RESUMEN
INTRODUCTION: The objective of this study was to investigate the role of fenofibrate, a peroxisome proliferator-activated receptor-α agonist, in obesity-induced kidney damage (lipotoxicity) in mice with uninephrectomy. METHODS: C57BL/6 mice underwent uninephrectomy and sham surgeries and were fed normocaloric or high-fat diets. After 10 weeks, obese mice were administered 0.02% fenofibrate for 10 weeks. Kidney function and morphology were evaluated, as well as levels of inflammatory and fibrotic mediators and lipid metabolism markers. RESULTS: High-fat diet-fed mice developed characteristic obesity and hyperlipidemia, with subsequent renal lipid accumulation and damage, including mesangial expansion, interstitial fibrosis, inflammation, and proteinuria. These changes were greater in obese uninephrectomy mice than in obese sham mice. Fenofibrate treatment prevented hyperlipidemia and glomerular lesions, lowered lipid accumulation, ameliorated renal dysfunction, and attenuated inflammation and renal fibrosis. Furthermore, fenofibrate treatment downregulated renal tissue expression of plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and local expression of fibroblast growth factor-21. CONCLUSION: Peroxisome proliferator-activated receptor-α activation by fenofibrate, with subsequent lipolysis, attenuated glomerular and tubulointerstitial lesions induced by renal lipotoxicity, thus protecting the kidneys of uninephrectomy mice from obesity-induced lesions. The study findings suggest a pathway in the pharmacological action of fenofibrate, providing insight into the mechanisms involved in kidney damage caused by obesity in kidney donors.
Asunto(s)
Dieta Alta en Grasa , Fenofibrato , Hipolipemiantes , Ratones Endogámicos C57BL , Nefrectomía , Obesidad , Animales , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Ratones , Obesidad/complicaciones , Obesidad/metabolismo , Masculino , Hipolipemiantes/uso terapéutico , Hipolipemiantes/farmacología , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/prevención & control , Enfermedades Renales/metabolismo , Metabolismo de los Lípidos/efectos de los fármacosRESUMEN
PURPOSE: To investigate the neuroprotective effects of the SOD2 gene in cerebral ischemia reperfusion injury function and the underlying mechanisms in a mice model of middle cerebral artery ischemia reperfusion. METHODS: SOD2 transgenic mice were engineered using transcription activator-like effector nucleases, and the genotype was identified using PCR after every three generations. Transgenic and C57BL/6J wild type mice were simultaneously subjected to the middle cerebral artery occlusion model. RESULTS: SOD2 expression in the brain, heart, kidney, and skeletal muscle of transgenic mice was significantly higher than that in the wild type. Following ischemia reperfusion, the infarct volume of wild type mice decreased after treatment with fenofibrate compared to the CMC group. Infarction volume in SOD2 transgenic mice after CMC and fenofibrate treatment was significantly reduced. The recovery of cerebral blood flow in wild type mice treated with fenofibrate was significantly enhanced compared with that in the CMC group. CONCLUSIONS: The expression of SOD2 in transgenic mice was significantly higher than that in wild type mice, the neuroprotective role of fenofibrate depends on an increase in SOD2 expression.
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Modelos Animales de Enfermedad , Fenofibrato , Ratones Endogámicos C57BL , Ratones Transgénicos , Daño por Reperfusión , Superóxido Dismutasa , Animales , Daño por Reperfusión/genética , Superóxido Dismutasa/genética , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Isquemia Encefálica/genética , Humanos , Masculino , Ratones , Infarto de la Arteria Cerebral Media/genética , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
Chagas disease, caused by Trypanosoma cruzi, stands as the primary cause of dilated cardiomyopathy in the Americas. Macrophages play a crucial role in the heart's response to infection. Given their functional and phenotypic adaptability, manipulating specific macrophage subsets could be vital in aiding essential cardiovascular functions including tissue repair and defense against infection. PPARα are ligand-dependent transcription factors involved in lipid metabolism and inflammation regulation. However, the role of fenofibrate, a PPARα ligand, in the activation profile of cardiac macrophages as well as its effect on the early inflammatory and fibrotic response in the heart remains unexplored. The present study demonstrates that fenofibrate significantly reduces not only the serum activity of tissue damage biomarker enzymes (LDH and GOT) but also the circulating proportions of pro-inflammatory monocytes (CD11b+ LY6Chigh). Furthermore, both CD11b+ Ly6Clow F4/80high macrophages (MΦ) and recently differentiated CD11b+ Ly6Chigh F4/80high monocyte-derived macrophages (MdMΦ) shift toward a resolving phenotype (CD206high) in the hearts of fenofibrate-treated mice. This shift correlates with a reduction in fibrosis, inflammation, and restoration of ventricular function in the early stages of Chagas disease. These findings encourage the repositioning of fenofibrate as a potential ancillary immunotherapy adjunct to antiparasitic drugs, addressing inflammation to mitigate Chagas disease symptoms.
