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NAFLD or non-alcoholic fatty liver disease is one of the complications of obesity and diabetes, the prevalence of which is increasing. The causes of the pathology and its development towards its severe form, NASH or non-alcoholic steatohepatitis, are multiple and still poorly understood. Many different pharmacological classes are being tested in clinical trials to treat NASH, but no pharmaceutical treatment is currently on the market. Moreover, the diagnosis of certainty is only possible by liver biopsy and histological analysis, an invasive procedure with high risk for the patient. It is therefore necessary to better understand the natural history of the disease in order to identify therapeutic targets, but also to identify markers for the diagnosis and monitoring of the disease using a blood sample, which will allow an improvement in patient management.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia , Hepatopatia Gordurosa não Alcoólica/complicações , BiópsiaRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most important cause of chronic liver disease in the western world. Steatosis can be accompanied by inflammation and cell damage (non-alcoholic steatohepatitis, NASH), and even liver fibrosis. Sphingolipids are a heterogeneous class of lipids and essential components of the plasma membrane and plasma lipoproteins. The atypical class of deoxy-sphingolipids has been implicated in the metabolic syndrome and type 2 diabetes. AIM: To determine if circulating (deoxy)sphingolipids are associated with NAFLD and its different entities, steatosis, inflammatory changes (inflammation and ballooning) and fibrosis. METHODS: Sphingolipids were analysed by LC-MS after hydrolysing the N-acyl and O-linked headgroups in plasma of obese adults who underwent a liver biopsy in suspicion of NAFLD. RESULTS: Two-hundred and eighty-eight patients were included. There was no association between typical sphingolipids and NAFLD and its different entities. There was a significant association between the presence of steatosis and the concentrations of deoxy-sphinganine [exp(B) 11.163 with CI (3.432, 36.306) and p < 0.001] and deoxy-sphingosine [exp(B) 8.486 with CI (3.437, 20.949) and p < 0.001]. There was no association between these deoxy-sphingolipids and activity of the steatohepatitis, nor was there any association with fibrosis. Differences in deoxy-sphingolipids also correlated independently with the presence of the metabolic syndrome, but not diabetes. CONCLUSION: Deoxy-sphingolipids are elevated in patients with steatosis compared to those without fatty liver, but not different between the different NAFLD subtypes, suggesting that deoxy-sphingolipid bases might be involved in steatogenesis, but not in the further progression of NAFLD to NASH nor in fibrogenesis.
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Fígado Gorduroso/sangue , Cirrose Hepática/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/patologia , Esfingolipídeos/sangue , Adulto , Bélgica/epidemiologia , Biópsia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Progressão da Doença , Doença Hepática Terminal/sangue , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/epidemiologia , Doença Hepática Terminal/patologia , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/epidemiologia , Fígado Gorduroso/patologia , Feminino , Humanos , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/sangue , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/patologia , PrognósticoRESUMO
BACKGROUND: Ivermectin (IVM) is widely used in both human and veterinary medicine to treat parasitic infections. Recent reports have suggested that IVM could also have anti-inflammatory properties. METHODS: Here, we investigated the activity of IVM in a murine model of atopic dermatitis (AD) induced by repeated exposure to the allergen Dermatophagoides farinae, and in standard cellular immunological assays. RESULTS: Our results show that topical IVM improved allergic skin inflammation by reducing the priming and activation of allergen-specific T cells, as well as the production of inflammatory cytokines. While IVM had no major impact on the functions of dendritic cells in vivo and in vitro, IVM impaired T-cell activation, proliferation, and cytokine production following polyclonal and antigen-specific stimulation. CONCLUSION: Altogether, our results show that IVM is endowed with topical anti-inflammatory properties that could have important applications for the treatment of T-cell-mediated skin inflammatory diseases.
