RESUMEN
The neutral result of the PROMINENT trial has led to questions about the future for pemafibrate. This commentary discusses possible reasons for the lack of benefit observed in the trial. There were, however, indicators suggesting therapeutic potential in microvascular ischaemic complications associated with peripheral artery disease, with subsequent analysis showing reduction in the incidence of lower extremity ischaemic ulceration or gangrene. Reassurance about the safety of pemafibrate, together with emerging data from PROMINENT and experimental studies, also suggest benefit with pemafibrate in non-alcoholic fatty liver disease (alternatively referred to as metabolic dysfunction-associated steatotic liver disease) and microangiopathy associated with diabetes, which merit further study.
Asunto(s)
Benzoxazoles , Butiratos , Animales , Humanos , Benzoxazoles/uso terapéutico , Benzoxazoles/efectos adversos , Butiratos/uso terapéutico , Butiratos/efectos adversos , Hipolipemiantes/uso terapéutico , Hipolipemiantes/efectos adversos , Isquemia/tratamiento farmacológico , Isquemia/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad Arterial Periférica/tratamiento farmacológico , Factores de Riesgo , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: Adoption of poor lifestyles (inactivity and energy-dense diets) has driven the worldwide increase in the metabolic syndrome, type 2 diabetes mellitus and non-alcoholic steatohepatitis (NASH). Of the defining features of the metabolic syndrome, an atherogenic dyslipidaemia characterised by elevated triglycerides (TG) and low plasma concentration of high-density lipoprotein cholesterol is a major driver of risk for atherosclerotic cardiovascular disease. Beyond lifestyle intervention and statins, targeting the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) is a therapeutic option. However, current PPARα agonists (fibrates) have limitations, including safety issues and the lack of definitive evidence for cardiovascular benefit. Modulating the ligand structure to enhance binding at the PPARα receptor, with the aim of maximising beneficial effects and minimising adverse effects, underlies the SPPARMα concept. RECENT FINDINGS: This review discusses the history of SPPARM development, latterly focusing on evidence for the first licensed SPPARMα, pemafibrate. Evidence from animal models of hypertriglyceridaemia or NASH, as well as clinical trials in patients with atherogenic dyslipidaemia, are overviewed. The available data set the scene for therapeutic application of SPPARMα in the metabolic syndrome, and possibly, NASH. The outstanding question, which has so far eluded fibrates in the setting of current evidence-based therapy including statins, is whether treatment with pemafibrate significantly reduces cardiovascular events in patients with atherogenic dyslipidaemia. The PROMINENT study in patients with type 2 diabetes mellitus and this dyslipidaemia is critical to evaluating this.
Asunto(s)
Benzoxazoles/uso terapéutico , Butiratos/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/metabolismo , PPAR alfa/metabolismo , Animales , HumanosRESUMEN
PURPOSE OF REVIEW: Chronic kidney disease (CKD) poses a major global challenge, which is exacerbated by aging populations and the pandemic of type 2 diabetes mellitus. Much of the escalating burden of CKD is due to cardiovascular complications. Current treatment guidelines for dyslipidemia in CKD prioritize low-density lipoprotein cholesterol management, but still leave a high residual cardiovascular risk. Targeting elevated triglycerides and low plasma high-density lipoprotein cholesterol, a common feature of CKD, could offer additional benefit. There are, however, safety issues with current fibrates (peroxisome proliferator-activated receptor alpha [PPARα] agonists), notably the propensity for elevation in serum creatinine, indicating the need for new approaches. RECENT FINDINGS: Interactions between the ligand and PPARα receptor influence the specificity and potency of receptor binding, and downstream gene and physiological effects. The peroxisome proliferator-activated receptor alpha modulator (SPPARMα) concept aims to modulate the ligand structure so as to enhance binding at the PPARα receptor, thereby improving the ligand's selectivity, potency, and safety profile. This concept has led to the development of pemafibrate, a novel SPPARMα agent. This review discusses evidence that differentiates pemafibrate from current fibrates, especially the lack of evidence for elevation in serum creatinine or worsening of renal function in high-risk patients, including those with CKD. Differentiation of pemafibrate from current fibrates aims to address unmet clinical needs in CKD. The ongoing PROMINENT study will provide critical information regarding the long-term efficacy and safety of pemafibrate in patients with type 2 diabetes mellitus, including those with CKD, and whether the favorable lipid-modifying profile translates to reduction in residual cardiovascular risk.