Asunto(s)
Cardiomiopatía Chagásica , Fenofibrato , Macrófagos , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Animales , Ratones , Cardiomiopatía Chagásica/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Miocardio/patología , Masculino , Trypanosoma cruzi/efectos de los fármacos , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Miocarditis/tratamiento farmacológico , Miocarditis/parasitologíaRESUMEN
Chronic cardiomyopathy is one of the most relevant outcomes of Chagas disease associated with parasite persistence and exacerbated inflammatory response. Fenofibrate, a third generation fibric acid derivative and peroxisome proliferator-activated receptor-α ligand, is involved in the regulation of inflammatory response. However, the participation of macrophages in this scenario has not been elucidated. Here we show, for the first time, that macrophages play a fundamental role in the fenofibrate-mediated modulation of heart pro-inflammatory response and fibrosis caused by the infection with Trypanosoma cruzi. Furthermore, macrophages are required for fenofibrate to improve the loss of ventricular function and this restoration correlates with an anti-inflammatory microenvironment. Understanding the contributions of macrophages to the healing properties of fenofibrate reinforces its potential use as a therapeutic drug, with the aim of helping to solve a public health problem, such as chronic Chagas disease.
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Cardiomiopatías , Cardiomiopatía Chagásica , Enfermedad de Chagas , Fenofibrato , Humanos , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Cardiomiopatía Chagásica/tratamiento farmacológico , Cardiomiopatía Chagásica/complicaciones , Cardiomiopatía Chagásica/parasitología , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/complicaciones , MacrófagosRESUMEN
Acerola (Malpighia emarginata) by-product (ABP) has various bioactive compounds with hypoglycaemic, antioxidant and anti-inflammatory activity. The ABP effects on the biochemical changes in the enterohepatic axis caused by a high-fat diet (HFD) remains unclear. This study assessed whether the ABP or fenofibrate administration for 28 days interferes in lipid, glucose, or inflammatory changes in the enterohepatic axis of rats fed HFD. ABP induced in the rats fed HFD a reduction in body weight, serum lipids, blood glucose, and liver fat accumulation; increased insulin tolerance, and faecal bile acid excretion; regulated organic acid synthesis, faecal and colonic microbial growth; reduced M1 macrophage and increased M2 macrophage infiltration in the colon and liver, respectively. The fenofibrate did not improve the lipid or glucose alterations in enterohepatic axis of rats fed HFD. ABP has functional/nutraceutical potential in treating HFD-induced metabolic disorders with beneficial effects on lipid and glucose metabolism, and reduction of inflammation.
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Fenofibrato , Malpighiaceae , Ratas , Animales , Dieta Alta en Grasa/efectos adversos , Glucosa/metabolismo , Fenofibrato/análisis , Fenofibrato/metabolismo , Fenofibrato/farmacología , Frutas/química , Hígado/metabolismo , Malpighiaceae/química , Lípidos/análisis , Metabolismo de los LípidosRESUMEN
Parkinson's disease is a neurodegenerative disease, the etiology of which remains unknown, but some likely causes include oxidative stress, mitochondrial dysfunction and neuroinflammation. Peroxisome-proliferator-activated receptor (PPAR) agonists have been studied in animal models of Parkinson's disease and have shown neuroprotective effects. In this study, we aimed to (1) confirm the neuroprotective effects of PPAR-alpha agonist fenofibrate. To this end, male rats received fenofibrate (100 mg/kg) orally for 15 days, 5 days before the intraperitoneal injections of rotenone (2.5 mg/kg for 10 days). After finishing the treatment with rotenone and fenofibrate, animals were subjected to the open field, the forced swim test and the two-way active avoidance task. Subsequently, rats were euthanized for measurement of dopamine and metabolites levels in the striatum and quantification of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (SNpc). In addition, we aimed to (2) evaluate the neuroprotective effects of fenofibrate on the accumulation of α-synuclein aggregates. Here, rats were treated for 5 days with fenofibrate continuing for over 28 days with rotenone. Then, animals were perfused for immunohistochemistry analysis of α-synuclein. The results showed that fenofibrate reduced depressive-like behavior and memory impairment induced by rotenone. Moreover, fenofibrate diminished the depletion of striatal dopamine and protected against dopaminergic neuronal death in the SNpc. Likewise, the administration of fenofibrate attenuated the aggregation of α-synuclein in the SNpc and striatum in the rotenone-lesioned rats. Our study confirmed that fenofibrate exerted neuroprotective effects because parkinsonian rats exhibited reduced behavioral, neurochemical and immunohistochemical changes, and importantly, a lower number of α-synuclein aggregates.
