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Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice develop the metabolic syndrome upon being fed a high-fat high-cholesterol diet, show large inter-individual variation in the parameters of the metabolic syndrome, despite a lack of genetic and environmental variation. In the present study, we set out to resolve what mechanisms could underlie this variation. We used measurements of glucose and lipid metabolism from a six-month longitudinal study on the development of the metabolic syndrome. Mice were classified as mice with either high plasma triglyceride (responders) or low plasma triglyceride (non-responders) at the baseline. Subsequently, we fitted the data to a dynamic computational model of whole-body glucose and lipid metabolism (MINGLeD) by making use of a hybrid modelling method called Adaptations in Parameter Trajectories (ADAPT). ADAPT integrates longitudinal data, and predicts how the parameters of the model must change through time in order to comply with the data and model constraints. To explain the phenotypic variation in plasma triglycerides, the ADAPT analysis suggested a decreased cholesterol absorption, higher energy expenditure and increased fecal fatty acid excretion in non-responders. While decreased cholesterol absorption and higher energy expenditure could not be confirmed, the experimental validation demonstrated that the non-responders were indeed characterized by increased fecal fatty acid excretion. Furthermore, the amount of fatty acids excreted strongly correlated with bile acid excretion, in particular deoxycholate. Since bile acids play an important role in the solubilization of lipids in the intestine, these results suggest that variation in bile acid homeostasis may in part drive the phenotypic variation in the APOE*3-Leiden.CETP mice.
Assuntos
Apolipoproteína E3 , Proteínas de Transferência de Ésteres de Colesterol , Dieta Hiperlipídica , Síndrome Metabólica , Animais , Camundongos , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Glucose/metabolismo , Fígado/metabolismo , Estudos Longitudinais , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Fenótipo , Análise de Sistemas , Triglicerídeos , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismoRESUMO
It is well established that, besides facilitating lipid absorption, bile acids act as signaling molecules that modulate glucose and lipid metabolism. Bile acid metabolism, in turn, is controlled by several nutrient-sensitive transcription factors. Altered intrahepatic glucose signaling in type 2 diabetes associates with perturbed bile acid synthesis. We aimed to characterize the regulatory role of the primary intracellular metabolite of glucose, glucose-6-phosphate (G6P), on bile acid metabolism. Hepatic gene expression patterns and bile acid composition were analyzed in mice that accumulate G6P in the liver, that is, liver-specific glucose-6-phosphatase knockout (L-G6pc-/- ) mice, and mice treated with a pharmacological inhibitor of the G6P transporter. Hepatic G6P accumulation induces sterol 12α-hydroxylase (Cyp8b1) expression, which is mediated by the major glucose-sensitive transcription factor, carbohydrate response element-binding protein (ChREBP). Activation of the G6P-ChREBP-CYP8B1 axis increases the relative abundance of cholic-acid-derived bile acids and induces physiologically relevant shifts in bile composition. The G6P-ChREBP-dependent change in bile acid hydrophobicity associates with elevated plasma campesterol/cholesterol ratio and reduced fecal neutral sterol loss, compatible with enhanced intestinal cholesterol absorption. Conclusion: We report that G6P, the primary intracellular metabolite of glucose, controls hepatic bile acid synthesis. Our work identifies hepatic G6P-ChREBP-CYP8B1 signaling as a regulatory axis in control of bile acid and cholesterol metabolism.