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Alérgenos/imunologia , Dermatite Atópica/imunologia , Ivermectina/administração & dosagem , Administração Tópica , Animais , Antígenos de Dermatophagoides/imunologia , Linhagem Celular , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Modelos Animais de Doenças , ELISPOT , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Receptores Purinérgicos P2X4/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Roux-en-Y gastric bypass (RYGB) surgery is widely used in the management of morbid obesity. RYGB improves metabolism independently of weight loss by still unknown mechanisms. Bile acids (BAs) are good candidates to explain this benefit, since they regulate metabolic homeostasis and their systemic concentrations increase upon RYGB. Here we analyzed the mechanisms underlying the increase in systemic BA concentrations after RYGB and the role of the liver therein. To this aim, we used the Göttingen-like minipig, a human-size mammalian model, which allows continuous sampling and simultaneous analysis of pre-hepatic portal and systemic venous blood. BA concentrations and pool composition were measured in portal blood, containing intestinal reabsorbed BAs and compared to systemic blood during a standardized meal test before and after RYGB. Systemic total BA concentrations increased after RYGB, due to an increase in conjugated BAs. Interestingly, the ratio of portal:systemic conjugated BAs decreased after RYGB, indicating a role for the liver in systemic BA concentrations changes. In line, hepatic expression of BA transporter genes decreased after RYGB. Our results show that the increase in systemic BAs after surgery is due to decreased selective hepatic recapture. Thus, alterations in hepatic function contribute to the increase in systemic BAs after RYGB.
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Ácidos e Sais Biliares/metabolismo , Derivação Gástrica , Fígado/metabolismo , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Porco Miniatura/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Suínos , Redução de Peso/fisiologiaRESUMO
Macrophages are central cells in the genesis and development of atherosclerosis, one of the major causes of cardiovascular diseases. Macrophages take up lipids (mainly cholesterol and triglycerides) from lipoproteins thus transforming into foam cells. Moreover, through the efflux pathway, macrophages are the main actors of the elimination of excessive tissue cholesterol toward extra-cellular acceptors. Macrophages participate in the control of inflammation by displaying different functional phenotypes, from the M1 pro-inflammatory to the M2 anti-inflammatory state. The nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)ß (also called PPARδ or PPARß/δ) is expressed in macrophages where it plays a different role in the control of lipid metabolism, inflammation and phagocytosis of apoptotic cells. This review will summarize our current understanding of how PPARß regulates macrophage biology and its impact on atherosclerosis. Differences between studies and species-specific macrophage gene regulation will be discussed.
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Aterosclerose/metabolismo , Macrófagos/metabolismo , PPAR beta/metabolismo , Animais , Transporte Biológico , Colesterol/metabolismo , Humanos , Inflamação/metabolismoRESUMO
BACKGROUND: Roux-en-Y gastric bypass (RYGBP) is the most widely used bariatric surgery procedure, which induces profound metabolic and physiological effects, such as substantial improvements in obesity, type 2 diabetes and their comorbidities. Increasing evidence identifies bile acids (BAs) as signaling molecules that contribute to the metabolic improvement after RYGBP. However, how and to what extent BAs mediate the metabolic effects of RYGBP still remains unclear and requires mechanism of action studies using preclinical models. In this study, we compared plasma BA profiles before and after RYGBP in two animal models, rats and pigs, with humans to evaluate their translational potential. METHODS: Plasma BAs were profiled in rats, pigs and humans by liquid chromatography coupled with tandem mass spectrometry before and after RYGBP. RESULTS: RYGBP increased baseline plasma total BA concentrations in humans and in the two animal models to a similar extent (â¼3-fold increase), despite differences in presurgery BA levels and profiles between the models. However, qualitatively, RYGBP differently affected individual plasma BA species, with similar increases in some free species (cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA)), different increases in glyco-conjugated species depending on the model and globally no increase in tauro-conjugated species whatever the model. CONCLUSIONS: The tested animal models share similar quantitative RYGBP-induced increases in peripheral blood BAs as humans, which render them useful for mechanistic studies. However, they also present qualitative differences in BA profiles, which may result in different signaling responses. Such differences need to be taken into account when translating results to humans.
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Ácidos e Sais Biliares/sangue , Derivação Gástrica , Obesidade/sangue , Obesidade/cirurgia , Adulto , Animais , Glicemia/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Ratos , Transdução de Sinais , Suínos , Porco Miniatura , Resultado do Tratamento , Redução de PesoRESUMO
Since the publication of the above article it has been noted that the author S O'Brien should have been listed as CS O'Brien. The authors should therefore appear as follows: R Dutia, M Embrey, CS O'Brien, RA Haeusler, KK Agénor, P Homel, J McGinty, RP Vincent, J Alaghband-Zadeh, B Staels, CW le Roux, J Yu and B Laferrère The corrected article html and online pdf versions have been amended. The authors wish to apologise for any inconvenience caused.