Asunto(s)
Benzoxazoles/efectos adversos , Butiratos/efectos adversos , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dislipidemias/complicaciones , Dislipidemias/tratamiento farmacológico , Ácidos Fíbricos/uso terapéutico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Animales , Benzoxazoles/química , Butiratos/química , Enfermedades Cardiovasculares/sangre , Ácidos Fíbricos/química , Ácidos Fíbricos/farmacología , Factores de Riesgo de Enfermedad Cardiaca , Humanos , PPAR alfa/agonistas , Resultado del TratamientoRESUMEN
Ballooning degeneration of hepatocytes is a major distinguishing histological feature of non-alcoholic steatosis (NASH) progression that can lead to cirrhosis and hepatocellular carcinoma (HCC). In this study, we evaluated the effect of the selective PPARα modulator (SPPARMα) pemafibrate (Pema) and sodium-glucose cotransporter 2 (SGLT2) inhibitor tofogliflozin (Tofo) combination treatment on pathological progression in the liver of a mouse model of NASH (STAM) at two time points (onset of NASH progression and HCC survival). At both time points, the Pema and Tofo combination treatment significantly alleviated hyperglycemia and hypertriglyceridemia. The combination treatment significantly reduced ballooning degeneration of hepatocytes. RNA-seq analysis suggested that Pema and Tofo combination treatment resulted in an increase in glyceroneogenesis, triglyceride (TG) uptake, lipolysis and liberated fatty acids re-esterification into TG, lipid droplet (LD) formation, and Cidea/Cidec ratio along with an increased number and reduced size and area of LDs. In addition, combination treatment reduced expression levels of endoplasmic reticulum stress-related genes (Ire1a, Grp78, Xbp1, and Phlda3). Pema and Tofo treatment significantly improved survival rates and reduced the number of tumors in the liver compared to the NASH control group. These results suggest that SPPARMα and SGLT2 inhibitor combination therapy has therapeutic potential to prevent NASH-HCC progression.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Animales , Compuestos de Bencidrilo/farmacología , Benzoxazoles/farmacología , Butiratos/farmacología , Carcinoma Hepatocelular/prevención & control , Glucósidos/farmacología , Neoplasias Hepáticas/prevención & control , Ratones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , PPAR alfa/antagonistas & inhibidores , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , TriglicéridosRESUMEN
Hypertriglyceridemia is an independent risk factor for coronary artery disease. Because apolipoprotein (Apo)A5 regulates plasma triglyceride levels, we investigated the impact of human (h)ApoA5 on atherogenesis. The influence of hApoA5 transgenic expression was studied in the ApoE2 knock-in mouse model of mixed dyslipidemia. Our results demonstrate that hApoA5 lowers plasma triglyceride levels in Western diet-fed ApoE2 knock-in mice. Moreover, atherosclerotic lesion development was significantly decreased in the hApoA5 transgenic mice. Finally, pharmacologic activation of hApoA5 expression by the peroxisome proliferator-activated receptor-alpha agonist fenofibrate resulted in an enhanced atheroprotection. These results identify an atheroprotective role of hApoA5 in a mouse model of mixed dyslipidemia.