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Ácidos e Sais Biliares/biossíntese , Glucose-6-Fosfato/fisiologia , Fígado/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/fisiologia , Colesterol/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esteroide 12-alfa-Hidroxilase/fisiologiaRESUMO
The Metabolic Syndrome (MetS) is a complex, multifactorial disorder that develops slowly over time presenting itself with large differences among MetS patients. We applied a systems biology approach to describe and predict the onset and progressive development of MetS, in a study that combined in vivo and in silico models. A new data-driven, physiological model (MINGLeD: Model INtegrating Glucose and Lipid Dynamics) was developed, describing glucose, lipid and cholesterol metabolism. Since classic kinetic models cannot describe slowly progressing disorders, a simulation method (ADAPT) was used to describe longitudinal dynamics and to predict metabolic concentrations and fluxes. This approach yielded a novel model that can describe long-term MetS development and progression. This model was integrated with longitudinal in vivo data that was obtained from male APOE*3-Leiden.CETP mice fed a high-fat, high-cholesterol diet for three months and that developed MetS as reflected by classical symptoms including obesity and glucose intolerance. Two distinct subgroups were identified: those who developed dyslipidemia, and those who did not. The combination of MINGLeD with ADAPT could correctly predict both phenotypes, without making any prior assumptions about changes in kinetic rates or metabolic regulation. Modeling and flux trajectory analysis revealed that differences in liver fluxes and dietary cholesterol absorption could explain this occurrence of the two different phenotypes. In individual mice with dyslipidemia dietary cholesterol absorption and hepatic turnover of metabolites, including lipid fluxes, were higher compared to those without dyslipidemia. Predicted differences were also observed in gene expression data, and consistent with the emergence of insulin resistance and hepatic steatosis, two well-known MetS co-morbidities. Whereas MINGLeD specifically models the metabolic derangements underlying MetS, the simulation method ADAPT is generic and can be applied to other diseases where dynamic modeling and longitudinal data are available.
Assuntos
Biologia Computacional/métodos , Simulação por Computador , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Modelos Biológicos , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , CamundongosRESUMO
Immunity and cellular metabolism are tightly interconnected but it is not clear whether different pathogens elicit specific metabolic responses. To address this issue, we studied differential metabolic regulation in peripheral blood mononuclear cells (PBMCs) of healthy volunteers challenged by Candida albicans, Borrelia burgdorferi, lipopolysaccharide, and Mycobacterium tuberculosis in vitro. By integrating gene expression data of stimulated PBMCs of healthy individuals with the KEGG pathways, we identified both common and pathogen-specific regulated pathways depending on the time of incubation. At 4 h of incubation, pathogenic agents inhibited expression of genes involved in both the glycolysis and oxidative phosphorylation pathways. In contrast, at 24 h of incubation, particularly glycolysis was enhanced while genes involved in oxidative phosphorylation remained unaltered in the PBMCs. In general, differential gene expression was less pronounced at 4 h compared to 24 h of incubation. KEGG pathway analysis allowed differentiation between effects induced by Candida and bacterial stimuli. Application of genome-scale metabolic model further generated a Candida-specific set of 103 reporter metabolites (e.g., desmosterol) that might serve as biomarkers discriminating Candida-stimulated PBMCs from bacteria-stimuated PBMCs. Our analysis also identified a set of 49 metabolites that allowed discrimination between the effects of Borrelia burgdorferi, lipopolysaccharide and Mycobacterium tuberculosis. We conclude that analysis of pathogen-induced effects on PBMCs by a combination of KEGG pathways and genome-scale metabolic model provides deep insight in the metabolic changes coupled to host defense.
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BACKGROUND: Lipids and lipoproteins are recognized as the most important modifiable risk factors for cardiovascular disease. Although reference values for the major lipoproteins, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides, have been collected in numerous studies and cohorts, complete contemporary percentile-based reference values are underreported. OBJECTIVE: We set out to provide such reference lipid data using a large contemporary population-based cohort study. STUDY DESIGN AND SETTING: Lifelines is a cross-sectional population-based Dutch cohort study. We analyzed 133,540 adult fasting participants without cardiovascular disease and without lipid-lowering drug use. Lipid levels were directly measured and selected percentiles of all lipid parameters were calculated. Friedewald LDL-C estimation was calculated as well. RESULTS: From 20 till 49 years of age, men were found to exhibit a steep 64% increase of LDL-C (median +54 mg/dL), while triglyceride levels increased almost two-fold. In women, LDL-C levels did not change from 18 till 35 years, followed by a steep 42% increase till 59 years (median +42 mg/dL). In contrast to men, triglycerides were stable in ageing women. Overall, Friedewald LDL-C levels are lower compared with the direct measurement, especially with increasing triglyceride levels. CONCLUSIONS: This observational study highlights striking gender- and age-related differences in plasma lipid profiles. The given reference ranges of plasma lipids can assist in early identification of individuals with hypocholesterolemia and hypercholesterolemia, especially familial hypercholesterolemia. These reference ranges are available for physicians and patients at www.my-cholesterol.care/.
