Gut-liver axis modulation in fructose-fed mice: a role for PPAR-alpha and linagliptin.

Fructose dietary intake affects the composition of the intestinal microbiota and influences the development of hepatic steatosis. Endotoxins produced by gram-negative bacteria alter intestinal permeability and cause bacterial translocation. This study evaluated the effects of gut microbiota modulation by a purified PPAR-alpha agonist (WY14643), a DPP-4 inhibitor (linagliptin), or their association on intestinal barrier integrity, endotoxemia, and hepatic energy metabolism in high-fructose-fed C57BL/6 mice. Fifty mice were divided to receive the control diet (C group) or the high-fructose diet (HFRU) for 12 weeks. Subsequently, the HFRU group was divided to initiate the treatment with PPAR-alpha agonist (3.5 mg/kg/BM) and DPP-4 inhibitor (15 mg/kg/BM). The HFRU group had glucose intolerance, endotoxemia, and dysbiosis (with increased Proteobacteria) without changes in body mass in comparison with the C group. HFRU group showed damaged intestinal ultrastructure, which led to liver inflammation and marked hepatic steatosis in the HFRU group when compared to the C group. PPAR-alpha activation and DPP-4 inhibition countered glucose intolerance, endotoxemia, and dysbiosis, ameliorating the ultrastructure of the intestinal barrier and reducing Tlr4 expression in the liver of treated animals. These beneficial effects suppressed lipogenesis and mitigated hepatic steatosis. In conclusion, the results herein propose a role for PPAR-alpha activation, DPP-4 inhibition, and their association in attenuating hepatic steatosis by gut-liver axis modulation in high-fructose mice model. These observations suggest these treatments as potential targets to treat hepatic steatosis and avoid its progression.

Medium-chain dicarboxylic acylcarnitines as markers of n-3 PUFA-induced peroxisomal oxidation of fatty acids.

SCOPE: Omega-3 polyunsaturated fatty acids (n-3 PUFA) found in fish oil activate PPAR-α, stimulate peroxisomal fatty acid (FA) ß-oxidation and prevent impairments on glucose homeostasis. METHODS AND RESULTS: Glucose metabolism and FA oxidation were studied in C57/Bl6 mice fed with diets containing either 3.6 and 31.5% fish oil or lard. To assess the effects of peroxisomal proliferation on FA oxidation independent of n-3 PUFA intake, mice were treated with the PPAR-α agonist WY-14643. n-3 PUFA-fed mice were protected from glucose intolerance and dyslipidemia compared to animals fed a lard-based high-fat diet. Most importantly, mice fed on the hyperlipidic diet based on fish oil as well as the WY-14643 treated mice showed twofold increase of odd, medium-chain, dicarboxylic acylcarnitines in the liver suggesting that not only ß-oxidation, but also α- and ω-oxidation of FA were increased. Finally, an oxidation assay using liver homogenates and palmitic acid as substrate revealed an over tenfold increased production of similar acylcarnitines, indicating that FA are their precursors. CONCLUSION: This study shows at the metabolite level that peroxisome proliferation induced either by fish oil or WY-14643 is associated with increased α- and ω-oxidation of FA producing specific acylcarnitines that can be utilized as biomarkers of peroxisomal FA oxidation.

The dual role of free fatty acid signaling in inflammation and therapeutics.

Obesity, type 2 diabetes, insulin resistance, dyslipidemia, cardiovascular diseases and atherosclerosis have all been associated with high levels of free fatty acid (FFA). In the present review, we suggest that FFA may act as either pro- or anti-inflammatory agents depending on the chemical structure. Saturated fatty acids (SFA) and polyunsaturated fatty acids (PUFA) significantly differ in their contributions to inflammation. While SFAs have been shown to induce inflammation, PUFAs have anti-inflammatory effects by downregulating NF-kappaB, IL-1ß, TNF-α and IL-6 despite upregulating of IL-10. It is suggested that FFA may activate Toll Like Receptor-4 (TLR4) and G protein-coupled receptors (GPCR) activating signaling pathways that promote production and release of inflammatory cytokines (IL-6 and TFN-α). Fatty acid action on TLR4, peroxisome proliferator-activated receptors (PPARs) and GPCRs are potential therapeutic targets for controlling FFA-induced inflammation. Approaches that downregulate the inflammatory properties of free fatty acid are discussed in this manuscript. In this review, some patents associated with controlling FFA effects are also reported.