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Fenofibrato , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Enfermedad de Parkinson , Masculino , Ratas , Animales , Rotenona/farmacología , Enfermedad de Parkinson/metabolismo , Fenofibrato/farmacología , alfa-Sinucleína , Neuroprotección , Fármacos Neuroprotectores/farmacología , Dopamina/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/farmacología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas , Sustancia NegraRESUMEN
OBJECTIVE: The purpose of this study is to investigate the pathogenic role of PPARα in periodontal antigen treated gingival cells in vitro and in experimental periodontitis in vivo . METHODOLOGY: Gingival fibroblasts, gingival epithelial cells and splenocytes were isolated from C57BL/6J wild type (WT) mice and treated with fixed P. gingivalis at for 48 hours. The mRNA levels of PPARs, TNFα, IL-1ß and IL-10 were detected by Real-time quantitative PCR. Silk ligatures after being soaked in the P.gingivalis suspension were tied around both maxillary second molars of WT mice or PPARα knock-out (KO) mice for two weeks. PPARα agonist fenofibrate and vehicle control were injected into the different side of the palatal gingiva on days 3, 6, and 9. At day 14, bone resorption and gingival mRNA expression levels of PPARs, TNFα, IL-1ß and IL-10 were measured by micro-computed tomography and RT-qPCR respectively. RESULTS: P. gingivalis treatment downregulated the expression of PPARα, but not PPARß or PPARγ, and increased the expression of TNF-α and IL-1ß in Gingival fibroblasts, gingival epithelial cells and splenocytes from WT mice. Gingival mRNA levels of PPARα were significantly decreased in experimental periodontitis in WT mice. The bone loss of PPARα KO mice in experimental periodontitis was significantly higher than WT mice and was not reduced by fenofibrate treatment. Gingival TNFα protein expressions were significantly increased by P. gingivalis associated ligation and decreased by fenofibrate treatment in WT mice but not in PPARα KO mice. CONCLUSION: This study suggests that PPARα plays an essential role in periodontitis.
Asunto(s)
Pérdida de Hueso Alveolar , Fenofibrato , PPAR alfa , Periodontitis , Pérdida de Hueso Alveolar/patología , Animales , Fenofibrato/farmacología , Encía/patología , Interleucina-10/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , PPAR alfa/metabolismo , Periodontitis/metabolismo , Periodontitis/patología , Porphyromonas gingivalis/metabolismo , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Microtomografía por Rayos XRESUMEN
2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin; TCDD) is an environmental contaminant that elicits a variety of toxic effects, many of which are mediated through activation of the aryl hydrocarbon receptor (AhR). Interaction between AhR and the peroxisome proliferator-activated receptor-alpha (PPAR-α), which regulates fatty acid metabolism, has been suggested. Furthermore, with recognition of the prevalence of inflammatory conditions, there is current interest in the potential for inflammatory stress to modulate the response to environmental agents. The aim of this work was to assess the interaction of TCDD with hepatic inflammation modulated by fenofibrate, a PPAR-α agonist. Female, C57BL/6 mice were treated orally with vehicle or fenofibrate (250 mg/kg) for 13 days, and then were given vehicle or 30 µg/kg TCDD. Four days later, the animals received an i.p. injection of lipopolysaccharide-galactosamine (LPS-GalN) (0.05x107 EU/kg and 500 mg/kg, respectively) to incite inflammation, or saline as vehicle control. After 4 h, the mice were euthanized, and blood and liver samples were collected for analysis. Livers of animals treated with TCDD with or without LPS-GalN had increased lipid deposition, and this effect was blocked by fenofibrate. In TCDD/LPS-GalN-treated mice, fenofibrate caused an increase in plasma activity of alanine aminotransferase, a marker of hepatocellular injury. TCDD reduced LPS-GalN-induced apoptosis, an effect that was prevented by fenofibrate pretreatment. LPS-GalN induced an increase in the concentration of interleukin-6 in plasma and accumulation of neutrophils in liver. TCDD exposure enhanced the former response and inhibited the latter one. These results suggest that fenofibrate counteracts the changes in lipid metabolism induced by TCDD but increases inflammation and liver injury in this model of inflammation-TCDD interaction.