Assuntos
Envelhecimento/sangue , Análise Química do Sangue/normas , Lipoproteínas/sangue , Caracteres Sexuais , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , HDL-Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Triglicerídeos/sangue , Adulto JovemRESUMO
PURPOSE OF REVIEW: To highlight very recent studies identifying novel regulatory molecules and mechanisms in plasma lipid metabolism. RECENT FINDINGS: Two novel regulatory mechanisms of LDL receptor (LDLR) intracellular trafficking have been described. The "COMMD/CCDC22/CCDC93" and "Wiskott-Aldrich syndrome protein and SCAR homologue" complexes were found to be involved in LDLR endosomal sorting and recycling, whereas the GRP94 was shown to protect LDLR from early degradation within the hepatocyte secretory pathway. Additionally, the transcription factors PHD1 and Bmal1 were identified to regulate LDL-C levels in mice by modulating cholesterol excretion. Important advances are reported on the relevance of two Genome Wide Association Studies hits: Reassessment of GALNT2 showed, in contrast to previous reports, that loss of GALNT2 reduces HDL-cholesterol in humans and other mammalian species, while phospholipid transfer protein was identified as an additional target of GALNT2. Tetratricopeptide repeat domain protein 39B was found to promote ubiquitination and degradation of Liver X receptor, and its deficiency increased HDL-cholesterol and cholesterol removal while also inhibiting lipogenesis in mice. SUMMARY: The unraveling of mechanisms how new factors modulate plasma lipid levels keep providing interesting opportunities to rationally design novel therapies to treat cardiovascular disease but also metabolic disorders.
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Lipídeos/sangue , Proteínas/metabolismo , Animais , HumanosRESUMO
BACKGROUND & AIMS: The role of the intestine in the maintenance of cholesterol homeostasis increasingly is recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport pathway, to which biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway, however, are poorly understood. We aimed to identify mechanisms that regulate and stimulate TICE. METHODS: We performed studies with C57Bl/6J mice, as well as with mice with intestine-specific knockout of the farnesoid X receptor (FXR), mice that express an FXR transgene specifically in the intestine, and ABCG8-knockout mice. Mice were fed a control diet or a diet supplemented with the FXR agonist PX20606, with or without the cholesterol absorption inhibitor ezetimibe. Some mice with intestine-specific knockout of FXR were given daily injections of fibroblast growth factor (FGF)19. To determine fractional cholesterol absorption, mice were given intravenous injections of cholesterol D5 and oral cholesterol D7. Mice were given 13C-acetate in drinking water for measurement of cholesterol synthesis. Bile cannulations were performed and biliary cholesterol secretion rates were assessed. In a separate set of experiments, bile ducts of male Wistar rats were exteriorized, allowing replacement of endogenous bile by a model bile. RESULTS: In mice, we found TICE to be regulated by intestinal FXR via induction of its target gene Fgf15 (FGF19 in rats and human beings). Stimulation of this pathway caused mice to excrete up to 60% of their total cholesterol content each day. PX20606 and FGF19 each increased the ratio of muricholate:cholate in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool stimulated robust secretion of cholesterol into the intestinal lumen via the sterol-exporting heterodimer adenosine triphosphate binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, the increase in TICE induced by PX20606 was independent of changes in cholesterol absorption. CONCLUSIONS: Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Strategies that alter bile salt pool composition might be developed for the prevention of cardiovascular disease. Transcript profiling: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=irsrayeohfcntqx&acc=GSE74101.