Asunto(s)
Apolipoproteínas A/genética , Apolipoproteínas A/metabolismo , Aterosclerosis/fisiopatología , Dislipidemias/fisiopatología , Triglicéridos/sangre , Alimentación Animal , Animales , Apolipoproteína A-V , Apolipoproteína E2/sangre , Apolipoproteína E2/genética , Aterosclerosis/metabolismo , Colesterol/sangre , Grasas de la Dieta/farmacología , Modelos Animales de Enfermedad , Dislipidemias/tratamiento farmacológico , Dislipidemias/metabolismo , Femenino , Fenofibrato/farmacología , Homeostasis/fisiología , Humanos , Hipolipemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Apolipoprotein A-V is an important determinant of plasma triglyceride level in both humans and mice. This study showed the physiological impact of apoA-V on insulin secretion in rat pancreatic beta-cells (INS-1 cells). In order to precise the mechanism of action, binding experiments coupled to mass spectrometry were performed to identify a potential membrane receptor. Results showed an interaction between apoA-V and midkine protein. Confocal microscopy confirmed the plasma membrane co-localisation of this two-proteins after the treatment of INS-1 cells with the apo-AV recombinant protein and indicated that the cell surface midkine could be involved in apoA-V endocytosis, since these two proteins were co-translocated at the plasma membrane or in the cytosol compartment. This co-localisation is correlated with an increase in insulin secretion in a dose dependant manner during short incubation period. Reduction of midkine expression by small interfering RNA duplexes revealed a decrease in the ability of these transfected cells to secrete insulin in presence of apoA-V. Competition experiments for the apoA-V-midkine binding at the cell surface using antibody directed against midkine is able to influence INS-1 cell function as insulin secretion. Our results showed apoA-V ability to enhance insulin secretion in beta-cells and provide evidence of an internalization pathway involving the midkine as partner.
Asunto(s)
Apolipoproteínas/metabolismo , Citocinas/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Secuencia de Aminoácidos , Animales , Apolipoproteína A-V , Apolipoproteínas/análisis , Línea Celular Tumoral , Citocinas/análisis , Citocinas/genética , Endocitosis , Inmunoprecipitación , Secreción de Insulina , Midkina , Datos de Secuencia Molecular , Unión Proteica , ARN Interferente Pequeño/metabolismo , Ratas , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Elevated plasma levels of VLDL triglycerides (TGs) are characteristic of patients with type 2 diabetes mellitus (T2DM) and are associated with increased production rates (PRs) of VLDL TGs and apoB. Lipoprotein lipase-mediated (LPL-mediated) lipolysis of VLDL TGs may also be reduced in T2DM if the level of LPL is decreased and/or the level of plasma apoC-III, an inhibitor of LPL-mediated lipolysis, is increased. We studied the effects of pioglitazone (Pio), a PPARgamma agonist that improves insulin sensitivity, on lipoprotein metabolism in patients with T2DM. Pio treatment reduced TG levels by increasing the fractional clearance rate (FCR) of VLDL TGs from the circulation, without changing direct removal of VLDL particles. This indicated increased lipolysis of VLDL TGs during Pio treatment, a mechanism supported by our finding of increased plasma LPL mass and decreased levels of plasma apoC-III. Lower apoC-III levels were due to reduced apoC-III PRs. We saw no effects of Pio on the PR of either VLDL TG or VLDL apoB. Thus, Pio, a PPARgamma agonist, reduced VLDL TG levels by increasing LPL mass and inhibiting apoC-III PR. These 2 changes were associated with an increased FCR of VLDL TGs, almost certainly due to increased LPL-mediated lipolysis.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Lipoproteínas/metabolismo , PPAR gamma/agonistas , Tiazolidinedionas/farmacología , Adiponectina , Adulto , Anciano , Glucemia , HDL-Colesterol/sangre , Ácidos Grasos/sangre , Femenino , Humanos , Insulina/sangre , Péptidos y Proteínas de Señalización Intercelular/sangre , Masculino , Persona de Mediana Edad , Pioglitazona , Triglicéridos/sangreRESUMEN
While type 1 hyperlipidemia is associated with lipoprotein lipase or apoCII deficiencies, the etiology of type 5 hyperlipidemia remains largely unknown. We explored a new candidate gene, APOA5, for possible causative mutations in a pedigree of late-onset, vertically transmitted hyperchylomicronemia. A heterozygous Q139X mutation in APOA5 was present in both the proband and his affected son but was absent in 200 controls. It was subsequently found in 2 of 140 cases of hyperchylomicronemia. Haplotype analysis suggested the new Q139X as a founder mutation. Family studies showed that 5 of 9 total Q139X carriers had hyperchylomicronemia, 1 patient being homozygote. Severe hypertriglyceridemia in 8 heterozygotes was strictly associated with the presence on the second allele of 1 of 2 previously described triglyceride-raising minor APOA5 haplotypes. Furthermore, ultracentrifugation fraction analysis indicated in carriers an altered association of Apoa5 truncated and WT proteins to lipoproteins, whereas in normal plasma, Apoa5 associated with VLDL and HDL/LDL fractions. APOB100 kinetic studies in 3 severely dyslipidemic patients with Q139X revealed a major impairment of VLDL catabolism. Lipoprotein lipase activity and mass were dramatically reduced in dyslipidemic carriers, leading to severe lipolysis defect. Our observations strongly support in humans a role for APOA5 in lipolysis regulation and in familial hyperchylomicronemia.