Peroxisome proliferators reduce spatial memory impairment, synaptic failure, and neurodegeneration in brains of a double transgenic mice model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid-ß peptide (Aß), increase of oxidative stress, and synaptic alterations. The scavenging of reactive oxygen species through their matrix enzyme catalase is one of the most recognized functions of peroxisomes. The induction of peroxisome proliferation is attained through different mechanisms by a set of structurally diverse molecules called peroxisome proliferators. In the present work, a double transgenic mouse model of AD that co-expresses a mutant human amyloid-ß protein precursor (AßPPswe) and presenilin 1 without exon 9 (PS1dE9) was utilized in order to assess the effect of peroxisomal proliferation on Aß neurotoxicity in vivo. Mice were tested for spatial memory and their brains analyzed by cytochemical, electrophysiological, and biochemical methods. We report here that peroxisomal proliferation significantly reduces (i) memory impairment, found in this model of AD; (ii) Aß burden and plaque-associated acetylcholinesterase activity; (iii) neuroinflammation, measured by the extent of astrogliosis and microgliosis; and (iv) the decrease in postsynaptic proteins, while promoting synaptic plasticity in the form of long-term potentiation. We concluded that peroxisomal proliferation reduces various AD neuropathological markers and peroxisome proliferators may be considered as potential therapeutic agents against the disease.

Polimorfismo Gly482Ser del gen coactivador-1a dl receptor activado de proliferación de los peroxisomas y en individuos de la ciudad de Maracaibo estado Zulia Venezuela: estudio preliminar / Gly482Ser polymorphism of the coactivator-1a of the activated receptor of peroxisone y proliferation in individuals from Maracaibo Venezuela

El objetivo de este estudio fue determinar la asociación entre el polimorfismo Gly482Ser del gen PGC-1 con resistencia a la insulina y la diabetes mellitus tipo 2 en individuos de la ciudad de Maracaibo. Se estudiaron 64 individuos no diabético (36 sin resistencia a la insulina, 28 resistentes a la insulina) y 13 diabéticos tipo 2. Se realizó una historia clínica nutricional que incluyó la evaluación de parámetros antropométricos. Se midieron los niveles de glicemia e insulina basal, colesterol total, HDL-C y LDL-C. El polimorfismo Gly482Ser fue detectado empleando la reacción en cadena de la polimerasa y polimorfismo de restricción de fragmentos largos. Se encontró que las frecuencias alélicas para A y G resultaron 0,36 y 0,64 respectivamente. La población se encontró en equilibrio genético de Hardy Weinberg. Al asociar los genotipos del polimorfismo Gly482Ser con la resistencia a la insulina y la diabetes mellitus tipo 2, no se encontró asociación estadística significativa (OR=1,320, p=0,74; OR=2, p=0,47 respectivamente). Sin embargo, los individuos diabéticos con genotipo AA presentaron valores de LDL-C más elevados (p<0,05) que los individuos con el genotipo GG y GA. Los diabéticos con el genotipo GA mostraron concentraciones significativamente elevadas de triglicéridos (>150 mg/dL) comparados con los del genotipo GG. De acuerdo a los resultados obtenidos, el polimorfismo Gly482Ser del gen PGC-1 podría contribuir al riesgo cardiovascular en los individuos diabéticos tipo 2, mientras que en los individuos resistentes a la insulina este polimorfismo no estuvo asociado a factores de riesgo cardiovascular.

The aim of this study was to determine the association of the Gly482Ser polymorphism of the PGC-1 gene with insulin resistance and type 2 diabetes mellitus in subjects from the city of Maracaibo. The study was performed on 64 no-diabetic subjects (36 without insulin resistance and 28 with insulin resistance) and 13 with type 2 diabetes. A clinical and nutritional history was carried out and the evaluation of anthropometric parameters was included. Fasting serum glucose, fasting serum insulin, total cholesterol, HDL-C and LDL-C, were measured. The Gly482Ser polymorphism was detected by PCR-RFLP. It was found that the allelic frequencies for A and G were 0.36 and 0.64, respectively. The population was found in genetic equilibrium of Hardy Weinberg. The genotypes of the polymorphism Gly482Ser were not associated with insulin resistance and type 2 diabetes mellitus (OR=1.320, p=0.74; OR = 2, p=0.47 respectively). Nevertheless, the diabetic subjects with the genotype AA presented values of LDL-C higher (p<0.05) than the individuals with the genotypes GG and GA. The diabetics with the genotype GA showed significantly higher concentrations of triglycerides (>150 mg/dL) compared with the genotype GG. According to the results, the polymorphism Gly482Ser of the PGC-1 gene would be able to contribute to the cardiovascular risk in type 2 diabetics, while in the insulin resistant individuals, this polymorphism was not associated with cardiovascular risk factors.