Assuntos
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Eliminação Intestinal/genética , Mucosa Intestinal/metabolismo , Lipoproteínas/genética , Receptores Citoplasmáticos e Nucleares/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Benzoatos/farmacologia , Ductos Biliares , Ezetimiba/farmacologia , Eliminação Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Isoxazóis/farmacologia , Lipoproteínas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/agonistasRESUMO
Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins reduce plasma cholesterol levels, but whether this is actually caused by inhibition of de novo cholesterol synthesis has not been clearly established. Using three different statins, we investigated the effects on cholesterol metabolism in mice in detail. Surprisingly, direct measurement of whole body cholesterol synthesis revealed that cholesterol synthesis was robustly increased in statin-treated mice. Measurement of organ-specific cholesterol synthesis demonstrated that the liver is predominantly responsible for the increase in cholesterol synthesis. Excess synthesized cholesterol did not accumulate in the plasma, as plasma cholesterol decreased. However, statin treatment led to an increase in cholesterol removal via the feces. Interestingly, enhanced cholesterol excretion in response to rosuvastatin and lovastatin treatment was mainly mediated via biliary cholesterol secretion, whereas atorvastatin mainly stimulated cholesterol removal via the transintestinal cholesterol excretion pathway. Moreover, we show that plasma cholesterol precursor levels do not reflect cholesterol synthesis rates during statin treatment in mice. In conclusion, cholesterol synthesis is paradoxically increased upon statin treatment in mice. However, statins potently stimulate the excretion of cholesterol from the body, which sheds new light on possible mechanisms underlying the cholesterol-lowering effects of statins.
Assuntos
Colesterol/biossíntese , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fígado/metabolismo , Lovastatina/farmacologia , Animais , Colesterol/sangue , Avaliação Pré-Clínica de Medicamentos , Expressão Gênica/efeitos dos fármacos , Glutaratos/metabolismo , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Eliminação Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BLRESUMO
When considering the variation in the genome, transcriptome, proteome and metabolome, and their interaction with the environment, every individual can be rightfully considered as a unique biological entity. Individualized medicine promises to take this uniqueness into account to optimize disease treatment and thereby improve health benefits for every patient. The success of individualized medicine relies on a precise understanding of the genotype-phenotype relationship. Although omics technologies advance rapidly, there are several challenges that need to be overcome: Next generation sequencing can efficiently decipher genomic sequences, epigenetic changes, and transcriptomic variation in patients, but it does not automatically indicate how or whether the identified variation will cause pathological changes. This is likely due to the inability to account for (1) the consequences of gene-gene and gene-environment interactions, and (2) (post)transcriptional as well as (post)translational processes that eventually determine the concentration of key metabolites. The technologies to accurately measure changes in these latter layers are still under development, and such measurements in humans are also mainly restricted to blood and circulating cells. Despite these challenges, it is already possible to track dynamic changes in the human interactome in healthy and diseased states by using the integration of multi-omics data. In this review, we evaluate the potential value of current major bioinformatics and systems biology-based approaches, including genome wide association studies, epigenetics, gene regulatory and protein-protein interaction networks, and genome-scale metabolic modeling. Moreover, we address the question whether integrative analysis of personal multi-omics data will help understanding of personal genotype-phenotype relationships.
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PURPOSE OF REVIEW: Long-term exposure to elevated concentrations of LDL cholesterol increases the risk of cardiovascular events. The main player in clearing LDL cholesterol is the LDL receptor (LDLR) trafficking pathway; however, our fundamental knowledge about the mechanisms regulating this pathway is still incomplete. RECENT FINDINGS: The LDLR pathway is very complex and involves multiple proteins. Endocytosis is regulated by two different adaptor proteins, that is, autosomal recessive hypercholesterolemia and Disabled-2. The proteolysis of the LDLR is regulated by inducible degrader of the LDLR and proprotein convertase subtilisin/kexin type 9. However, only a few proteins have been identified that provide insights into the endosomal sorting and recycling of the LDLR. SUMMARY: Since the discovery of LDLR, knowledge about its function has greatly expanded. As a result of its importance in maintaining homeostatic LDL levels, the LDLR pathway has emerged as a key therapeutic target to reduce circulating cholesterol. In order to be able to treat and diagnose individuals with hypercholesterolemia in the future, it is important to learn more about the LDLR trafficking pathway, as we still lack a full mechanistic understanding of how LDLR trafficking is controlled.