Asunto(s)
Apolipoproteínas/genética , Codón sin Sentido/genética , Predisposición Genética a la Enfermedad , Hipertrigliceridemia/genética , Errores Innatos del Metabolismo Lipídico/genética , Lipoproteína Lipasa/sangre , Secuencia de Aminoácidos/genética , Apolipoproteína A-V , Apolipoproteínas/sangre , Apolipoproteínas A , Femenino , Genotipo , Humanos , Hipertrigliceridemia/sangre , Hipertrigliceridemia/enzimología , Errores Innatos del Metabolismo Lipídico/sangre , Errores Innatos del Metabolismo Lipídico/enzimología , Lipólisis/genética , Lipoproteína Lipasa/genética , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Linaje , Mutación Puntual/genética , Eliminación de Secuencia/genética , Triglicéridos/sangreRESUMEN
The apolipoprotein A5 gene (APOA5) has been repeatedly implicated in lowering plasma triglyceride levels. Since several studies have demonstrated that hyperinsulinemia is associated with hypertriglyceridemia, we sought to determine whether APOA5 is regulated by insulin. Here, we show that cell lines and mice treated with insulin down-regulate APOA5 expression in a dose-dependent manner. Furthermore, we found that insulin decreases human APOA5 promoter activity, and subsequent deletion and mutation analyses uncovered a functional E box in the promoter. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated that this APOA5 E box binds upstream stimulatory factors (USFs). Moreover, in transfection studies, USF1 stimulates APOA5 promoter activity, and the treatment with insulin reduced the binding of USF1/USF2 to the APOA5 promoter. The inhibition of the phosphatidylinositol 3-kinase (PI3K) pathway abolished insulin's effect on APOA5 gene expression, while the inhibition of the P70 S6 kinase pathway with rapamycin reversed its effect and increased APOA5 gene expression. Using an oligonucleotide precipitation assay for USF from nuclear extracts, we demonstrate that phosphorylated USF1 fails to bind to the APOA5 promoter. Taken together, these data indicate that insulin-mediated APOA5 gene transrepression could involve a phosphorylation of USFs through the PI3K and P70 S6 kinase pathways that modulate their binding to the APOA5 E box and results in APOA5 down-regulation. The effect of exogenous hyperinsulinemia in men showed a decrease in the plasma ApoAV level. These results suggest a potential contribution of the APOA5 gene in hypertriglyceridemia associated with hyperinsulinemia.
Asunto(s)
Apolipoproteínas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Insulina/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Adulto , Animales , Apolipoproteína A-V , Apolipoproteínas A , Células Cultivadas , Cartilla de ADN/genética , Proteínas de Unión al ADN/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Femenino , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Ratones , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Sirolimus/farmacología , Factores de Transcripción/metabolismo , Factores Estimuladores hacia 5'RESUMEN
Hepatic lipase (HL) has a well-established role in lipoprotein metabolism. However, its role in atherosclerosis is poorly understood. Here we demonstrate that HL deficiency raises the proatherogenic apoB-containing lipoprotein levels in plasma but reduces atherosclerosis in lecithin cholesterol acyltransferase (LCAT) transgenic (Tg) mice, similar to results previously observed with HL-deficient apoE-KO mice. These findings suggest that HL has functions that modify atherogenic risk that are separate from its role in lipoprotein metabolism. We used bone marrow transplantation (BMT) to generate apoE-KO and apoE-KO x HL-KO mice, as well as LCAT-Tg and LCAT-Tg x HL-KO mice, chimeric for macrophage HL gene expression. Using in situ RNA hybridization, we demonstrated localized production of HL by donor macrophages in the artery wall. We found that expression of HL by macrophages enhances early aortic lesion formation in both apoE-KO and LCAT-Tg mice, without changing the plasma lipid profile, lipoprotein lipid composition, or HL and lipoprotein lipase activities. HL does, however, enhance oxidized LDL uptake by peritoneal macrophages. These combined data demonstrate that macrophage-derived HL significantly contributes to early aortic lesion formation in two independent mouse models and identify a novel mechanism, separable from the role of HL in plasma lipoprotein metabolism, by which HL modulates atherogenic risk in vivo.