Estudo para participação do receptor nuclear PPARy na resposta do hospedeiro frente à infecção por Mycobacterium bovis, BCG / Study for involvement of nuclear receptor PPARy in front of the host response to infection by Mycobacterium bovis, BCG

Os macrófagos são os principais agentes de defesa contra patógenos intracelulares e têm importante papel no metabolismo de lipídios e processos inflamatórios. Vários estudos demonstraram a participação de macrófagos “espumoso” durante a infecção intracelular por microbactérias, mas seu significado funcional é pouco entendido. Nosso laboratório tem mostrado que os corpúsculos lipídicos são organelas dinâmicas e funcionalmente ativas, que funcionam com sítios de sinalização em leocócitos para regulação do metabolismo lipídico e síntese de mediadores inflamatórios. Os mecanismos que regulam o acúmulo intracelular de lipídios, bem como a ativação de fatores transcricionais envolvidos no metabolismo lipídico de macrófagos, durante processos infecciosos, e seu signficado na patofisiologia e no curso de doenças desencadeadas por patógenos intracelulares não são completamente entendidos. Os Receptores Ativados por Proliferadores de Peroxissomos (PPARs) atuam em vários processos inflamatórios e imunoregulatórios devido à propriedade de regular a expressão de vários genes, estando desta maneira implicados na patofisiologia da aterosclerose, inflamação, diabetes e resposta imune. O papel do PPARy na resposta do hospedeiro frente à patógenos ainda não se encontra esclarecido. Assim nosso objetivo foi caracterizar o envolvimento do receptor nuclear PPARy na resposta do hospedeiro frente a infecções pelo patógeno intracelular Mycobacterium bovis, BCG. Em paralelo, investigamos o papel do receptor Toll-like 2 (TLR2) e outras moléculas sinalizadoras com CD14, CD11b/CD18, CD36, dectina-1 além de lipid rafts na resposta inflamatória durante a infecção por BCG. Nossos resultados demonstram que a infecção de macrófagos peritoneais de camundongos por M. bovis, BCG in vitro induziu aumento da expressão de PPARy, o qual foi acompanhado pela indução da formação de corpúsculos lipídicos, bem como aumento da produção de mediadores inflamatórios como PGE2 e citocinas. A expressão de PPARy e a produção de corpúsculos lipídicos e mediadores inflamatórios foram drasticamente inibidas em camundongos deficientes para o receptor TLR2, sugerindo um papel importante do TLR2 neste fenômeno. Demonstramos também que ativação de macrófagos in vitro pro agonistas de TLR2 (M. smegmatis, Pam3cys e zimosan) não foi capaz de induzir formação de corpúsculos lipídicos, sugerindo que ativação de TLR2, embora essencial para induzir expressão de PPARy ou formação de corpúsculos lipídicos na infecção, não é suficiente para desencadear vias de formação de corpúsculos lipídicos, indicando que outros co-fatores podem esta envolvidos. Nós verificamos de maneira significativa o envolvimento de CD14, CD11b, CD36, lipid raffs e dectina-1, na formação de corpúsculos lipídicos e produção de mediadores inflamatórios. Além disso, a neutralização do CD36 levou à inibição da expressão de PPARy induzida por BCG. Desta maneira sugerimos que a infecção por BCG altera significativamente os níveis de expressão de PPARy de maneira dependente de TLR2 e CD36 e que receptores nucleares ativados por lipídios podem modular a formação de corpúsculos lipídicos, síntese de PGE2, e a função de macrófagos durante infecções micobacterianas. O estudo da regulação e ativação de PPARy durante infecções por patógenos intracelulares poderá trazer contribuições sobre os mecanismos básicos de interação e escape na resposta patógeno-hospedeiro e poderá contribuir para a identificação de novos alvos terapêuticos para a tuberculose.