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Dioxinas/toxicidad , Hígado Graso/tratamiento farmacológico , Fenofibrato/farmacología , PPAR alfa/agonistas , Alanina Transaminasa/sangre , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Hígado Graso/sangre , Hígado Graso/metabolismo , Hígado Graso/patología , Femenino , Fenofibrato/uso terapéutico , Interleucina-6/sangre , Ratones , Ratones Endogámicos C57BLRESUMEN
Chronic Chagas disease cardiomyopathy (CCC) is the most important clinical manifestation of infection with Trypanosma cruzi (T. cruzi) due to its frequency and effects on morbidity and mortality. Peripheral blood mononuclear cells (PBMC) infiltrate the tissue and differentiate into inflammatory macrophages. Advances in pathophysiology show that myeloid cell subpopulations contribute to cardiac homeostasis, emerging as possible therapeutic targets. We previously demonstrated that fenofibrate, PPARα agonist, controls inflammation, prevents fibrosis and improves cardiac function in a murine infection model. In this work we investigated the spontaneous release of inflammatory cytokines and chemokines, changes in the frequencies of monocyte subsets, and fenofibrate effects on PBMC of seropositive patients with different clinical stages of Chagas disease. The results show that PBMC from Chagas disease patients display higher levels of IL-12, TGF-ß, IL-6, MCP1, and CCR2 than cells from uninfected individuals (HI), irrespectively of the clinical stage, asymptomatic (Asy) or with Chagas heart disease (CHD). Fenofibrate reduces the levels of pro-inflammatory mediators and CCR2 in both Asy and CHD patients. We found that CHD patients display a significantly higher percentage of classical monocytes in comparison with Asy patients and HI. Besides, Asy patients have a significantly higher percentage of non-classical monocytes than CHD patients or HI. However, no difference in the intermediate monocyte subpopulation was found between groups. Moreover, monocytes from Asy or CHD patients exhibit different responses upon stimulation in vitro with T. cruzi lysates and fenofibrate treatment. Stimulation with T. cruzi significantly increases the percentage of classical monocytes in the Asy group whereas the percentage of intermediate monocytes decreases. Besides, there are no changes in their frequencies in CHD or HI. Notably, stimulation with T. cruzi did not modify the frequency of the non-classical monocytes subpopulation in any of the groups studied. Moreover, fenofibrate treatment of T. cruzi-stimulated cells, increased the frequency of the non-classical subpopulation in Asy patients. Interestingly, fenofibrate restores CCR2 levels but does not modify HLA-DR expression in any groups. In conclusion, our results emphasize a potential role for fenofibrate as a modulator of monocyte subpopulations towards an anti-inflammatory and healing profile in different stages of chronic Chagas disease.
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Enfermedad de Chagas , Fenofibrato , Animales , Citocinas/metabolismo , Fenofibrato/metabolismo , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Humanos , Leucocitos Mononucleares/metabolismo , Ratones , Monocitos/metabolismoRESUMEN
BACKGROUND: The anti-cancer effect of peroxisome proliferator-activated receptor (PPAR) α ligands on growth and metastatic potential of melanoma cells has been shown previously. However, the mechanism underlying these effects remains to be elucidated. Here, we investigated the effects of fenofibrate (PPAR ligand) on Toll-like receptor-4 (TLR-4) signaling in mice melanoma. METHODS: Mice melanoma cells (B16F10) were treated with fenofibrate or LPS or LPS + fenofibrate or pre-treated with CLI-095 (a TLR4 inhibitor), followed by fenofibrate. In in vivo model, C57BL/6 mice were subcutaneously injected with B16F10 cells (with/without LPS pre-treatment), and fenofibrate was administrated after development of palpable tumors. Cell proliferation, the expression level of Tlr4, Myd88, Nf-κb1 genes, TLR-4 protein expression, TNF-α levels, and tumor volume were measured. RESULT: Our results indicated that fenofibrate significantly inhibited the Tlr-4, Myd-88, and Nf-kb1 mRNA expression and TNF-α concentration in B16F10 LPS-stimulated cells. In addition, blocking TLR-4 signaling increased the anti-inflammatory potential of fenofibrate. Also fenofibrate can reduce LPS-induced tumor volume, Tlr-4, Myd-88, Nf-kb1 mRNA, and TLR-4 protein expression in tumor tissue and also TNF-α level in tumor tissue lysate. CONCLUSION: Our data indicate that fenofibrate may exert its anti-melanoma effects via interaction with TLR4-dependent signaling pathway (TLR-4/MyD-88/ NF-kB).
