in the development of atherosclerosis and cardiovascular disease, and this is particularly relevant to diabetes mellitus and the postprandial state. RECENT FINDINGS: Recent evidence suggests that insulin resistance in diabetes induces postprandial dyslipidemia by increasing the enterocytic production of chylomicrons and their remnant particles, but an impaired clearance capacity is also involved. Postprandial dyslipidaemia in diabetes induces oxidative stress, inflammation and endothelial dysfunction and this may be compounded by dysglycaemia. New guidelines for managing hypertriglyceridaemia in diabetes have been published, first-line therapies being improved glycaemic control, treatment of other secondary causes of dyslipidaemia and statin therapy, followed by judicious use of fibrates, n-3 fatty acids or niacin. A new role for incretin-based therapies in regulating dyslipidaemia has been identified. SUMMARY: Postprandial dyslipidaemia is a pivotal mechanism whereby diabetes can induce and accelerate atherosclerosis. Regulating the plasma concentrations of triglyceride-rich lipoproteins may decrease the cardiovascular complications of diabetes. The mechanisms of action of incretin-based treatments on dyslipidaemia and endothelial dysfunction need further investigation. The efficacy of new therapies targeted at postprandial dysmetabolism in diabetes need to be confirmed, against best current levels of care, in clinical endpoint trials.
Assuntos
Complicações do Diabetes/terapia , Dislipidemias/terapia , Período Pós-Prandial , Aterosclerose/complicações , Complicações do Diabetes/complicações , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/epidemiologia , Dislipidemias/complicações , Dislipidemias/epidemiologia , HumanosRESUMO
We examined the effects of fenofibrate and atorvastatin on very low density lipoprotein (VLDL) apolipoprotein (apo)E metabolism in the metabolic syndrome (MetS). We studied 11 MetS men in a randomized, double-blind, crossover trial. VLDL-apoE kinetics were examined using stable isotope methods and compartmental modeling. Compared with placebo, fenofibrate (200 mg/day) and atorvastatin (40 mg/day) decreased plasma apoE concentrations (P < 0.05). Fenofibrate decreased VLDL-apoE concentration and production rate (PR) and increased VLDL-apoE fractional catabolic rate (FCR) compared with placebo (P < 0.05). Compared with placebo, atorvastatin decreased VLDL-apoE concentration and increased VLDL-apoE FCR (P < 0.05). Fenofibrate and atorvastatin had comparable effects on VLDL-apoE concentration. The increase in VLDL-apoE FCR with fenofibrate was 22% less than that with atorvastatin (P < 0.01). With fenofibrate, the change in VLDL-apoE concentration was positively correlated with change in VLDL-apoB concentration, and negatively correlated with change in VLDL-apoB FCR. In MetS, fenofibrate and atorvastatin decreased plasma apoE concentrations. Fenofibrate decreased VLDL-apoE concentration by lowering VLDL-apoE production and increasing VLDL-apoE catabolism. By contrast, atorvastatin decreased VLDL-apoE concentration chiefly by increasing VLDL-apoE catabolism. Our study provides new insights into the mechanisms of action of two different lipid-lowering therapies on VLDL-apoE metabolism in MetS.