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BACKGROUND: Atherosclerosis is an inflammatory disease in which macrophages play a crucial role. Macrophages are present in different phenotypes, with at the extremes of the spectrum the classical M1 pro-inflammatory and the alternative M2 anti-inflammatory macrophages. The neuron-derived orphan receptor 1 (NOR1), together with Nur77 and Nurr1, are members of the NR4A orphan nuclear receptor family, expressed in human atherosclerotic lesion macrophages. However, the role of NOR1 in human macrophages has not been studied yet. OBJECTIVES: To determine the expression and the functions of NOR1 in human alternative macrophages. METHODS AND RESULTS: In vitro IL-4 polarization of primary monocytes into alternative M2 macrophages enhances NOR1 expression in human but not in mouse macrophages. Moreover, NOR1 expression is most abundant in CD68+MR+ alternative macrophage-enriched areas of human atherosclerotic plaques in vivo. Silencing NOR1 in human alternative macrophages decreases the expression of several M2 markers such as the Mannose Receptor (MR), Interleukin-1 Receptor antagonist (IL-1Ra), CD200 Receptor (CD200R), coagulation factor XIII A1 polypeptide (F13A1), Interleukin 10 (IL-10) and the Peroxisome Proliferator-Activated Receptor (PPAR)γ. Bioinformatical analysis identified F13A1, IL-1Ra, IL-10 and the Matrix Metalloproteinase-9 (MMP9) as potential target genes of NOR1 in human alternative macrophages. Moreover, expression and enzymatic activity of MMP9 are induced by silencing and repressed by NOR1 overexpression in M2 macrophages. CONCLUSIONS: These data identify NOR1 as a transcription factor induced during alternative differentiation of human macrophages and demonstrate that NOR1 modifies the alternative macrophage phenotype.
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Doenças das Artérias Carótidas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Animais , Biomarcadores/metabolismo , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/imunologia , Doenças das Artérias Carótidas/patologia , Diferenciação Celular , Células Cultivadas , Proteínas de Ligação a DNA/genética , Inativação Gênica , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-4/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Fenótipo , Placa Aterosclerótica , Cultura Primária de Células , Interferência de RNA , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , Fatores de Tempo , TransfecçãoRESUMO
INTRODUCTION: Gastric bypass surgery (GBP) leads to sustained weight loss and significant improvement in type 2 diabetes (T2DM). Bile acids (BAs), signaling molecules which influence glucose metabolism, are a potential mediator for the improvement in T2DM after GBP. This study sought to investigate the effect of GBP on BA levels and composition in individuals with T2DM. METHODS: Plasma BA levels and composition and fibroblast growth factor (FGF)-19 levels were measured during fasting and in response to an oral glucose load before and at 1 month and 2 years post GBP in 13 severely obese women with T2DM. RESULTS: A striking temporal change in BA levels and composition was observed after GBP. During the fasted state, BA concentrations were generally reduced at 1 month, but increased 2 years post GBP. Postprandial BA levels were unchanged 1 month post GBP, but an exaggerated postprandial peak was observed 2 years after the surgery. A significant increase in the 12α-hydroxylated/non12α-hydroxylated BA ratio during fasting and postprandially at 2 years, but not 1 month, post GBP was observed. Significant correlations between BAs vs FGF-19, body weight, the incretin effect and peptide YY (PYY) were also found. CONCLUSIONS: This study provides evidence that GBP temporally modifies the concentration and composition of circulating BAs in individuals with T2DM, and suggests that BAs may be linked to the improvement in T2DM after GBP.