Asunto(s)
Apolipoproteínas E/deficiencia , Arteriosclerosis/etiología , Lipasa/fisiología , Macrófagos Peritoneales/enzimología , Fosfatidilcolina-Esterol O-Aciltransferasa/fisiología , Animales , Apolipoproteínas E/genética , Arteriosclerosis/genética , Arteriosclerosis/fisiopatología , Trasplante de Médula Ósea , Femenino , Expresión Génica , Lipasa/deficiencia , Lipasa/genética , Lípidos/sangre , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Fosfatidilcolina-Esterol O-Aciltransferasa/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de RiesgoRESUMEN
Liver X receptors (LXRs) are members of the nuclear receptor superfamily, which have been implicated in lipid homeostasis and more recently in glucose metabolism. Here, we show that glucose does not change LXRalpha protein level, but affects its localization in pancreatic beta-cells. LXRalpha is found in the nucleus at 8 mM glucose and in the cytoplasm at 4.2 mM. Addition of glucose translocates LXRalpha from the cytoplasm into the nucleus. Moreover, after the activation of LXR by its synthetic non-steroidal agonist (T0901317), insulin secretion and glucose uptake are increased at 8 mM and decreased at 4.2 mM glucose in a dose-dependent manner. Furthermore, at low glucose condition, okadaic acid reversed LXRalpha effect on insulin secretion, suggesting the involvement of glucose signaling through a phosphorylation-dependent mechanism.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Glucosa/metabolismo , Células Secretoras de Insulina/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Células Cultivadas , Proteínas de Unión al ADN/genética , Inhibidores Enzimáticos/metabolismo , Hidrocarburos Fluorados , Insulina/metabolismo , Células Secretoras de Insulina/citología , Receptores X del Hígado , Ácido Ocadaico/metabolismo , Receptores Nucleares Huérfanos , Péptidos/genética , Péptidos/metabolismo , Ratas , Receptores Citoplasmáticos y Nucleares/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Sulfonamidas/metabolismo , Receptor fas/metabolismoRESUMEN
Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor family. Recently, cholesterol (derivatives) has been identified as an RORalpha ligand and deorphanized this receptor. RORalpha is expressed in many tissues and is therefore a regulator of multiple biological processes. Studies of staggerer mice and in vitro assays indicate a beneficial modulatory role of RORalpha in the pathogenesis of dyslipidemia, inflammation and atherosclerosis. This paper provides an overview on the role of RORalpha in lipid metabolism and discusses its potential therapeutic option for treating lipid and inflammatory disorders leading to atherosclerosis.
Asunto(s)
Aterosclerosis/metabolismo , Dislipidemias/metabolismo , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Transactivadores/efectos de los fármacos , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/patología , Colesterol/fisiología , Dislipidemias/tratamiento farmacológico , Metabolismo Energético , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Ligandos , Metabolismo de los Lípidos , Ratones , Músculo Esquelético/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores NuclearesRESUMEN
OBJECTIVE: The newly identified apolipoprotein A5 (APOA5), selectively expressed in the liver, is a crucial determinant of plasma triglyceride levels. Because elevated plasma triglyceride concentrations constitute an independent risk factor for cardiovascular diseases, it is important to understand how the expression of this gene is regulated. In the present study, we identified the retinoic acid receptor-related orphan receptor-alpha (RORalpha) as a regulator of human APOA5 gene expression. METHODS AND RESULTS: Using electromobility shift assays, we first demonstrated that RORalpha1 and RORalpha4 proteins can bind specifically to a direct repeat 1 site present at the position -272/-260 in the APOA5 gene promoter. In addition, using transient cotransfection experiments in HepG2 and HuH7 cells, we demonstrated that both RORalpha1 and RORalpha4 strongly increase APOA5 promoter transcriptional activity in a dose-dependent manner. Finally, adenoviral overexpression of hRORalpha in HepG2 cells led to enhanced hAPOA5 mRNA accumulation. We show that the homologous region in mouse apoa5 promoter is not functional. Moreover, we show that in staggerer mice, apoa5 gene is not affected by RORalpha. CONCLUSIONS: These findings identify RORalpha1 and RORalpha4 as transcriptional activators of human APOA5 gene expression. These data suggest an additional important physiological role for RORalpha in the regulation of genes involved in lipid homeostasis and probably in the development of atherosclerosis.