Assuntos
Apolipoproteínas E/metabolismo , Fenofibrato/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Lipoproteínas VLDL/metabolismo , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Pirróis/uso terapêutico , Adulto , Apolipoproteínas B/sangue , Apolipoproteínas B/metabolismo , Apolipoproteínas E/sangue , Atorvastatina , Método Duplo-Cego , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteínas VLDL/sangue , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-IdadeRESUMO
The effects of Therapeutic Lifestyle Change (TLC) diets, low and high in dietary fish, on apolipoprotein metabolism were examined. Subjects were provided with a Western diet for 6 weeks, followed by 24 weeks of either of two TLC diets (10/group). Apolipoprotein kinetics were determined in the fed state using stable isotope methods and compartmental modeling at the end of each phase. Only the high-fish diet decreased median triglyceride-rich lipoprotein (TRL) apoB-100 concentration (-23%), production rate (PR, -9%), and direct catabolism (-53%), and increased TRL-to-LDL apoB-100 conversion (+39%) as compared with the baseline diet (all P < 0.05). This diet also decreased TRL apoB-48 concentration (-24%), fractional catabolic rate (FCR, -20%), and PR (-50%) as compared with the baseline diet (all P < 0.05). The high-fish and low-fish diets decreased LDL apoB-100 concentration (-9%, -23%), increased LDL apoB-100 FCR (+44%, +48%), and decreased HDL apoA-I concentration (-15%, -14%) and PR (-11%, -12%) as compared with the baseline diet (all P < 0.05). On the high-fish diet, changes in TRL apoB-100 PR were negatively correlated with changes in plasma eicosapentaenoic and docosahexaenoic acids. In conclusion, the high-fish diet decreased TRL apoB-100 and TRL apoB-48 concentrations chiefly by decreasing their PR. Both diets decreased LDL apoB-100 concentration by increasing LDL apoB-100 FCR and decreased HDL apoA-I concentration by decreasing HDL apoA-I PR.
Assuntos
Dieta , Gorduras Insaturadas na Dieta/análise , Peixes , Estilo de Vida , Lipoproteínas/metabolismo , Adulto , Idoso , Animais , Gorduras Insaturadas na Dieta/sangue , Jejum , Ácidos Graxos Ômega-3/farmacologia , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-IdadeRESUMO
Cholesteryl ester transfer protein (CETP) facilitates the transfer of HDL cholesteryl ester to triglyceride-rich lipoproteins (TRL). This study aimed to determine the effects of CETP inhibition with torcetrapib on TRL composition and apoB-48 metabolism. Study subjects with low HDL cholesterol (<40 mg/dl), either untreated (n = 9) or receiving atorvastatin 20 mg daily (n = 9), received placebo for 4 weeks, followed by torcetrapib 120 mg once daily for the next 4 weeks. A subset of the subjects not treated with atorvastatin participated in a third phase (n = 6), in which they received torcetrapib 120 mg twice daily for an additional 4 weeks. At the end of each phase, all subjects received a primed-constant infusion of [5,5,5-(2)H(3)]L-leucine, while in the constantly fed state, to determine the kinetics of TRL apoB-48 and TRL composition. Relative to placebo, torcetrapib markedly reduced TRL CE levels in all groups (≥-69%; P < 0.005). ApoB-48 pool size (PS) and production rate (PR) decreased in the nonatorvastatin once daily (PS: -49%, P = 0.007; PR: -49%, P = 0.005) and twice daily (PS: -30%, P = 0.01; PR: -27%, P = 0.13) cohorts. In the atorvastatin cohort, apoB-48 PS and PR, which were already lowered by atorvastatin, did not change with torcetrapib. Our findings indicate that CETP inhibition reduced plasma apoB-48 concentrations by reducing apoB-48 production but did not have this effect in subjects already treated with atorvastatin.
Assuntos
Apolipoproteína B-48/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Lipoproteínas/química , Lipoproteínas/metabolismo , Triglicerídeos , Apolipoproteína B-48/sangue , Feminino , Humanos , Cinética , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Quinolinas/farmacologiaRESUMO
AIMS: Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose-response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid. METHODS AND RESULTS: Bempedoic acid and statin dosing and LDL-C data were pooled from 14 phase 1-3 clinical studies. Dose-response models were developed for bempedoic acid monotherapy and bempedoic acid-statin combinations using previously published statin parameters. Simulations were performed using these models to predict change in LDL-C levels following treatment with bempedoic acid combined with clinically relevant doses of atorvastatin, rosuvastatin, simvastatin, and pravastatin. Dose-response models predicted that combining bempedoic acid with the lowest statin dose of commonly used statins would achieve a similar degree of LDL-C lowering as quadrupling that statin dose; for example, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and 42% with simvastatin 40 mg compared with 46% with simvastatin 10 mg + bempedoic acid 180 mg. CONCLUSION: These findings suggest bempedoic acid combined with lower statin doses offers similar LDL-C lowering compared with statin monotherapy at higher doses, potentially sparing patients requiring additional lipid-lowering therapies from the adverse events associated with higher statin doses.