Modulação da ativação dos receptores ativados por proliferadores de peroxissoma (PPAR) e dos receptores X hepáticos (LXR) por LN´O IND. 2´ / Modulation of activity of peroxissome prolifetor-activated (PPAR) and liver X receptors(LXR) by LN´O IND. 2´

A atividade dos receptores ativados por proliferadores de peroxissoma (PPAR) e receptor X hepático (LXR) são regulados por ácidos graxos. Entretanto, o papel do LNO2, um produto endógeno da nitração do ácido linoléico por espécies reativas derivadas de óxido nítrico (•NO), na via de sinalização que regula a ativação destes receptores ainda não está elucidada. Assim, considerando a propriedade do LNO2 como doador de NO, nós investigamos a participação da via de sinalização p21Ras/Raf/ERK na ativação de PPAR e LXR por LNO2. Os resultados obtidos demonstraram que LNO2, na concentração de 0.01µM, foi um potente ativador de PPAR quando comparado ao ligante natural ácido linoléico, o qual apresentou ativação equivalente do PPAR na concentração de 0.01µM. O LN02, contudo não teve efeito na ativação de LXR. LNO2 foi um potente ativador de p21Ras quando comparado ao ácido linoléico. A ativação de Ras ocorreu após 5 minutos de incubação com LNO2 em células parentais. Entretanto, em células transfectadas com p21RasC118S, o LNO2 não foi capaz de ativar Ras. A ativação de Ras e PP AR foi dependente da liberação de NO a partir de LN02, o que foi evidenciado na presença de C-PTIO, um seqüestrador de NO. LNO2 ativou ERK, mas não demonstrou efeito relevante na ativação de p38 MAP kinase...

Peroxisomal proliferation protects from beta-amyloid neurodegeneration.

Alzheimer disease is a neurodegenerative process that leads to severe cognitive impairment as a consequence of selective death of neuronal populations. The molecular pathogenesis of Alzheimer disease involves the participation of the beta-amyloid peptide (Abeta) and oxidative stress. We report here that peroxisomal proliferation attenuated Abeta-dependent toxicity in hippocampal neurons. Pretreatment with Wy-14.463 (Wy), a peroxisome proliferator, prevent the neuronal cell death and neuritic network loss induced by the Abeta peptide. Moreover, the hippocampal neurons treated with this compound, showed an increase in the number of peroxisomes, with a concomitant increase in catalase activity. Additionally, we evaluate the Wy protective effect on beta-catenin levels, production of intracellular reactive oxygen species, cytoplasmic calcium uptake, and mitochondrial potential in hippocampal neurons exposed to H(2) O(2) and Abeta peptide. Results show that the peroxisomal proliferation prevents beta-catenin degradation, reactive oxygen species production, cytoplasmic calcium increase, and changes in mitochondrial viability. Our data suggest, for the first time, a direct link between peroxisomal proliferation and neuroprotection from Abeta-induced degenerative changes.

Los Receptores activados por proliferadores peroxisómicos. Su papel en la aterosclerosis, obesidad e hipertensión arterial

Los receptores activados por proliferadores peroxisómicos son una familia de factores de transcripción que pertenecen a la superfamilia de los receptores esteroides y que incluye tres subtipos: PPARá, PPAR©¬ y PPAR ã. Estos receptores se unen a repeticiones directas hexaméricas en forma de heterodímeros con el receptor del retinoide. Los PPAR regulan la expresión de una amplia variedad de genes que codifican proteínas implicadas en el metabolismo lipídico, la homeostasis energética, la diferenciación celular y la formación de tumores. En esta revisión se describen las características, regulación y los genes diana de los PPAR y se destacan sus implicaciones fisiopatológicas y farmacológicas sobre la regulación del metabolismo de los lípidos y la glucosa, la homeostasis energética, la hipertensión arterial y la disfunción endotelial(AU)

Rastreamento molecular do gene do receptor ativado por proliferadores de peroxissoma gama (PPAR`gama´) em pacientes com diabetes melito do tipo 2 / Molecular scanning of the peroxisome proliferator-activated receptors gamma (PPAR`gamma´) gene in patients with Type 2 diabetes mellitus

No presente estudo utilizaram-se as técnicas do polimorfismo conformacional de fita simples (PCR-SSCP) e sequenciamento na prospecção e caracterização de polimorfismos no gene do Peroxisome Proliferator-Activated Receptors Gamma (PPAR`gama´) em pacientes com diabetes melito do tipo 2 (DM2). Foi possível, portanto, caracterizar cinco polimorfismos, sendo um destes localizado em região intrônica (IVS3+21A>T) e quatro em região codificadora (exon B: 34C>G; exon 1: 90C>A e 159C>T e exon 6: 161C>T) no gene do PPAR`gama´. As regiões referentes aos polimorfismos 34C>G e 161C>T foram amplificadas pela técnica da PCR e analisadas por restrição enzimática...