Asunto(s)
Apolipoproteínas/genética , Aterosclerosis/fisiopatología , Receptores de Superficie Celular/genética , Receptores Citoplasmáticos y Nucleares/genética , Transactivadores/genética , Activación Transcripcional/fisiología , Adenoviridae/genética , Animales , Apolipoproteína A-V , Apolipoproteínas A , Aterosclerosis/genética , Carcinoma Hepatocelular , Línea Celular Tumoral , Homeostasis/fisiología , Humanos , Neoplasias Hepáticas , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Regiones Promotoras Genéticas/fisiología , ARN Mensajero/metabolismo , Proteínas Tirosina Quinasas Receptoras , Receptores Huérfanos Similares al Receptor Tirosina Quinasa , Receptores de Superficie Celular/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transactivadores/metabolismo , Triglicéridos/sangreRESUMEN
Mouse studies indicated that plasma phospholipid transfer protein (PLTP) determines the plasma distribution of vitamin E, a potent lipophilic antioxidant. Vitamin E distribution, antioxidant status, and titer of anti-oxidized LDLs (oxLDL) autoantibodies were evaluated in plasma from control subjects (n = 31) and type 2 diabetic patients (n = 31) with elevated plasma PLTP concentration. Unlike diabetic and control HDLs, which displayed similar vitamin E contents, diabetic VLDLs and diabetic LDLs contained fewer vitamin E molecules than normal counterparts. Plasma PLTP concentration in diabetic plasmas correlated negatively with vitamin E in VLDL+LDL, but positively with vitamin E in HDL, with an even stronger correlation with the VLDL+LDL-to-HDL vitamin E ratio. Circulating levels of oxLDL were significantly higher in diabetic plasmas than in control plasmas. Whereas the titer of IgG autoantibodies to modified LDL did not differ significantly between diabetic patients and control subjects, diabetic plasmas showed significantly lower levels of potentially protective IgM autoantibodies. The present observations support a pathophysiological role of PLTP in decreasing the vitamin E content of apolipoprotein B-containing lipoproteins, but not of HDL in plasma of type 2 diabetic patients, contributing to a greater potential for LDL oxidation.
Asunto(s)
Apolipoproteínas B/sangre , Proteínas Portadoras/sangre , Diabetes Mellitus Tipo 2/sangre , Proteínas de la Membrana/sangre , Proteínas de Transferencia de Fosfolípidos , Vitamina E/sangre , Antioxidantes/metabolismo , Autoanticuerpos/sangre , Índice de Masa Corporal , Colesterol/sangre , Femenino , Humanos , Inmunoglobulina M/sangre , Lipoproteínas/sangre , Lipoproteínas HDL/sangre , Masculino , Persona de Mediana Edad , Valores de Referencia , Triglicéridos/sangreRESUMEN
Postprandial hypertriglyceridemia is considered as a risk factor for cardiovascular disease in Type 2 diabetes. However, little is known about the underlying mechanisms. Since the recently discovered apolipoprotein (apo) AV was identified as a modulator of triglyceride (TG) metabolism, the aim of the study was to determine the postprandial apoAV profile of Type 2 diabetic patients. We compared data from 11 patients with Type 2 diabetes mellitus to that of 12 non-diabetic normolipidemic subjects following the ingestion of a lipid-rich cream. Postprandial apoAV was elevated in diabetic patients but no correlation was observed either with plasma TG concentration or with the intensity of lipoprotein lipase-dependent lipolysis. These data obtained in human subjects suggest that plasma apoAV concentration does not play an acute or a direct role in the regulation of plasma TG in the postprandial state.