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Ácidos e Sais Biliares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Derivação Gástrica , Hidroxilação , Obesidade Mórbida/cirurgia , Redução de Peso , Adulto , Jejum/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade Mórbida/metabolismo , Peptídeo YY/metabolismo , Período Pós-Operatório , Período Pós-Prandial , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Coronary artery disease (CAD) is a major cause of morbidity and mortality. Mutations in C6ORF105, associated with decreased gene expression, positively correlate with the risk of CAD in Chinese populations. Moreover, the C6ORF105-encoded protein may play a role in coagulation. Here, we report that C6ORF105 gene expression is lower in circulating mononuclear cells from obese diabetic than lean subjects. Moreover, C6ORF105 is expressed in human macrophages and atherosclerotic lesions, where its expression positively correlates with expression of the transcription factor Peroxisome Proliferator-Activated Receptor (PPAR)γ. Activation of PPARγ increases, in a PPARγ-dependent manner, the expression of C6ORF105 in human macrophages and atherosclerotic lesions.
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Doença da Artéria Coronariana/genética , Macrófagos/metabolismo , Proteínas de Membrana/genética , PPAR gama/fisiologia , Aterosclerose/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Expressão Gênica , Humanos , Proteínas de Membrana/biossíntese , Obesidade/metabolismo , Ativação TranscricionalRESUMO
Glucuronidation, catalyzed by uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA-glucuronide (BA-G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid-lowering drug fenofibrate on the circulating BA-G profile in 300 volunteers and 5 cholestatic patients. Eleven BA-Gs were determined in pre- and postfenofibrate samples. Men exhibited higher BA-G concentrations, and various genotype/BA-G associations were discovered in relevant UGT genes. The chenodeoxycholic acid-3G (CDCA-3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA-3G formation. Fenofibrate exposure increased the serum levels of five BA-G species, including CDCA-3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver.
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Ácidos e Sais Biliares/sangue , Colestase/tratamento farmacológico , Fenofibrato/farmacologia , Glucuronídeos/sangue , Glucuronosiltransferase/genética , Hipolipemiantes/farmacologia , Caracteres Sexuais , Colestase/sangue , Colestase/enzimologia , Feminino , Fenofibrato/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipolipemiantes/uso terapêutico , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , PPAR alfa/agonistas , Proliferadores de Peroxissomos/farmacologia , Polimorfismo Genético/genética , Pirimidinas/farmacologiaRESUMO
OBJECTIVE: Mechanisms explaining the relationship in non-alcoholic fatty liver disease (NAFLD), obesity, and insulin resistance are poorly understood. A genetic basis has been suggested. We studied the association between the genes patatin-like phospholipase domain-containing protein 3 (PNPLA3) and apolipoprotein C3 (APOC3) and metabolic and histological parameters of NAFLD in obese patients. DESIGN AND METHODS: Overweight and obese patients underwent a metabolic and liver assessment. If NAFLD was suspected, liver biopsy was proposed. APOC3 variant rs2854117 and PNPLA3 variant rs738409 were genotyped. RESULTS: Four hundred seventy patients were included (61.1% had liver biopsy). The percentage of patients with non-alcoholic steatohepatitis (NASH) was significantly different according to the PNPLA3 variant. After adjustment for age and body mass index, the PNPLA3 variant was associated with alanine aminotransferase (P < 0.001) and aspartate aminotransferase (P < 0.001). The PNPLA3 variant was associated with more severe features of steatohepatitis: steatosis (P < 0.001), lobular inflammation (P < 0.001), and ballooning (P = 0.002), but not with liver fibrosis, anthropometry, or insulin resistance. No significant difference in liver histology, anthropometric, or metabolic parameters was found between carriers and non-carriers of the APOC3 variant. CONCLUSIONS: PNPLA3 polymorphism rs738409 was associated with NASH and the severity of necroinflammatory changes independently of metabolic factors. No association between APOC3 gene variant rs2854117 and histological or metabolic parameters of NAFLD was found.