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Fenofibrato/farmacología , Melanoma/tratamiento farmacológico , PPAR alfa/agonistas , Receptor Toll-Like 4/fisiología , Animales , Línea Celular Tumoral , Ratones , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide/genética , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacología , Receptor Toll-Like 4/análisis , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/genética , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Previous studies demonstrated modifications of high-density lipoproteins (HDL) structure and apolipoprotein (apo) A-I catabolism induced by the atorvastatin and fenofibrate combination. However, it remains unknown whether such structural and metabolic changes of HDL were related to an improvement of the HDL-cholesteryl esters (HDL-CE) metabolism. Therefore, we determined the structure of HDL and performed kinetic studies of HDL-CE radiolabeled with tritium in rabbits treated with atorvastatin, fenofibrate, and a combination of both drugs. The atorvastatin and fenofibrate combination increased the HDL size and the cholesterol and phospholipid plasma concentrations of the largest HDL subclasses. Moreover, the relative amount of unsaturated fatty acids contained in HDL increased, in detriment of saturated fatty acids as determined by gas chromatography-mass spectrometry. The transfers of cholesteryl esters (CE) from HDL to very low-density lipoproteins/low-density lipoproteins (VLDL/LDL) and vice versa were enhanced with atorvastatin, alone or in combination. Moreover, the direct elimination of CE from plasma via VLDL/LDL decreased with fenofibrate, whereas the direct elimination of CE via HDL augmented with the combination treatment. Taken together, the rise of unsaturated fatty acid content and the size increase of HDL, suggest that atorvastatin and fenofibrate induce more fluid HDL particles, which in turn favor an enhanced CE exchange between HDL and VLDL/LDL. Our results contribute to a better understanding of the relationship between the structure and function of HDL during the use of anti-dyslipidemic drugs.
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Atorvastatina/farmacología , Ésteres del Colesterol/metabolismo , Fenofibrato/farmacología , Hipolipemiantes/farmacología , Lipoproteínas HDL/metabolismo , Animales , Anticolesterolemiantes/farmacología , Ésteres del Colesterol/análisis , Cinética , Lipoproteínas HDL/química , ConejosRESUMEN
Statins may precipitate the onset of type 2 diabetes (T2D) in high-risk patients. In contrast, only the subset of individuals with insulin resistance and/or diabetes receives cardiovascular benefits with fibrates. In this context, previous observations from our laboratory suggested that atorvastatin induced an increase in visceral adipose tissue (VAT), whereas fenofibrate had the opposite effects in rabbits. Therefore, we determined the mass, morphology, and vascularization of VAT in New Zealand white rabbits (n = 6/group) that received 0.33 or 2.6 mg/kg/d of atorvastatin or fenofibrate, respectively, during 2 months. As expected, the cholesterol from the atorvastatin group was lower after treatment, while triglycerides decreased in the fenofibrate group. The mass of VAT from the fenofibrate group was 46% lower compared to the controls, meanwhile atorvastatin was associated with a larger diameter of adipocytes (+65%) than that of the control and fenofibrate groups. Fibroblast growth factor 2 (FGF2) gene expression was lower in the fenofibrate group than in the control group (-54%). By contrast, vascular endothelial growth factor A (VEGF-A) gene expression in fenofibrate-treated rabbits was 110% higher than in the control group. In agreement with the gene expression, the marker of angiogenesis platelet endothelial cell adhesion molecule 1 was slightly but significantly higher (+10%) in rabbits treated with fenofibrate than in controls, as determined by immunohistochemistry. These results suggest that fenofibrate is associated with a favorable remodeling of VAT, that is, reduced mass and increased vascularization in normolipemic rabbits; in contrast, atorvastatin induced a nonfavorable remodeling of VAT. These results may be related to the cardiovascular benefits of fenofibrate and the increased risk of T2D in high-risk patients induced by atorvastatin.