Asunto(s)
Apolipoproteínas/sangre , Diabetes Mellitus Tipo 2/sangre , Hipertrigliceridemia/sangre , Triglicéridos/sangre , Adulto , Apolipoproteína A-V , Apolipoproteínas A , Humanos , Lipólisis/fisiología , Masculino , Persona de Mediana Edad , Periodo Posprandial/fisiologíaRESUMEN
OBJECTIVE: Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are strongly altered by changes in the expression of either of these 2 genes. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. These similar findings raised the issue of the relationship between these 2 genes and altered triglycerides. METHODS AND RESULTS: To address this issue, we generated independent lines of mice that either overexpressed ("double transgenic") or completely lacked ("double knockout") both apolipoprotein genes. We report that both "double transgenic" and "double knockout" mice display normal triglyceride concentrations compared with overexpression or deletion of either gene alone. Furthermore, we find that human ApoAV plasma protein levels in the "double transgenic" mice are approximately 500-fold lower than human ApoCIII levels, supporting ApoAV as a potent triglyceride modulator despite its low concentration. CONCLUSIONS: Together, these data support that APOA5 and APOC3 independently influence plasma triglyceride concentrations but in an opposing manner.
Asunto(s)
Apolipoproteínas C/sangre , Apolipoproteínas/sangre , Triglicéridos/sangre , Animales , Apolipoproteína A-V , Apolipoproteína C-III , Apolipoproteínas/genética , Apolipoproteínas/fisiología , Apolipoproteínas A , Apolipoproteínas C/genética , Apolipoproteínas C/fisiología , Femenino , Humanos , Hipertrigliceridemia/sangre , Hipertrigliceridemia/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteínas Recombinantes de Fusión/sangre , Proteínas Recombinantes de Fusión/fisiologíaRESUMEN
Atherosclerosis is a complex disease resulting from the interaction of multiple genes, including those causing dyslipidemia. Relatively few of the causative genes have been identified. Previously, we identified Apoa2 as a major determinant of high-density lipoprotein cholesterol (HDL-C) levels in the mouse model. To identify additional HDL-C level quantitative trait loci (QTLs), while controlling for the effect of the Apoa2 locus, we performed linkage analysis in 179 standard diet-fed F(2) mice derived from strains BALB/cJ and B6.C-H25(c) (a congenic strain carrying the BALB/c Apoa2 allele). Three significant QTLs and one suggestive locus were identified. A female-specific locus mapping to chromosome 6 (Chr 6) also exhibited effects on plasma non-HDL-C, apolipoprotein AII (apoAII), apoB, and apoE levels. A Chr 6 QTL was independently isolated in a related congenic strain (C57BL/6J vs. B6.NODc6: P = 0.003 and P = 0.0001 for HDL-C and non-HDL-C levels, respectively). These data are consistent with polygenic inheritance of HDL-C levels in the mouse model and provide candidate loci for HDL-C and non-HDL-C level determination in humans.
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Alelos , Apolipoproteína A-II/genética , HDL-Colesterol/sangre , Mapeo Cromosómico/métodos , Sitios de Carácter Cuantitativo/genética , Animales , Cruzamiento , Colesterol/sangre , Cromosomas/genética , Femenino , Ligamiento Genético/genética , Hipercolesterolemia/genética , Ratones , Ratones Congénicos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Herencia Multifactorial/genéticaRESUMEN
The apolipoprotein A5 gene (APOA5) is a key player in determining triglyceride concentrations in humans and mice. Since diabetes is often associated with hypertriglyceridemia, this study explores whether APOA5 gene expression is regulated by alteration in glucose homeostasis and the related pathways. d-Glucose activates APOA5 gene expression in a time- and dose-dependent manner in hepatocytes, and the glycolytic pathway involved was determined using d-glucose analogues and metabolites. Together, transient transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation assays show that this regulation occurs at the transcriptional level through an increase of USF1/2 binding to an E-box in the APOA5 promoter. We show that this phenomenon is not due to an increase of mRNA or protein expression levels of USF. Using protein phosphatases 1 and 2A inhibitor, we demonstrate that d-glucose regulates the APOA5 gene via a dephosphorylation mechanism, resulting in an enhanced USF1/2-promoter binding. Last, subsequent suppressions of USF1/2 and phosphatases mRNA through siRNA gene silencing abolished the regulation. We demonstrate that the APOA5 gene is up regulated by d-glucose and USF through phosphatase activation. These findings may provide a new cross-talk between glucose and lipid metabolism.