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Apolipoproteína C-III/genética , Fígado Gorduroso/genética , Predisposição Genética para Doença , Lipase/genética , Proteínas de Membrana/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Apolipoproteína C-III/metabolismo , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Índice de Massa Corporal , Estudos Transversais , Feminino , Genótipo , Humanos , Gordura Intra-Abdominal/metabolismo , Lipase/metabolismo , Metabolismo dos Lipídeos/genética , Fígado/patologia , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Hepatopatia Gordurosa não AlcoólicaRESUMO
AIMS/HYPOTHESIS: Human adipose tissue macrophages (ATMs) display an alternatively activated (M2) phenotype, but are still able to produce excessive inflammatory mediators. However, the processes driving this particular ATM phenotype are not understood. Genome-wide association studies associated the CDKN2A locus, encoding the tumour suppressor p16(INK4A), with the development of type 2 diabetes. In the present study, p16(INK4A) levels in human ATMs and the role of p16(INK4A) in acquiring the ATM phenotype were assessed. METHODS: Gene expression of p16 ( INK4A ) in ATMs was analysed and compared with that in monocyte-derived macrophages (MDMs) from obese patients or with macrophages from human atherosclerotic plaques (AMs). Additionally, p16(INK4A) levels were studied during macrophage differentiation and polarisation of monocytes isolated from healthy donors. The role of p16(INK4A) in MDMs from healthy donors was investigated by small interfering (si)RNA-mediated silencing or adenovirus-mediated overproduction of p16(INK4A). RESULTS: Compared with MDMs and AMs, ATMs from obese patients expressed lower levels of p16 ( INK4A ). In vitro, IL-4-induced M2 polarisation resulted in lower p16(INK4A) protein levels after differentiation of monocytes from healthy donors in macrophages. Silencing of p16(INK4A) in MDMs mediated by siRNA increased the expression of M2 marker genes and enhanced the response to lipopolysaccharide (LPS), to give a phenotype resembling that of ATM. By contrast, adenovirus-mediated overproduction of p16(INK4A) in MDMs diminished M2 marker gene expression and the response to LPS. Western blot analysis revealed that p16(INK4A) overproduction inhibits LPS- and palmitate-induced Toll-like receptor 4 (TLR4)-nuclear factor of κ light polypeptide gene enhancer in B cells (NF-κB) signalling. CONCLUSIONS/INTERPRETATION: These results show that p16(INK4A) inhibits the acquisition of the ATM phenotype. The age-related increase in p16(INK4A) level may thus influence normal ATM function and contribute to type 2 diabetes risk.
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Tecido Adiposo/metabolismo , Polaridade Celular , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Macrófagos/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Diabetes Mellitus Tipo 2/metabolismo , Regulação para Baixo , Feminino , Inativação Gênica , Humanos , Masculino , NF-kappa B/metabolismo , Obesidade/metabolismo , Placa Aterosclerótica/metabolismo , RNA Interferente Pequeno/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
BACKGROUND AND PURPOSE: Humanized mice for the nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ), termed PPARδ knock-in (PPARδ KI) mice, were generated for the investigation of functional differences between mouse and human PPARδ and as tools for early drug efficacy assessment. EXPERIMENTAL APPROACH: Human PPARδ function in lipid metabolism was assessed at baseline, after fasting or when challenged with the GW0742 compound in mice fed a chow diet or high-fat diet (HFD). KEY RESULTS: Analysis of PPARδ mRNA levels revealed a hypomorph expression of human PPARδ in liver, macrophages, small intestine and heart, but not in soleus and quadriceps muscles, white adipose tissue and skin. PPARδ KI mice displayed a small decrease of high-density lipoprotein-cholesterol whereas other lipid parameters were unaltered. Plasma metabolic parameters were similar in wild-type and PPARδ KI mice when fed chow or HFD, and following physiological (fasting) and pharmacological (GW0742 compound) activation of PPARδ. Gene expression profiling in liver, soleus muscle and macrophages showed similar gene patterns regulated by mouse and human PPARδ. The anti-inflammatory potential of human PPARδ was also similar to mouse PPARδ in liver and isolated macrophages. CONCLUSIONS AND IMPLICATIONS: These data indicate that human PPARδ can compensate for mouse PPARδ in the regulation of lipid metabolism and inflammation. Overall, this novel PPARδ KI mouse model shows full responsiveness to pharmacological challenge and represents a useful tool for the preclinical assessment of PPARδ activators with species-specific activity.
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Inflamação/tratamento farmacológico , Inflamação/genética , PPAR delta/genética , PPAR delta/metabolismo , Animais , DNA Complementar/genética , Dieta Hiperlipídica/métodos , Jejum/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , PPAR delta/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tiazóis/farmacologiaRESUMO
Macrophages play a pivotal role in the development of atherosclerosis. After recruitment in the sub-endothelial space, monocytes differentiate into macrophages, accumulate lipids thus forming foam cells and secrete pro-inflammatory and matrix-degrading factors, thus playing a role in plaque development, inflammation and instability. Therefore, pharmacological modulation of macrophage functions represents an attractive strategy for the prevention and treatment of cardiovascular diseases caused by atherosclerosis. In this review, recent advances on the role of the peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) transcription factors in the modulation of macrophage lipid homeostasis will be discussed.