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Receptores de LDL/metabolismo , Animais , Células Cultivadas , Endocitose , Humanos , Transporte Proteico , ProteóliseRESUMO
Dyslipidaemia is a major risk factor for cardiovascular diseases. Pharmacological lowering of LDL-C levels using statins reduces cardiovascular risk. However, a substantial residual risk persists especially in patients with type 2 diabetes mellitus. Because of the inverse association observed in epidemiological studies of HDL-C with the risk for cardiovascular diseases, novel therapeutic strategies to raise HDL-C levels or improve HDL functionality are developed as complementary therapy for cardiovascular diseases. However, until now most therapies targeting HDL-C levels failed in clinical trials because of side effects or absence of clinical benefits. This chapter will highlight the emerging small molecules currently developed and tested in clinical trials to pharmacologically modulate HDL-C and functionality including new CETP inhibitors (anacetrapib, evacetrapib), novel PPAR agonists (K-877, CER-002, DSP-8658, INT131 and GFT505), LXR agonists (ATI-111, LXR-623, XL-652) and RVX-208.
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Doenças Cardiovasculares/prevenção & controle , Desenho de Fármacos , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Dislipidemias/complicações , Dislipidemias/metabolismo , Humanos , Hipolipemiantes/química , Receptores X do Fígado , Terapia de Alvo Molecular , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Quinazolinas/uso terapêutico , Quinazolinonas , Transdução de Sinais/efeitos dos fármacosRESUMO
INTRODUCTION: Adrenal steroidogenesis is essential for human survival and depends on the availability of the precursor cholesterol. Male subjects with low plasma levels of high density lipoprotein (HDL) cholesterol are characterized by decreased adrenal function. Whether this is also the case in female subjects with low plasma HDL-C levels is unresolved to date. FINDINGS: 15 female ATP binding cassette transporter AI (ABCAI) and 14 female lecithin-cholesterol acyltransferase (LCAT) were included in the study. HDL-C levels were 38% and 41% lower in ABCA1 and LCAT mutation carriers compared to controls, respectively. Urinary steroid excretion of 17-ketogenic steroids or 17-hydroxy corticosteroids did not differ between 15 female ABCA1 mutation carriers (p = 0.27 vs 0.30 respectively) and 30 matched normolipidemic controls or between 14 female LCAT mutation carriers and 28 matched normolipidemic controls (p = 0.10 and 0.14, respectively). Cosyntropin testing in an unselected subgroup of 8 ABCA1 mutation carriers and 3 LCAT mutation carriers did not reveal differences between carriers and controls. CONCLUSION: Adrenal function in females with molecularly defined low HDL-C levels is not different from controls. The discrepancy with the finding of impaired steroidogenesis in males with molecularly defined low HDL-C levels underscores the importance of gender specific analyses in cholesterol-related research.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Glândulas Suprarrenais/metabolismo , HDL-Colesterol/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , 17-Cetosteroides/metabolismo , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Mutação/genética , Fosfatidilcolina-Esterol O-Aciltransferase/genéticaRESUMO
BACKGROUND: Macrophages are crucial cells in the pathogenesis of atherosclerosis. Macrophages are plastic cells which can switch from a classical pro-inflammatory M1 to an alternative anti-inflammatory M2 macrophage phenotype, depending on the environmental stimuli. Because high-density lipoprotein (HDL) cholesterol levels are inversely correlated to cardiovascular disease and since HDL displays anti-inflammatory properties, we investigated whether HDL can affect alternative macrophage differentiation of primary human monocytes in the presence of interleukin (IL)-4, a M2 macrophage polarization driver, in vitro and ex vivo. METHODS AND RESULTS: M2 macrophages are highly responsive to HDL stimulation, since the expression of pentraxin 3 (PTX3), a well known HDL target gene, is induced by HDL more strongly in M2 macrophages than in control unpolarized resting macrophages (RM). As expected, the expression of M2 markers, such as Mannose Receptor (MR), CD200 Receptor (CD200R), Coagulation factor XIII A1 (F13A1), IL-1 receptor antagonist (IL-1RA) and IL10, was induced in IL-4 polarized M2 macrophages compared to RM. However, incubation with HDL added in vitro did not modulate the gene expression of M2 macrophage polarization markers. Moreover, monocytes isolated from subjects with genetically low HDL levels, carrying ABCA1 or LCAT mutations, differentiated ex vivo into M2 macrophages without any difference in the alternative macrophage marker expression profile. CONCLUSIONS: These in vitro and ex vivo results indicate that, contrary to mouse macrophages, HDL does not influence macrophage M2 polarization of human monocyte-derived macrophages. Thus, the anti-inflammatory properties of HDL in humans are probably not related to the enhancement of the M2 macrophage phenotype.