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Adipocitos/efectos de los fármacos , Adiposidad/efectos de los fármacos , Atorvastatina/farmacología , Fenofibrato/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipolipemiantes/farmacología , Grasa Intraabdominal/irrigación sanguínea , Grasa Intraabdominal/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Adipocitos/metabolismo , Animales , Colesterol/sangre , Factor 2 de Crecimiento de Fibroblastos/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Grasa Intraabdominal/metabolismo , Masculino , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Conejos , Transducción de Señal , Triglicéridos/sangre , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
AIMS: High fat diet consumes and thyroid hormones (THs) disorders may affect nutrients metabolism, but their impact on the absorptive epithelium, the first place of nutrients access, remains unknown. Our aim was to evaluate the intestinal morphology and nutrients transporters content in mice fed standard (LFD) or high fat (HFD) diets in hypo or hyperthyroidism-induced condition. MATERIAL AND METHODS: C57BL/6 male mice fed LFD or HFD diets for 12â¯weeks, followed by saline, PTU (antithyroid drug) or T3 treatment up to 30â¯days. The mice were euthanized and proximal intestine was removed to study GLUT2, GLUT5, PEPT1, FAT-CD36, FATP4, NPC1L1 and NHE3 distribution by Western blotting. Since PPAR-a is activated by fatty acids, which is abundant in the HFD, we also evaluated whether PPAR-a affects nutrients transporters. Thus, mice were treated with fenofibrate, a PPAR-a agonist. KEY FINDINGS: HFD decreased GLUT2, PEPT1, FAT-CD6 and NPC1L1, but increased NHE3, while GLUT5 and FATP4 remained unaltered. THs did not alter distribution of nutrients transporters neither in LFD nor in HFD groups, but they increased villi length and depth crypt in LFD and HFD, respectively. Fenofibrate did not affect content of nutrients transporters, excluding PPAR-a involvement on the HFD-induced changes. SIGNIFICANCE: We assume that chronic HFD consumption reduced most of the nutrients transporters content in the small intestine of mice, which might limit the entrance of nutrients and gain weight. Since NHE3 promotes sodium absorption, and it was increased in HFD group, this finding could contribute to explain the hypertension observed in obesity.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Hipertiroidismo/metabolismo , Hipotiroidismo/metabolismo , Mucosa Intestinal/metabolismo , Proteínas de Transporte de Membrana/metabolismo , PPAR alfa/metabolismo , Animales , Antitiroideos/farmacología , Fenofibrato/farmacología , Prueba de Tolerancia a la Glucosa , Hipertiroidismo/inducido químicamente , Hipolipemiantes/farmacología , Hipotiroidismo/inducido químicamente , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Intestinos/efectos de los fármacos , Intestinos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , PPAR alfa/antagonistas & inhibidores , Propiltiouracilo/farmacología , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Hormonas Tiroideas/metabolismo , Triyodotironina/farmacologíaRESUMEN
The effect of fenofibrate on the metabolism of skeletal muscle and visceral white adipose tissue of diet-induced obese (DIO) mice was investigated. C57BL/6J male mice were fed either a control or high-fat diet for 8 weeks. Fenofibrate (50 mg/Kg BW, daily) was administered by oral gavage during the last two weeks of the experimental period. Insulin-stimulated glucose metabolism in soleus muscles, glucose tolerance test, insulin tolerance test, indirect calorimetry, lipolysis of visceral white adipose tissue, expression of miR-103-3p in adipose tissue, and miR-1a, miR-133a/b, miR-206, let7b-5p, miR-23b-3p, miR-29-3p, miR-143-3p in soleus muscle, genes related to glucose and fatty acid metabolism in adipose tissue and soleus muscle, and proteins (phospho-AMPKα2, Pgc1α, Cpt1b), intramuscular lipid staining, and activities of fatty acid oxidation enzymes in skeletal muscle were investigated. In DIO mice, fenofibrate prevented weight gain induced by HFD feeding by increasing energy expenditure; improved whole body glucose homeostasis, and in skeletal muscle, increased insulin dependent glucose uptake, miR-1a levels, reduced intramuscular lipid accumulation, and phospho-AMPKα2 levels. In visceral adipose tissue of obese mice, fenofibrate decreased basal lipolysis rate and visceral adipocytes hypertrophy, and induced the expression of Glut-4, Irs1, and Cav-1 mRNA and miR-103-3p suggesting a higher insulin sensitivity of the adipocytes. The evidence is presented herein that beneficial effects of fenofibrate on body weight, glucose homeostasis, and muscle metabolism might be related to its action in adipose tissue. Moreover, fenofibrate regulates miR-1a-3p in soleus and miR-103-3p in adipose tissue, suggesting these microRNAs might contribute to fenofibrate beneficial effects on metabolism.
Asunto(s)
Adipocitos/efectos de los fármacos , Dieta Alta en Grasa , Fenofibrato/farmacología , Hipolipemiantes/farmacología , Músculo Esquelético/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético/efectos de los fármacos , Glucosa/metabolismo , Resistencia a la Insulina/genética , Grasa Intraabdominal/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismoAsunto(s)
Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Hígado/efectos de los fármacos , PPAR alfa/agonistas , PPAR gamma/agonistas , Consumo de Bebidas Alcohólicas/prevención & control , Animales , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Gemfibrozilo/farmacología , Humanos , Ratones , RatasRESUMEN
The anti-atherogenic properties of high-density lipoproteins (HDLs) may be related to their structure and metabolism. The HDL physicochemical characteristics that determine their plasma clearance during treatment with statins and fibrates are not well understood. In this study, we analyzed HDL-apo AI fractional catabolic rates (FCRs), size distributions, and the lipid composition of the HDL subclasses in New Zealand white rabbits with exogenous dyslipidemia that received low doses of atorvastatin and fenofibrate. Hypercholesterolemia decreased only partially with the combination of both drugs. HDL size distribution shifted toward larger particles among the groups of rabbits that received atorvastatin, fenofibrate, or their combination, compared with both the control group and the dyslipidemic group. The HDL subclasses were significantly rich in cholesterol in each of the groups compared with controls. The structural changes noted in the HDL subclasses were not associated with impaired plasma paraoxonase-1 (PON1) activity. The groups receiving monotherapy and the drug combination group were all associated with a higher apo AI FCR value compared with both the dyslipidemic rabbits and the control group. In conclusion, the combination of atorvastatin and fenofibrate induced a more favorable HDL subclass profile than did the individual use of these drugs. Similarly, the apo AI FCR values were augmented in every group receiving drug treatment (either monotherapy or combination therapy) in the setting of hypercholesterolemia. The anti-atherogenic properties of HDLs, excluding their capacity to bind PON1, may be enhanced by the structural and metabolic modifications induced by the combination of atorvastatin and fenofibrate.
