RESUMEN
INTRODUCTION: The prevalence of hypertriglyceridemia (HTG) is increasing. Elevated triglyceride (TG) levels are associated with an increased cardiovascular disease (CVD) risk. Moreover, severe HTG results in an elevated risk of pancreatitis, especially in severe HTG with an up to 350-fold increased risk. Both problems emphasize the clinical need for effective TG lowering. AREAS COVERED: The purpose of this review is to discuss the currently available therapies and to elaborate the most promising novel therapeutics for TG lowering. EXPERT OPINION: Conventional lipid lowering strategies do not efficiently lower plasma TG levels, leaving a residual CVD and pancreatitis risk. Both apolipoprotein C-III (apoC-III) and angiopoietin-like 3 (ANGPTL3) are important regulators in TG-rich lipoprotein (TRL) metabolism. Several novel agents targeting these linchpins have ended phase II/III trials. Volanesorsen targeting apoC-III has shown reductions in plasma TG levels up to 90%. Multiple ANGPLT3 inhibitors (evinacumab, IONIS-ANGPTL3-LRx, ARO-ANG3) effectuate TG reductions up to 70% with concomitant potent reduction in all other apoB containing lipoprotein fractions. We expect these therapeutics to become players in the treatment for (especially) severe HTG in the near future.
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Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Apolipoproteína C-III/efectos de los fármacos , Hipertrigliceridemia/tratamiento farmacológico , Proteína 3 Similar a la Angiopoyetina , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Ensayos Clínicos como Asunto , Humanos , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/metabolismo , Lipoproteínas/metabolismo , Oligonucleótidos/farmacología , Oligonucleótidos/uso terapéutico , Pancreatitis/etiología , Pancreatitis/prevención & controlRESUMEN
OBJECTIVE: ApoC-III (apolipoprotein C-III) glycosylation can predict cardiovascular disease risk. Higher abundance of disialylated (apoC-III2) over monosialylated (apoC-III1) glycoforms is associated with lower plasma triglyceride levels. Yet, it remains unclear whether apoC-III glycosylation impacts TRL (triglyceride-rich lipoprotein) clearance and whether apoC-III antisense therapy (volanesorsen) affects distribution of apoC-III glycoforms. Approach and Results: To measure the abundance of human apoC-III glycoforms in plasma over time, human TRLs were injected into wild-type mice and mice lacking hepatic TRL clearance receptors, namely HSPGs (heparan sulfate proteoglycans) or both LDLR (low-density lipoprotein receptor) and LRP1 (LDLR-related protein 1). ApoC-III was more rapidly cleared in the absence of HSPG (t1/2=25.4 minutes) than in wild-type animals (t1/2=55.1 minutes). In contrast, deficiency of LDLR and LRP1 (t1/2=56.1 minutes) did not affect clearance of apoC-III. After injection, a significant increase in the relative abundance of apoC-III2 was observed in HSPG-deficient mice, whereas the opposite was observed in mice lacking LDLR and LRP1. In patients, abundance of plasma apoC-III glycoforms was assessed after placebo or volanesorsen administration. Volanesorsen treatment correlated with a statistically significant 1.4-fold increase in the relative abundance of apoC-III2 and a 15% decrease in that of apoC-III1. The decrease in relative apoC-III1 abundance was strongly correlated with decreased plasma triglyceride levels in patients. CONCLUSIONS: Our results indicate that HSPGs preferentially clear apoC-III2. In contrast, apoC-III1 is more effectively cleared by LDLR/LRP1. Clinically, the increase in the apoC-III2/apoC-III1 ratio on antisense lowering of apoC-III might reflect faster clearance of apoC-III1 because this metabolic shift associates with improved triglyceride levels.