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Aterosclerose/metabolismo , Colesterol/metabolismo , Macrófagos/metabolismo , Organelas/metabolismo , Fatores de Transcrição/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Proteínas de Ligação a DNA/metabolismo , Células Espumosas/metabolismo , Homeostase , Humanos , Hipolipemiantes/uso terapêutico , Ligantes , Metabolismo dos Lipídeos/genética , Receptores X do Fígado , Macrófagos/efeitos dos fármacos , Receptores Nucleares Órfãos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/efeitos dos fármacosRESUMO
Altered macrophage functions contribute to the pathogenesis of many infectious, immunological and inflammatory disease processes. Pharmacological modulation of macrophage activities therefore represents an important strategy for the prevention and treatment of inflammation-related diseases, such as atherosclerosis. This review focuses on recent advances on the role of the peroxisome proliferator-activated receptor transcription factor family in the modulation of lipid homeostasis and the inflammatory response in macrophages and the potential participation of these actions in the modulation of metabolic and cardiovascular disease.
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Aterosclerose , Doenças Cardiovasculares/tratamento farmacológico , Colesterol/metabolismo , Hipolipemiantes/uso terapêutico , Macrófagos/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Ensaios Clínicos como Assunto , Fenofibrato/efeitos adversos , Fenofibrato/uso terapêutico , Genfibrozila/efeitos adversos , Genfibrozila/uso terapêutico , Humanos , Macrófagos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/fisiologiaRESUMO
PPARs (peroxisome-proliferator-activated receptors) and LXRs (liver X receptors) are ligand-activated transcription factors that control lipid and glucose metabolism, as well as the inflammatory response. Since the macrophage plays an important role in host defence and immuno-inflammatory pathologies, particular attention has been paid to the role of PPARs and LXRs in the control of macrophage gene expression and function. Altered macrophage functions contribute to the pathogenesis of many infectious, immunological and inflammatory disease processes, including atherosclerosis. Research over the last few years has revealed important roles for PPARs and LXRs in macrophage inflammation and cholesterol homoeostasis with consequences in atherosclerosis development. This review will discuss the role of these transcription factors in the control of cholesterol trafficking in macrophages.
Assuntos
Colesterol/fisiologia , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Macrófagos/fisiologia , PPAR alfa/genética , Receptores Citoplasmáticos e Nucleares/genética , Transcrição Gênica , Animais , Humanos , Ligantes , Receptores X do Fígado , Modelos Biológicos , Receptores Nucleares Órfãos , Fatores de Transcrição/fisiologiaRESUMO
Peroxisome proliferator-activated receptors (PPARalpha, PPARbeta/delta and PPARgamma) are a family of nuclear receptors that are activated by binding of natural ligands, such as polyunsaturated fatty acids or by synthetic ligands. Synthetic molecules of the glitazone family, which bind to PPARgamma, are currently used to treat type II diabetes and also to attenuate the secondary clinical symptoms frequently associated with insulin resistance, including polycystic ovary syndrome (PCOS). PPARs are expressed in different compartments of the reproductive system (hypothalamus, pituitary, ovary, uterus and testis). Conservative functions of PPARs in mammalian species could be suggested through several in vivo and in vitro studies, especially in the ovary and during placental development. Several groups have described a strong expression of PPARgamma in ovarian granulosa cells, and glitazones modulate granulosa cell proliferation and steroidogenesis in vitro. All these recent data raise new questions about the biologic actions of PPARs in reproduction and their use in therapeutic treatments of fertility troubles such as PCOS or endometriosis. In this review, we first describe the roles of PPARs in different compartments of the reproductive axis (from male and female gametogenesis to parturition), with a focus on PPARgamma. Secondly, we discuss the possible molecular mechanisms underlying the effect of glitazones on PCOS. Like other 'insulin sensitizer' molecules, such as metformin, glitazones may in fact act directly on ovarian cells. Finally, we discuss the eventual actions of PPARs as mediators of environmental toxic substances for reproductive function.