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Apolipoproteína A-I/sangre , Atorvastatina/farmacología , HDL-Colesterol/sangre , Fenofibrato/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipercolesterolemia/tratamiento farmacológico , Hipolipemiantes/farmacología , Animales , Arildialquilfosfatasa/metabolismo , Atorvastatina/uso terapéutico , Glucemia/metabolismo , Sinergismo Farmacológico , Fenofibrato/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/sangre , Hipolipemiantes/uso terapéutico , Cinética , Lípidos/sangre , Masculino , ConejosRESUMEN
Obesity is considered a public health problem worldwide. Fenofibrate, a selective peroxisome proliferator-activated receptor α (PPAR-α) agonist, elicits weight loss in animal models. This study aimed to examine the effects of fenofibrate on energy expenditure, body mass (BM) and gene expression of thermogenic factors in brown adipose tissue of diet-induced obese mice. Male C57BL/6 mice were fed a standard chow (SC; 10% lipids) diet or a high-fat (HF; 50% lipids) diet for 10 weeks. Afterwards, groups were subdivided as SC, SC-F, HF and HF-F (n = 10, each). Treatment with fenofibrate (100 mg kg(-1) BM mixed into the diet) lasted 5 weeks. Treated groups had reduced final BM compared with their counterparts (p < 0·05), explained by the increase in energy expenditure, CO2 production and O2 consumption after treatment with fenofibrate (p < 0·05). Similarly, genes involved in thermogenesis as PPAR-α, PPAR-γ coactivator 1α, nuclear respiratory factor 1, mitochondrial transcription factor A (Tfam), PR domain containing 16 (PRDM16), ß-3 adrenergic receptor (ß3-AR), bone morphogenetic protein 8B and uncoupling protein 1 were significantly expressed in brown adipocytes after the treatment (p < 0·05). All observations ensure that selective PPAR-α agonist can induce thermogenesis by increasing energy expenditure and enhancing the expression of genes involved in the thermogenic pathway. These results suggest fenofibrate as a coadjutant drug for the treatment of obesity.
Asunto(s)
Adipocitos Marrones/metabolismo , Tejido Adiposo/metabolismo , Dieta/efectos adversos , Fenofibrato/farmacología , Obesidad/tratamiento farmacológico , PPAR alfa/agonistas , Pérdida de Peso/efectos de los fármacos , Adipocitos Marrones/efectos de los fármacos , Tejido Adiposo/citología , Tejido Adiposo/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Metabolismo Energético/efectos de los fármacos , Hipolipemiantes/farmacología , Técnicas para Inmunoenzimas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/etiología , Obesidad/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Browning is characterized by the formation of beige/brite fat depots in subcutaneous white adipose tissue (sWAT). This study aimed to examine whether the chronic activation of PPARalpha by fenofibrate could induce beige cell depots in the sWAT of diet-induced obese mice. High-fat fed animals presented overweight, insulin resistance and displayed adverse sWAT remodeling. Fenofibrate significantly attenuated these parameters. Treated groups demonstrated active UCP-1 beige cell clusters within sWAT, confirmed through higher gene expression of PPARalpha, PPARbeta, PGC1alpha, BMP8B, UCP-1, PRDM16 and irisin in treated groups. PPARalpha activation seems to be pivotal to trigger browning through irisin induction and UCP-1 transcription, indicating that fenofibrate increased the expression of genes typical of brown adipose tissue (BAT) in the sWAT, characterizing the formation of beige cells. These findings put forward a possible role of PPARalpha as a promising therapeutic for metabolic diseases via beige cell induction.