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Apolipoproteína C-III/sangre , Hipertrigliceridemia/tratamiento farmacológico , Lipoproteínas HDL3/metabolismo , Oligonucleótidos/administración & dosificación , Receptores de LDL/metabolismo , Animales , Apolipoproteína C-III/efectos de los fármacos , Modelos Animales de Enfermedad , Glicosilación/efectos de los fármacos , Humanos , Hipertrigliceridemia/sangre , Masculino , Ratones , Terapia Molecular Dirigida/métodos , Receptores de LDL/efectos de los fármacos , Valores de ReferenciaRESUMEN
AIMS: To investigate how apolipoprotein C-III (apoC-III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC-III, and whether improvement of glycaemic control using the glucagon-like peptide-1 analogue liraglutide for 16 weeks modifies apoC-III dynamics. MATERIALS AND METHODS: Postprandial apoC-III kinetics were assessed after a bolus injection of [5,5,5-2 H3 ]leucine using ultrasensitive mass spectrometry techniques. We compared apoC-III kinetics in two situations: in subjects with type 2 diabetes before and after liraglutide therapy, and in type 2 diabetic subjects with matched body mass index (BMI) non-diabetic subjects. Liver fat content, subcutaneous abdominal and intra-abdominal fat were determined using proton magnetic resonance spectroscopy. RESULTS: Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC-III secretion rate (561 ± 198 vs. 652 ± 196 mg/d, P = 0.03) and apoC-III levels (10.0 ± 3.8 vs. 11.7 ± 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC-III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC-III secretion rate was higher in subjects with type 2 diabetes compared with BMI-matched non-diabetic subjects (676 ± 208 vs. 505 ± 174 mg/d, P = 0.042). CONCLUSIONS: The results reveal that the secretion rate of apoC-III is associated with elevation of triglyceride-rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC-III.
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Apolipoproteína C-III/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Anciano , Apolipoproteína C-III/efectos de los fármacos , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dislipidemias/etiología , Femenino , Humanos , Hipoglucemiantes/farmacología , Liraglutida/farmacología , Masculino , Persona de Mediana Edad , Periodo Posprandial , Triglicéridos/sangreRESUMEN
Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden.
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Apolipoproteína C-III/genética , Lipoproteínas/metabolismo , Mutación Missense , Triglicéridos/metabolismo , Anciano , Animales , Anticuerpos Monoclonales/farmacología , Apolipoproteína C-III/efectos de los fármacos , Apolipoproteínas B/metabolismo , HDL-Colesterol/metabolismo , Cromatografía Liquida , Simulación por Computador , Enfermedad Coronaria/genética , Estudios Transversales , Femenino , Humanos , Immunoblotting , Metabolismo de los Lípidos/genética , Lipoproteínas/efectos de los fármacos , Lipoproteínas VLDL/metabolismo , Masculino , Espectrometría de Masas , Ratones , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Factores Protectores , Espectrometría de Masas en TándemRESUMEN
In the ILLUMINATE Trial, treatment with the cholesteryl ester transfer protein inhibitor torcetrapib resulted in a significant increase in both atherosclerotic cardiovascular disease events and total mortality which was not explained by changes in the routinely measured plasma lipids. To determine whether alterations in lipoproteins defined by their apoprotein content that are not estimated with conventional laboratory methods contributed to these unexpected events, we measured the apoB- and apoA-containing subclasses in a subgroup of ILLUMINATE participants. We find that torcetrapib treatment significantly increased the high-density lipoprotein subclasses LpA-I and LpA-I:A-II equally (p <0.0001) and the apoC-III content of high-density lipoprotein (p <0.001) without altering the apoB-containing subclasses. In conclusion, these findings provide further evidence that the untoward effects of torcetrapib were attributable to off-target effects and not related to disturbances in lipoprotein transport.
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Apolipoproteína C-III/sangre , Aterosclerosis/tratamiento farmacológico , Atorvastatina/administración & dosificación , Quinolinas/administración & dosificación , Anticolesterolemiantes/administración & dosificación , Apolipoproteína C-III/efectos de los fármacos , Apoproteínas/sangre , Aterosclerosis/sangre , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: The natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic LDL receptors (LDLRs); however, information on LDL metabolism in humans is limited. METHODS: Kinetics of autologous 125 I-LDL were determined in 12 male subjects at baseline and during treatment with CDCA (15 mg kg-1 day-1 ). In seven patients with gallstones treated with CDCA for 3 weeks before cholecystectomy, liver biopsies were collected and analysed for enzyme activities and for specific LDLR binding. Serum samples obtained before treatment and at surgery were analysed for markers of lipid metabolism, lipoproteins and the LDLR modulator proprotein convertase subtilisin/kexin type 9 (PCSK9). RESULTS: Chenodeoxycholic acid treatment increased plasma LDL cholesterol by ~10% as a result of reduced clearance of plasma LDL-apolipoprotein (apo)B; LDL production was somewhat reduced. The reduction in LDL clearance occurred within 1 day after initiation of treatment. In CDCA-treated patients with gallstones, hepatic microsomal cholesterol 7α-hydroxylase and HMG-CoA reductase activities were reduced by 83% and 54%, respectively, and specific LDLR binding was reduced by 20%. During treatment, serum levels of fibroblast growth factor 19 and total and LDL cholesterol increased, whereas levels of 7α-hydroxy-4-cholesten-3-one, lathosterol, PCSK9, apoA-I, apoC-III, lipoprotein(a), triglycerides and insulin were reduced. CONCLUSIONS: Chenodeoxycholic acid has a broad influence on lipid metabolism, including reducing plasma clearance of LDL. The reduction in circulating PCSK9 may dampen its effect on hepatic LDLRs and plasma LDL cholesterol. Further studies of the effects of other FXR agonists on cholesterol metabolism in humans seem warranted, considering the renewed interest for such therapy in liver disease and diabetes.