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Apolipoproteínas A/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/farmacología , Animales , Apolipoproteína A-V , Apolipoproteínas A/genética , Línea Celular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Glucólisis , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Regiones Promotoras Genéticas , Unión Proteica , Proteína Fosfatasa 1/farmacología , Proteína Fosfatasa 2/farmacología , ARN Mensajero/metabolismo , Ratas , Factores de Tiempo , Transcripción Genética , Factores Estimuladores hacia 5'/metabolismoRESUMEN
BACKGROUND: Genetic variation at the apolipoprotein A-V locus, recently discovered proximal to the APOA1/C3/A4 gene cluster, is associated with elevated triglyceride concentrations, a risk factor for atherosclerosis. METHODS: The goal of our study was to determine the association of two apolipoprotein A-V (APOA5) gene polymorphisms in a group of urban Romanian subjects with the prevalence of the metabolic syndrome. For this purpose, we assayed -1.131T>C and c.56C>G polymorphisms for 279 subjects divided into three groups: a control group, a metabolic syndrome group and a cardiovascular disease group. Then we correlated the minor allele frequencies with body mass index and biochemical parameters. RESULTS: We obtained higher frequency for -1.131C compared to c.56G alleles, both mainly distributed in overweight subjects. Body mass index and triglyceride levels were higher in -1.131C allele carriers in metabolic syndrome patients, but were not significantly different in c.56G carriers compared to those with the native gene. Metabolic syndrome -1.131C homozygotes presented lower high-density lipoprotein cholesterol and higher glucose levels compared to subjects with the native gene. Total cholesterol, low-density lipoprotein cholesterol and insulin were not different between -1.131C or c.56G allele carriers and those with the native gene. CONCLUSIONS: Our results demonstrate an independent risk for -1.131T>C APOA5 gene polymorphisms in the development of metabolic syndrome.
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Apolipoproteínas A/genética , Apolipoproteínas A/fisiología , Aterosclerosis/genética , Síndrome Metabólico/genética , Familia de Multigenes , Obesidad/genética , Polimorfismo Genético , Alelos , Apolipoproteína A-V , Enfermedades Cardiovasculares/genética , Colesterol/metabolismo , Frecuencia de los Genes , Variación Genética , Homocigoto , Humanos , Insulina/metabolismo , Factores de Riesgo , Triglicéridos/metabolismoRESUMEN
Hypertriglyceridemia is an independent risk factor for the development of cardiovascular disease and is often associated with diabetes, inflammation and the metabolic syndrome. Recently, apolipoprotein A5 (APOA5) was identified as a novel member of the APOA1/C3/A4 gene cluster. Data from mice over-expressing or lacking APOA5 provide direct evidence that this apolipoprotein plays a role in triglyceride metabolism. Moreover, plasma triglyceride levels were found to be strongly associated with APOA5 polymorphisms. The human APOA5 gene is regulated by transcription factors known to affect triglyceride metabolism such as PPARa, RORa, LXR and SREBP-1c and this supports its function. Insulin and interleukins regulate APOA5 gene expression and provide novel clues for the role of this apolipoprotein. To date, the triglyceride lowering action of apoA-V is attributed to the activation of lipoprotein lipase and an acceleration of very low density lipoprotein catabolism. Recent findings indicate that APOA5 could also influence cholesterol homeostasis and probably play a role in hypertriglyceridemia associated with diabetes and inflammation. This review aims to give a comprehensive summary of the current literature and supports the view that APOA5 plays a relevant role in lipid metabolism.