Assuntos
Aterosclerose/imunologia , Polaridade Celular/imunologia , HDL-Colesterol/imunologia , Inflamação/imunologia , Monócitos/imunologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/imunologia , Adulto , Antígenos de Superfície/genética , Antígenos de Superfície/imunologia , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores , Células Cultivadas , HDL-Colesterol/farmacologia , Fator XIII/genética , Fator XIII/imunologia , Feminino , Expressão Gênica/imunologia , Humanos , Inflamação/genética , Inflamação/patologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/patologia , Receptores de Orexina , Fenótipo , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Fosfatidilcolina-Esterol O-Aciltransferase/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Adulto JovemRESUMO
PURPOSE OF REVIEW: This review focuses on the recent developments in the field of drugs that affect HDL metabolism. Additionally, some general (retrospective) thoughts on fighting cardiovascular disease through modulating circulating lipids are discussed. RECENT FINDINGS: Recently, the large 'Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes', 'Treatment of HDL to Reduce the Incidence of Vascular Events' and dal-OUTCOMES studies have challenged the idea that raising HDL cholesterol (HDL-c) decreases cardiovascular disease risk. Concerning the failure of these trials, it may, however, be noted that patients with close to normal HDL-c levels were included. It is shown that anacetrapib and evacetrapib massively increase HDL-c, and both compounds are currently tested in phase-III clinical trials. More specific and stronger activators of liver X receptor and peroxisome proliferator-activated receptor (PPAR) are being developed and tested in a preclinical setting. RVX-208 treatment failed to decrease atheroma volume in coronary artery disease patients. Lecithin:cholesterol acyltransferase replacement therapy showed positive results in a patient with lecithin:cholesterol acyltransferase deficiency. SUMMARY: Inhibition of cholesteryl ester transfer protein, antagomirs against microRNA-33, ApoA-I mimetics and PPARα or PPARα/δ agonists hold on the basis of the current data most promise. However, it will in our opinion be the key that patients with low HDL-c and increased triglyceride should be treated and not those at generally increased risk only. In the poststatin era, personalized medicine, which is inevitably on the horizon, is likely to be helpful for patients who do not reach the goals for LDL cholesterol and HDL-c according to the guidelines. Furthermore, functions of HDL will hopefully be identified as future pharmacological targets.
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Lipoproteínas HDL/metabolismo , Farmacologia/métodos , Animais , Transporte Biológico/efeitos dos fármacos , Química Farmacêutica , Colesterol/metabolismo , Humanos , Lipoproteínas HDL/químicaAssuntos
Doenças Cardiovasculares/metabolismo , HDL-Colesterol/genética , Metabolismo dos Lipídeos , Doenças Cardiovasculares/patologia , HDL-Colesterol/metabolismo , Predisposição Genética para Doença , Variação Genética , Humanos , Fatores de Risco , Triglicerídeos/genética , Triglicerídeos/metabolismoRESUMO
Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans. While there is evidence against a role for low-density lipoprotein (LDL), it is unresolved whether high density lipoprotein (HDL) contributes to adrenal steroidogenesis. To study this, steroid hormone profiles in urine were assessed in male subjects suffering from functional mutations in ATP binding cassette transporter A1 (ABCA1) (n = 24), lecithin:cholesterol acyltransferase (LCAT) (n = 40), as well as in 11 subjects with low HDL cholesterol (HDL-C) without ABCA1/LCAT mutations. HDL-C levels were 39% lower in the ABCA1, LCAT, and low HDL-C groups compared with controls (all P < 0.001). In all groups with low HDL-C levels, urinary excretion of 17-ketogenic steroids was reduced by 33%, 27%, and 32% compared with controls (all P < 0.04). In seven carriers of either type of mutation, adrenocorticotropic hormone (ACTH) stimulation did not reveal differences from normolipidemic controls. In conclusion, this study shows that basal but not stimulated corticosteroid metabolism is attenuated in subjects with low HDL-C, irrespective of its molecular origin. These findings lend support to a role for HDL as a cholesterol donor for basal adrenal steroidogenesis in humans.