Effect of a peroxysomal proliferator agent on intracellular cholesterol accumulation in cultured fibroblasts from Niemann-Pick type C disease patients.

BACKGROUND: Niemann-Pick type C (NP-C) disease is a lysosomal storage disorder. It is possible that peroxisomes are also modified and their alterations can be an early event in the process of the disease. As the use of peroxisomal inducers restores the original function of the organelle, the importance of peroxisomes is further emphasized and can suggest future therapeutic interventions. METHODS: We treated fibroblast cultures from NP-C patients and normal individuals with 200 and 400 micromol/l clofibrate and evaluated its action on intracellular cholesterol content that was determined by filipin staining and quantitative measurement of unesterified cholesterol. RESULTS: The fibroblasts from NP-C patients that did not receive any drug presented a pattern of intense perinuclear fluorescence associated with the accumulation of unesterified cholesterol which was not observed in normal fibroblasts. Comparing the NP-C fibroblasts that were incubated with clofibrate and the same cells without this treatment, there were no changes in cholesterol content by filipin staining, but normal fibroblasts after incubation with this drug showed a slight increase in its cholesterol content. However, unesterified cholesterol was significantly increased in both cells treated with clofibrate when compared to untreated cells. CONCLUSIONS: Clofibrate is probably not useful for treatment of NP-C patients because it seems to contribute to an increase the cholesterol in the cells of these individuals.

Cytochemical and biochemical demonstration of an ATPase in membranes of human peroxisomes.

We demonstrated a neutral Mg-ATPase activity in human peroxisomal membranes. To establish the precise experimental conditions for detection of this ATPase, both cytochemical and biochemical characterizations were first carried out in liver peroxisomes from control and cipofibrate-treated rats. The results demonstrated an Mg-ATPase reaction in both normal and proliferated peroxisomes. The nucleotidase activity, with marked preference for ATP, was sensitive to the inhibitors N-ethylmaleimide and 7-chloro-4-nitro-benzo-2-oxadiazole (NBDCl). An ultrastructural cytochemical analysis was developed to evaluate the peroxisomal localization, which localized the reaction product to the peroxisomal membrane. These characteristics can help to differentiate the peroxisomal ATPase from the activity found in mitochondria and endoplasmic reticulum. The conditions established for detecting the rat peroxisomal ATPase were then applied to human peroxisomes isolated from liver and skin fibroblasts in culture. A similar Mg-ATPase activity was readily shown, both cytochemically and biochemically, in the membranes of human peroxisomes. These results, together with previous evidence, strongly support the presence of a specific ATPase in the human peroxisomal membrane. This ATPase may play a crucial role in peroxisome biogenesis.

Evidence for the involvement of polyunsaturated fatty acids in the regulation of long-chain acyl CoA thioesterases and peroxisome proliferation in rat carcinosarcoma.

The feeding of high-fat diets rich in polyunsaturated fatty acids (PUFAs) caused a marked increase in the acyl CoA thioesterase activity of the Walker 256 tumour. Diets containing lower levels of PUFAs did not alter the activity of acyl CoA thioesterase and the exposure of LLC-WRC256 tumour cells, in culture, to PUFAs (150 microM) also was ineffective in altering activity. The tumours from n-3 PUFA-rich and control diets were analysed by transmission electron microscopy in order to compare peroxisomal content. The presence of PUFAs led to an almost 10-fold increase in the number of peroxisomes present in the tumour tissue. A common feature of the PUFA-treated tumour was the presence of many cells containing highly condensed heterochromatin at the periphery of the nucleus, indicative of apoptosis. The sparsity of endoplasmic reticulum and the lack of detection of mitochondrial acyl CoA thioesterase, MTE-I, led to the conclusion that the increase in tumour acyl CoA thioesterase activity may be due to an increase in the activity of the peroxisomal enzyme.