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Apolipoproteína C-III/efectos de los fármacos , Ácido Quenodesoxicólico/farmacología , LDL-Colesterol/efectos de los fármacos , Lipoproteína(a)/efectos de los fármacos , Proproteína Convertasa 9/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/agonistas , Apolipoproteína C-III/sangre , Ácido Quenodesoxicólico/uso terapéutico , LDL-Colesterol/sangre , Cálculos Biliares/tratamiento farmacológico , Humanos , Hígado/enzimología , Masculino , Proproteína Convertasa 9/sangre , Receptores de LDL/metabolismoRESUMEN
Apoprotein C-III (apoC-III), originating from the apoA-I/C-III/A-IV gene cluster affected by multiple regulating factors, has been demonstrated to have a validated link with hypertriglyceridemia in humans. Following genome studies establishing the impact of apoC-III on both plasma triglyceride (TG) level and cardiovascular disease (CVD), apoC-III offers us a novel explanation attempting to resolve the long-existing confusion with regard to the atherogenic effect of TG. Notably, apoC-III exerts its atherogenic effect by means of not only intervening in the function and metabolism of various lipid molecules, but also accelerating pro-inflammatory effects between monocytes and endothelial cells. Data have suggested that diabetes, a common endocrine disease, also correlates closely with apoC-III in its apoptosis process of islet ßcells. In fact, apoC-III genes, with various mutations among individuals, are also found to have relevance to other diseases, including fatty liver disease. Fortunately, besides present day therapeutic strategies, such as lifestyle changes and lipid-lowering drug treatments, a promising new antisense drug specifically targeting on apoC-III gene expression opens up new avenues. This article mainly summarizes the clinical implication of apoC-III and its future directions of treatment.
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Apolipoproteína C-III/fisiología , Elementos sin Sentido (Genética)/uso terapéutico , Apolipoproteína C-III/sangre , Apolipoproteína C-III/efectos de los fármacos , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/terapia , Susceptibilidad a Enfermedades/sangre , HumanosRESUMEN
The comprehensive structure-activity relationships of triantennary GalNAc conjugated ASOs for enhancing potency via ASGR mediated delivery to hepatocytes is reported. Seventeen GalNAc clusters were assembled from six distinct scaffolds and attached to ASOs. The resulting ASO conjugates were evaluated in ASGR binding assays, in primary hepatocytes, and in mice. Five structurally distinct GalNAc clusters were chosen for more extensive evaluation using ASOs targeting SRB-1, A1AT, FXI, TTR, and ApoC III mRNAs. GalNAc-ASO conjugates exhibited excellent potencies (ED50 0.5-2 mg/kg) for reducing the targeted mRNAs and proteins. This work culminated in the identification of a simplified tris-based GalNAc cluster (THA-GN3), which can be efficiently assembled using readily available starting materials and conjugated to ASOs using a solution phase conjugation strategy. GalNAc-ASO conjugates thus represent a viable approach for enhancing potency of ASO drugs in the clinic without adding significant complexity or cost to existing protocols for manufacturing oligonucleotide drugs.