Assuntos
Gametogênese/fisiologia , Parto/fisiologia , Receptores Ativados por Proliferador de Peroxissomo/fisiologia , Corpo Lúteo/metabolismo , Desenvolvimento Embrionário/fisiologia , Estradiol/biossíntese , Feminino , Células da Granulosa/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/química , Sistema Hipotálamo-Hipofisário/fisiologia , Infertilidade Feminina/fisiopatologia , Masculino , Ovário/química , Ovário/fisiologia , Receptores Ativados por Proliferador de Peroxissomo/análise , Placenta/fisiopatologia , Síndrome do Ovário Policístico/fisiopatologia , Progesterona/biossíntese , Testículo/química , Testículo/fisiologiaRESUMO
Liver X receptors (LXRs) are nuclear receptors that regulate macrophage cholesterol efflux by inducing ATP-binding cassette transporter A1 (ABCA1) and ABCG1/ABCG4 gene expression. The Niemann-Pick C (NPC) proteins NPC1 and NPC2 are located in the late endosome, where they control cholesterol trafficking to the plasma membrane. The mobilization of cholesterol from intracellular pools to the plasma membrane is a determinant governing its availability for efflux to extracellular acceptors. Here we investigated the influence of LXR activation on intracellular cholesterol trafficking in primary human macrophages. Synthetic LXR activators increase the amount of free cholesterol in the plasma membrane by inducing NPC1 and NPC2 gene expression. Moreover, ABCA1-dependent cholesterol efflux induced by LXR activators was drastically decreased in the presence of progesterone, which blocks postlysosomal cholesterol trafficking, and reduced when NPC1 and NPC2 mRNA expression was depleted using small interfering RNA. The stimulation of cholesterol mobilization to the plasma membrane by LXRs led to a decrease in cholesteryl ester formation and Acyl-coenzyme A cholesterol acyltransferase-1 activity. These data indicate that LXR activation enhances cholesterol trafficking to the plasma membrane, where it becomes available for efflux, at the expense of esterification, thus contributing to the overall effects of LXR agonists in the control of macrophage cholesterol homeostasis.
Assuntos
Ésteres do Colesterol/metabolismo , Colesterol/metabolismo , Proteínas de Ligação a DNA/fisiologia , Macrófagos/metabolismo , Receptores Citoplasmáticos e Nucleares/fisiologia , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/fisiologia , Animais , Transporte Biológico , Proteínas de Transporte/fisiologia , Membrana Celular/metabolismo , Células Cultivadas , Ésteres do Colesterol/análise , Células Espumosas/metabolismo , Glicoproteínas/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Receptores X do Fígado , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína C1 de Niemann-Pick , Receptores Nucleares Órfãos , Progesterona/farmacologia , RNA Interferente Pequeno/farmacologia , Proteínas de Transporte VesicularRESUMO
The mobilization of cholesterol from intracellular pools to the plasma membrane is a determinant that governs its availability for efflux to extracellular acceptors. NPC1 and NPC2 are proteins localized in the late endosome and control cholesterol transport from the lysosome to the plasma membrane. Here, we report that NPC1 and NPC2 gene expression is induced by oxidized LDL (OxLDL) in human macrophages. Because OxLDLs contain natural activators of peroxisome proliferator-activated receptor alpha (PPARalpha), a fatty acid-activated nuclear receptor, the regulation of NPC1 and NPC2 by PPARalpha and the consequences on cholesterol trafficking were further studied. NPC1 and NPC2 expression is induced by synthetic PPARalpha ligands in human macrophages. Furthermore, PPARalpha activation leads to an enrichment of cholesterol in the plasma membrane. By contrast, incubation with progesterone, which blocks postlysosomal cholesterol trafficking, as well as NPC1 and NPC2 mRNA depletion using small interfering RNA, abolished ABCA1-dependent cholesterol efflux induced by PPARalpha activators. These observations identify a novel regulatory role for PPARalpha in the control of cholesterol availability for efflux that, associated with its ability to inhibit cholesterol esterification and to stimulate ABCA1 and scavenger receptor class B type I expression, may contribute to the stimulation of reverse cholesterol transport.