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Fármacos Antiobesidad/farmacología , Fenofibrato/farmacología , Obesidad/tratamiento farmacológico , Grasa Subcutánea/efectos de los fármacos , Animales , Fármacos Antiobesidad/uso terapéutico , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Tamaño de la Célula , Transdiferenciación Celular/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Fenofibrato/uso terapéutico , Expresión Génica , Canales Iónicos/genética , Canales Iónicos/metabolismo , Leptina/sangre , Masculino , Ratones Endogámicos C57BL , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , PPAR alfa/agonistas , PPAR alfa/metabolismo , Grasa Subcutánea/patología , Proteína Desacopladora 1RESUMEN
This study investigated the effects of the peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, Fenofibrate, on the secretion of vascular endothelial contraction factors in hypertensive rats to elucidate its possible mechanisms. The vascular ring contraction experiment was used to observe whether rat vascular tension of clean grade spontaneously hypertensive rats (SHR) changes after 1-h incubation of 0.1, 1.0, 10.0 µM Fenofibrate with 10.0 µM Fenofibrate, a PPAR-α antagonist (MK866), and a PPAR-γ antagonist (GW9662) in SHR. The results were compared with Wistar Kyoto rats. Enzyme-linked immunosorbent assay was used to detect the secretion of the serum vascular endothelial contraction factor prostacyclin-1α (PGF-1α), PGF-2α, and thromboxane B2 (TXB2). Western blot was used to detect COX-1 protein expression. A quantity of 10.0 µM Fenofibrate significantly reduced vasoconstriction in SHR compared to the control group (P = 0.013). The PPAR-α antagonist, MK866, significantly improved the vascular contractility of SHR when incubated with 10.0 µM Fenofibrate (P = 0.021). The PPAR-γ antagonist, GW9662, had no significant effect on the vascular contractility of SHR when incubated with 10.0 µM Fenofibrate (P = 0.071). The isolated aorta of SHR released significantly lower PGF- 1α (P = 0.014), PGF-2α (P = 0.023), and TXB2 (P = 0.017) levels in the 10.0 µM Fenofibrate group compared to the control group. COX-1 expression of SHR rat vascular endothelium was significantly depressed in the 10.0 µM Fenofibrate group compared to the control group (P = 0.027). In conclusion, Fenofibrate reduces the secretion of vascular endothelial contraction factors in hypertensive rats, which might arise through the endothelium influencing COX-1 expression.
Asunto(s)
Aorta/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Fenofibrato/farmacología , Hipolipemiantes/farmacología , PPAR alfa/genética , Vasoconstricción/efectos de los fármacos , Anilidas/farmacología , Animales , Aorta/metabolismo , Ciclooxigenasa 1/genética , Ciclooxigenasa 1/metabolismo , Dinoprost/metabolismo , Relación Dosis-Respuesta a Droga , Endotelio Vascular/metabolismo , Expresión Génica/efectos de los fármacos , Hipertensión/genética , Hipertensión/metabolismo , Hipertensión/patología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , PPAR alfa/agonistas , PPAR alfa/antagonistas & inhibidores , PPAR alfa/metabolismo , PPAR gamma/antagonistas & inhibidores , PPAR gamma/genética , PPAR gamma/metabolismo , Prostaglandinas F/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Tromboxano B2/metabolismo , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: Pentacyclic triterpenes in general exert beneficial effects in metabolic disorders. This study investigated the effects of α, ß-amyrin, a pentacyclic triterpene mixture from the resin of Protium heptaphyllum on blood sugar level and lipid profile in normal and streptozotocin (STZ)-induced diabetic mice, and in mice fed on a high-fat diet (HFD). FINDINGS: Mice treated with α, ß-amyrin (10, 30 and 100 mg/kg, p.o.) or glibenclamide (10 mg/kg, p.o.) had significantly reduced STZ-induced increases in blood glucose (BG), total cholesterol (TC) and serum triglycerides (TGs). Unlike glibenclamide that showed significant reductions in BG, TC and TGs in normoglycemic mice, α, ß-amyrin did not lower normal blood sugar levels but at 100 mg/kg, manifested a hypolipidemic effect. Also, α, ß-amyrin effectively reduced the elevated plasma glucose levels during the oral glucose tolerance test. Moreover, the plasma insulin level and histopathological analysis of pancreas revealed the beneficial effect of α, ß-amyrin in the preservation of beta cell integrity. In mice treated orally with α, ß-amyrin (10, 30 and 100 mg/kg) or fenofibrate (200 mg/kg), the HFD-associated rise in serum TC and TGs were significantly less. The hypocholesterolemic effect of α, ß-amyrin appeared more prominent at 100 mg/kg with significant decreases in VLDL and LDL cholesterol and an elevation of HDL cholesterol. Besides, the atherogenic index was significantly reduced by α, ß-amyrin. CONCLUSIONS: These findings reflect the potential antihyperglycemic and hypolipidemic effects of α, ß-amyrin mixture and suggest that it could be a lead compound for drug development effective in diabetes and atherosclerosis.