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Acetilgalactosamina/síntesis química , Acetilgalactosamina/farmacología , Hepatocitos/efectos de los fármacos , Oligonucleótidos Antisentido/síntesis química , Oligonucleótidos Antisentido/farmacología , Animales , Apolipoproteína C-III/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Factor XI/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores Depuradores de Clase B/biosíntesis , Receptores Depuradores de Clase B/genética , Relación Estructura-ActividadRESUMEN
Antisense oligonucleotides (ASOs) are short synthetic analogues of natural nucleic acids designed to specifically bind to a target messenger RNA (mRNA) by Watson-Crick hybridization, inducing selective degradation of the mRNA or prohibiting translation of the selected mRNA into protein. Antisense technology has the ability to inhibit unique targets with high specificity and can be used to inhibit synthesis of a wide range of proteins that could influence lipoprotein levels and other targets. A number of different classes of antisense agents are under development. To date, mipomersen, a 2'-O-methoxyethyl phosphorothioate 20-mer ASO, is the most advanced ASO in clinical development. It is a second-generation ASO developed to inhibit the synthesis of apolipoprotein B (apoB)-100 in the liver. In Phase 3 clinical trials, mipomersen has been shown to significantly reduce plasma low-density lipoprotein cholesterol (LDL-c) as well as other atherogenic apoB containing lipoproteins such as lipoprotein (a) [Lp(a)] and small-dense LDL particles. Although concerns have been raised because of an increase in intrahepatic triglyceride content, preliminary data from long-term studies suggest that with continued treatment, liver fat levels tend to stabilize or decline. Further studies are needed to evaluate potential clinical relevance of these changes. Proprotein convertase subtilisin/kexin-9 (PCSK9) is another promising novel target for lowering LDL-c by ASOs. Both second-generation ASOs and ASOs using locked nucleic acid technology have been developed to inhibit PCSK9 and are under clinical development. Other targets currently being addressed include apoC-III and apo(a) or Lp(a). By directly inhibiting the synthesis of specific proteins, ASO technology offers a promising new approach to influence the metabolism of lipids and to control lipoprotein levels. Its application to a wide variety of potential targets can be expected if these agents prove to be clinically safe and effective.
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Dislipidemias/terapia , Oligonucleótidos Antisentido/uso terapéutico , Animales , Apolipoproteína B-100/efectos de los fármacos , Apolipoproteína B-100/fisiología , Apolipoproteína C-III/efectos de los fármacos , Apolipoproteína C-III/fisiología , Apoproteína(a)/efectos de los fármacos , Apoproteína(a)/fisiología , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Haplorrinos , Humanos , Hipolipemiantes/administración & dosificación , Hipolipemiantes/efectos adversos , Hipolipemiantes/farmacología , Ratones , Oligonucleótidos/administración & dosificación , Oligonucleótidos/efectos adversos , Oligonucleótidos/farmacología , Oligonucleótidos Antisentido/farmacología , Proproteína Convertasa 9 , Proproteína Convertasas/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Serina Endopeptidasas/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: To delineate the hypotriglyceridemic effect of conjugated linoleic acid (CLA) in mice, the effect of this fatty acid on lipoprotein lipase (LPL) and apolipoprotein C-III (ApoCIII) mRNA accumulation in muscle, adipose and liver tissue was studied. METHODS: CD-1 mice were housed in groups of 6 and randomized to one of three experimental diets for 3 weeks: SUC: 65% sucrose by weight; CLA: 1% CLA oil (34.4% c9,t11; 35.1% t10,c12 and 4.1% other conjugated isomers) and 65% sucrose, and DEX: 65% dextrose, as a control. RESULTS: LPL mRNA levels in muscle tissue were increased in the DEX group and in the CLA group (240% increase) compared with the SUC group. In contrast, LPL mRNA levels were 81% lower in epididymal adipose tissue from the CLA group compared with the SUC group. There was no effect of dietary treatments on ApoCIII mRNA accumulation in the liver. CONCLUSIONS: These data suggest that dietary CLA may induce partitioning of circulating triglycerides to muscle tissue, preventing their accumulation in adipocytes.