Avances en la genética molecular de la obesidad / Advances in the molecular genetics of the obesity

In the last decade, specially after the discovery of leptin, several neuropeptides that regulate energy intake and expenditure have been described in animal models. This has partially unvelied the underlying mechanisms that regulate body composition and weight and therefore a promise of a more effective treatment of obesity and its comorbidities is ad portas

Aspectos genéticos de la obesidad humana / Genetic conditions of human obesity

La obesidad está asociada con distintas complicaciones metabólicas como la diabetes, la hipertensión y la hiperlipidemia. No obstante, no todos los individuos obesos presentan estas complicaciones, lo que sugiere que la obesidad es una condición heterogénia. La obesidad es la resultante de una compleja interacción entre factores genéticos y ambientales. Los resultados aportados por la epidemiología genética han sido muy útiles para demostrar que, a nivel poblacional, los factores genéticos tienen importancia en la etiología de la obesidad humana. A nivel individual, es bien conocido que no todos los sujetos son igualmente susceptibles a las consecuencias adversas de la obesidad y que hay diferencias inter-individuales en la respuesta al estimulo ambiental. Este artículo presenta una breve revisión respecto de la contribución de siete genes candidatos en esta compleja enfermedad

Nutrición molecular, papel del sistema PPAR en el metabolismo lipídico y su importancia en obesidad y diabetes mellitus / Molecular nutrition: regulation of lipid metabolism by peroxisome proliferator activated receptors, PPAR: their relatioship to obesity and diabetes mellitus

PPARs are transcription factors belonging to the super family of hormonal receptors. Their activity is regulated by fibrates, thiazolidinediones, certain anti inflammatory drugs and fatty acid derivatives, present in food. PPAR isoforms play a central role in lipid homeostasis, regulating anabolic (PPARg) and catabolic (PPARa) pathways of lipid metabolism. Additionally, these receptors participate in glucose homeostasis, influence cellular proliferation and differentiation and participate in inflammatory processes. The effects of PPARs on oxidative substrate partitioning suggests that they have a relevant role in the development of obesity and insulin resistance

High-affinity binding of fatty acyl-CoAs and peroxisome proliferator-CoA esters to glutathione S-transferases effect on enzymatic activity.

Acyl-CoAs are present at high concentrations within the cell, yet are strongly buffered by specific binding proteins in order to maintain a low intracellular unbound acyl-CoA concentration, compatible with their metabolic role, their importance in cell signaling, and as protection from their detergent properties. This intracellular regulation may be disrupted by nonmetabolizables acyl-CoA esters of xenobiotics, such as peroxisome proliferators, which are formed at relatively high concentration within the liver cell. The low molecular mass acyl-CoA binding protein (ACBP) and fatty acyl-CoA binding protein (FABP) have been proposed as the buffering system for fatty acyl-CoAs. Whether these proteins also bind xenobiotic-CoA is not known. Here we have identified new liver cytosolic fatty acyl-CoA and xenobiotic-CoA binding sites as glutathione S-transferase (GST), using fluorescent polarization and a acyl-etheno-CoA derivative of the peroxisome proliferator nafenopin as ligand. Rat liver GST and human liver recombinant GSTA1-1, GSTP1-1 and GSTM1-1 were used. Only class alpha rat liver GST and human GSTA1-1 bind xenobiotic-CoAs and fatty acyl-CoAs, with Kd values ranging from 200 nM to 5 microM. One mol of acyl-CoA is bound per mol of dimeric enzyme, and no metabolization or hydrolysis was observed. Binding results in strong inhibition of rat liver GST and human recombinant GSTA1-1 (IC50 at the nanomolar level for palmitoyl-CoA) but not GSTP1-1 and GSTM1-1. Acyl-CoAs do not interact with the GSTA1-1 substrate binding site, but probably with a different domain. Results suggest that under increased acyl-CoA concentration, as occurs after exposure to peroxisome proliferators, acyl-CoA binding to the abundant class alpha GSTs may result in strong inhibition of xenobiotic detoxification. Analysis of the binding properties of GSTs and other acyl-CoA binding proteins suggest that under increased acyl-CoA concentration GSTs would be responsible for xenobiotic-CoA binding whereas ACBP would preferentially bind fatty acyl-CoAs.

Receptores activadores de la proliferación peroxisomal / Activated receptors of the peroximonal proliferation

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors that belong to the steroid/retinoic acid receptor superfamily. All their characterized target genes encode proteins that participate in lipid homeostasis. The finding that antidiabetic thiazolidinediones and adipogenic prostanoids are ligans of one of the PPARS reveals a novel signaling pathway that directly links these compounds to processes involved in glucose homeostasis and lipid metabolism including adipocyte differentiation. An understanding of this pathway could designate PPARs as targets for the development and efficient treatments for several metabolic disorders