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Glândulas Suprarrenais/metabolismo , HDL-Colesterol/sangue , Esteroides/biossíntese , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/urina , Adulto , Idoso , HDL-Colesterol/urina , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Esteroides/urinaRESUMO
Lecithin:cholesterol acyltransferase (LCAT) is crucial to the maturation of high-density lipoprotein (HDL). Homozygosity for LCAT mutations underlies rare disorders characterized by HDL-cholesterol (HDL-c) deficiency while heterozygotes have half normal HDL-c levels. We studied the prevalence of LCAT mutations in referred patients with low HDL-c to better understand the molecular basis of low HDL-c in our patients. LCAT was sequenced in 98 patients referred for HDL-c <5th percentile and in four patients referred for low HDL-c and corneal opacities. LCAT mutations were highly prevalent: in 28 of the 98 participants (29%), heterozygosity for nonsynonymous mutations was identified while 18 patients carried the same mutation (p.T147I). The four patients with corneal opacity were compound heterozygotes. All previously identified mutations are documented to cause loss of catalytic activity. Nine novel mutations-c.402G>T (p.E134D), c.403T>A (p.Y135N), c.964C>T (p.R322C), c.296G>C (p.W99S), c.736G>T (p.V246F), c.802C>T (p.R268C), c.945G>A (p.W315X), c.1012C>T (p.L338F), and c.1039C>T (p.R347C)--were shown to be functional through in vitro characterization. The effect of several mutations on the core protein structure was studied by a three-dimensional (3D) model. Unlike previous reports, functional mutations in LCAT were found in 29% of patients with low HDL-c, thus constituting a common cause of low HDL-c in referred patients in The Netherlands.
Assuntos
HDL-Colesterol/genética , Deficiência da Lecitina Colesterol Aciltransferase/genética , Mutação , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Adulto , Idoso , Animais , Células COS , Pré-Escolar , Chlorocebus aethiops , HDL-Colesterol/sangue , Opacidade da Córnea/genética , Feminino , Variação Genética , Heterozigoto , Humanos , Deficiência da Lecitina Colesterol Aciltransferase/epidemiologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , PrevalênciaRESUMO
BACKGROUND: A large variety of proteins involved in inflammation, coagulation, lipid-oxidation and lipid metabolism have been associated with high-density lipoprotein (HDL) and it is anticipated that changes in the HDL proteome have implications for the multiple functions of HDL. Here, SELDI-TOF mass spectrometry (MS) was used to study the dynamic changes of HDL protein composition in a human experimental low-dose endotoxemia model. Ten healthy men with low HDL cholesterol (0.7+/-0.1 mmol/L) and 10 men with high HDL cholesterol levels (1.9+/-0.4 mmol/L) were challenged with endotoxin (LPS) intravenously (1 ng/kg bodyweight). We previously showed that subjects with low HDL cholesterol are more susceptible to an inflammatory challenge. The current study tested the hypothesis that this discrepancy may be related to differences in the HDL proteome. RESULTS: Plasma drawn at 7 time-points over a 24 hour time period after LPS challenge was used for direct capture of HDL using antibodies against apolipoprotein A-I followed by subsequent SELDI-TOF MS profiling. Upon LPS administration, profound changes in 21 markers (adjusted p-value < 0.05) were observed in the proteome in both study groups. These changes were observed 1 hour after LPS infusion and sustained up to 24 hours, but unexpectedly were not different between the 2 study groups. Hierarchical clustering of the protein spectra at all time points of all individuals revealed 3 distinct clusters, which were largely independent of baseline HDL cholesterol levels but correlated with paraoxonase 1 activity. The acute phase protein serum amyloid A-1/2 (SAA-1/2) was clearly upregulated after LPS infusion in both groups and comprised both native and N-terminal truncated variants that were identified by two-dimensional gel electrophoresis and mass spectrometry. Individuals of one of the clusters were distinguished by a lower SAA-1/2 response after LPS challenge and a delayed time-response of the truncated variants. CONCLUSIONS: This study shows that the semi-quantitative differences in the HDL proteome as assessed by SELDI-TOF MS cannot explain why subjects with low HDL cholesterol are more susceptible to a challenge with LPS than those with high HDL cholesterol. Instead the results indicate that hierarchical clustering could be useful to predict HDL functionality in acute phase responses towards LPS.