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Apolipoproteína C-III/metabolismo , Ácidos Linoleicos Conjugados/farmacología , Lipoproteína Lipasa/metabolismo , ARN Mensajero/metabolismo , Triglicéridos/metabolismo , Tejido Adiposo/química , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Apolipoproteína C-III/efectos de los fármacos , Apolipoproteína C-III/genética , Colesterol/sangre , Sacarosa en la Dieta/administración & dosificación , Sacarosa en la Dieta/farmacología , Epidídimo/química , Epidídimo/efectos de los fármacos , Epidídimo/metabolismo , Ácidos Grasos Volátiles/sangre , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucosa/administración & dosificación , Hipertrigliceridemia/sangre , Ácidos Linoleicos Conjugados/administración & dosificación , Lipoproteína Lipasa/efectos de los fármacos , Lipoproteína Lipasa/genética , Hígado/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Músculo Esquelético/química , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , ARN Mensajero/efectos de los fármacos , Distribución Aleatoria , Triglicéridos/sangreRESUMEN
BACKGROUND: Plasma apolipoprotein B (apo B) and VLDL and LDL with apolipoprotein C-III (apo C-III) are independent risk factors for cardiovascular disease (CVD). Dietary intake affects lipoprotein concentration and composition related to those apolipoproteins. OBJECTIVE: We studied differences in apo B lipoproteins with and without apo C-III after 3 healthy diets based on the Dietary Approaches to Stop Hypertension Trial diet. DESIGN: Healthy participants (n = 162) were fed each of 3 healthy diets for 6 wk in a crossover design. Diets differed by emphasis of either carbohydrate (Carb), unsaturated fat (Unsat), or protein (Prot). Blood was collected at baseline and after diets for analysis. RESULTS: Compared with the Carb diet, the Prot diet reduced plasma apo B and triglycerides in VLDL with apo C-III (16%, P = 0.07; 11%, P = 0.05, respectively) and apo B in LDL with apo C-III (16%, P = 0.04). Compared with the Unsat diet, the Prot diet reduced triglycerides in VLDL with apo C-III (16%, P = 0.02). Compared with baseline (subjects' usual diet was higher in saturated fat), the Prot diet reduced apo B in LDL with apo C-III (11%, P = 0.05), and all 3 diets reduced plasma total apo B (6-10%, P < 0.05) and apo B in the major type of LDL, LDL without apo C-III (8-10%, P < 0.01). All 3 diets reduced the ratio of apo C-III to apo E in VLDL. CONCLUSIONS: Substituting protein for carbohydrate in the context of a healthy dietary pattern reduced atherogenic apo C-III-containing LDL and its precursor, apo C-III-containing VLDL, resulting in the most favorable profile of apo B lipoproteins. In addition, compared with a typical high-saturated fat diet, healthy diets that emphasize carbohydrate, protein, or unsaturated fat reduce plasma total and LDL apo B and produce a lower more metabolically favorable ratio of apo C-III to apo E.
Asunto(s)
Apolipoproteínas B/sangre , Carbohidratos de la Dieta , Grasas Insaturadas en la Dieta , Proteínas en la Dieta , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , Adulto , Apolipoproteína C-III/sangre , Apolipoproteína C-III/efectos de los fármacos , Apolipoproteínas B/efectos de los fármacos , Proteínas Sanguíneas/metabolismo , Estudios Cruzados , Ingestión de Energía , Humanos , Lípidos/sangre , Lipoproteínas LDL/efectos de los fármacos , Lipoproteínas VLDL/efectos de los fármacos , Masculino , National Heart, Lung, and Blood Institute (U.S.) , Estados UnidosRESUMEN
OBJECTIVE: Dysregulated apolipoprotein (apo)C-III metabolism may account for hypertriglyceridemia and increased cardiovascular risk in the metabolic syndrome. This study investigated the dose-dependent effect of rosuvastatin on VLDL apoC-III transport in men with the metabolic syndrome. RESEARCH DESIGN AND METHODS: Twelve men with the metabolic syndrome were studied in a randomized double-blind crossover trial of 5-week intervention periods with placebo, 10 mg rosuvastatin, or 40 mg rosuvastatin, with 2-week placebo washouts between each period. VLDL apoC-III kinetics were examined using a stable isotope method and compartmental modeling at the end of each intervention period. RESULTS: Compared with placebo, there was a significant dose-dependent reduction with rosuvastatin in plasma triglyceride and VLDL apoC-III concentrations. Rosuvastatin significantly (P < 0.05) increased VLDL apoC-III fractional catabolic rate (FCR) and decreased its production rate, with a significant (P < 0.05) dose-related effect. With 40 mg rosuvastatin, changes in VLDL apoC-III concentration were inversely associated with changes in VLDL apoC-III FCR and positively associated with VLDL apoC-III production rate (P < 0.05). Changes in VLDL apoC-III concentration and production rate were positively correlated with changes in VLDL apoB concentration and production rate and inversely correlated with VLDL apoB FCR (P < 0.05). Similar associations were observed with 10 mg rosuvastatin but were either less or not statistically significant. CONCLUSIONS: In this study, rosuvastatin decreased the production and increased the catabolism of VLDL apoC-III, a mechanism that accounted for the significant reduction in VLDL apoC-III and triglyceride concentrations. This has implications for the management of cardiometabolic risk in obese subjects with the metabolic syndrome.