RESUMO
OBJECTIVE: Hypertriglyceridemia and fatty liver are common in patients with type 2 diabetes, but the factors connecting alterations in glucose metabolism with plasma and liver lipid metabolism remain unclear. Apolipoprotein CIII (apoCIII), a regulator of hepatic and plasma triglyceride metabolism, is elevated in type 2 diabetes. In this study, we analyzed whether apoCIII is affected by altered glucose metabolism. METHODS AND RESULTS: Liver-specific insulin receptor-deficient mice display lower hepatic apoCIII mRNA levels than controls, suggesting that factors other than insulin regulate apoCIII in vivo. Glucose induces apoCIII transcription in primary rat hepatocytes and immortalized human hepatocytes via a mechanism involving the transcription factors carbohydrate response element-binding protein and hepatocyte nuclear factor-4α. ApoCIII induction by glucose is blunted by treatment with agonists of farnesoid X receptor and peroxisome proliferator-activated receptor-α but not liver X receptor, ie, nuclear receptors controlling triglyceride metabolism. Moreover, in obese humans, plasma apoCIII protein correlates more closely with plasma fasting glucose and glucose excursion after oral glucose load than with insulin. CONCLUSIONS: Glucose induces apoCIII transcription, which may represent a mechanism linking hyperglycemia, hypertriglyceridemia, and cardiovascular disease in type 2 diabetes.
Assuntos
Apolipoproteína C-III/genética , Complicações do Diabetes/etiologia , Diabetes Mellitus Tipo 2/complicações , Dislipidemias/etiologia , Glucose/metabolismo , Hepatócitos/metabolismo , Ativação Transcricional , Adulto , Animais , Apolipoproteína C-III/sangue , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Glicemia/metabolismo , Células Cultivadas , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/genética , Dislipidemias/metabolismo , Proteínas de Choque Térmico/agonistas , Proteínas de Choque Térmico/metabolismo , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Insulina/sangue , Receptores X do Fígado , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/sangue , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Regiões Promotoras Genéticas , Interferência de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/agonistas , Proteínas de Ligação a RNA/metabolismo , Ratos , Receptor de Insulina/deficiência , Receptor de Insulina/genética , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Tempo , Fatores de Transcrição/agonistas , Fatores de Transcrição/metabolismo , Transfecção , Regulação para CimaRESUMO
The aim of the study was to test whether fasting or postprandial cholesteryl ester transfer protein (CETP) concentrations are associated with postprandial changes in high-density lipoprotein cholesterol (HDL-c) concentrations after fat-rich or carbohydrate-rich meals. Postmenopausal women (76 with normal glucose metabolism [NGM], 41 with type 2 diabetes mellitus [T2DM], and 38 T2DM women with statin therapy [T2DM-ST]) received 2 consecutive fat-rich or carbohydrate-rich meals on separate occasions. Linear regression analysis was performed to assess the associations of fasting CETP and postprandial changes of CETP with postprandial changes in HDL-c. Mean plasma HDL-c concentrations decreased significantly after the fat-rich meals: 0.18 +/- 0.09 mmol/L in NGM, 0.16 +/- 0.09 mmol/L in T2DM, and 0.14 +/- 0.08 mmol/L in T2DM-ST women. This effect was smaller after using carbohydrate-rich meals: 0.12 +/- 0.09 mmol/L in the NGM, 0.12 +/- 0.08 mmol/L in the T2DM, and 0.10 +/- 0.05 mmol/L in the T2DM-ST study group. Higher fasting but not postprandial CETP concentrations were associated with a larger postprandial decrease in HDL-c (beta -0.034; 95% confidence interval, -0.067 to -0.001) after the fat-rich meals. This association was independent of the postprandial increase in triglycerides and similar among the 3 study groups. A high fasting CETP concentration may contribute to the postprandial atherogenic lipoprotein profile in postmenopausal women by decreasing HDL-c after fat-rich meals. This effect is independent from the postprandial increase in triglycerides.