RESUMEN
BACKGROUND & AIMS: Reducing postprandial triglyceridemia may be a promising strategy to lower the risk of cardiovascular disorders associated with obesity and type 2 diabetes. In enterocytes, scavenger receptor class B, type 1 (SR-B1, encoded by SCARB1) mediates lipid-micelle sensing to promote assembly and secretion of chylomicrons. The nuclear receptor subfamily 1, group H, members 2 and 3 (also known as liver X receptors [LXRs]) regulate genes involved in cholesterol and fatty acid metabolism. We aimed to determine whether intestinal LXRs regulate triglyceride absorption. METHODS: C57BL/6J mice were either fed a cholesterol-enriched diet or given synthetic LXR agonists (GW3965 or T0901317). We measured the production of chylomicrons and localized SR-B1 by immunohistochemistry. Mechanisms of postprandial triglyceridemia and SR-B1 regulation were studied in Caco-2/TC7 cells incubated with LXR agonists. RESULTS: In mice and in the Caco-2/TC7 cell line, LXR agonists caused localization of intestinal SR-B1 from apical membranes to intracellular organelles and reduced chylomicron secretion. In Caco-2/TC7 cells, LXR agonists reduced SR-B1-dependent lipidic-micelle-induced Erk phosphorylation. LXR agonists also reduced intracellular trafficking of the apical apolipoprotein B pool toward secretory compartments. LXR reduced levels of SR-B1 in Caco-2/TC7 cells via a post-transcriptional mechanism that involves microRNAs. CONCLUSION: In Caco-2/TC7 cells and mice, intestinal activation of LXR reduces the production of chylomicrons by a mechanism dependent on the apical localization of SR-B1.
Asunto(s)
Absorción Intestinal , Mucosa Intestinal/metabolismo , Yeyuno/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Receptores Depuradores de Clase B/metabolismo , Triglicéridos/metabolismo , Animales , Apolipoproteína B-100/metabolismo , Apolipoproteínas B/metabolismo , Benzoatos/farmacología , Bencilaminas/farmacología , Células CACO-2 , Colesterol en la Dieta/metabolismo , Quilomicrones/metabolismo , ARN Helicasas DEAD-box/deficiencia , ARN Helicasas DEAD-box/genética , Regulación hacia Abajo , Humanos , Hidrocarburos Fluorados/farmacología , Absorción Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Yeyuno/efectos de los fármacos , Receptores X del Hígado , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , MicroARNs/metabolismo , Receptores Nucleares Huérfanos/agonistas , Transporte de Proteínas , Interferencia de ARN , Ribonucleasa III/deficiencia , Ribonucleasa III/genética , Receptores Depuradores de Clase B/deficiencia , Receptores Depuradores de Clase B/genética , Transducción de Señal , Sulfonamidas/farmacología , Transcripción Genética , TransfecciónRESUMEN
AIMS: Peroxisome proliferator-activated receptor (PPAR)-α is a transcription factor controlling lipid metabolism in liver, heart, muscle, and macrophages. Peroxisome proliferator-activated receptor-α activation increases plasma HDL cholesterol and exerts hypotriglyceridaemic actions via the liver. However, the intestine expresses PPAR-α, produces HDL and chylomicrons, and is exposed to diet-derived PPAR-α ligands. Therefore, we examined the effects of PPAR-α activation on intestinal lipid and lipoprotein metabolism. METHODS AND RESULTS: The impact of PPAR-α activation was evaluated in term of HDL-related gene expression in mice, ex vivo in human jejunal biopsies and in Caco-2/TC7 cells. Apolipoprotein-AI/HDL secretion, cholesterol esterification, and trafficking were also studied in vitro. In parallel to improving plasma lipid profiles and increasing liver and intestinal expression of fatty acid oxidation genes, treatment with the dual PPAR-α/δ ligand GFT505 resulted in a more pronounced increase in plasma HDL compared with fenofibrate in mice. GFT505, but not fenofibrate, increased the expression of HDL production genes such as apolipoprotein-AI and ATP-binding cassette A1 transporter in murine intestines. A similar increase was observed upon PPAR-α activation of human biopsies and Caco-2/TC7 cells. Additionally, HDL secretion by Caco-2/TC7 cells increased. Moreover, PPAR-α activation decreased the cholesterol esterification capacity of Caco-2/TC7 cells, modified cholesterol trafficking, and reduced apolipoprotein-B secretion. CONCLUSION: Peroxisome proliferator-activated receptor-α activation reduces cholesterol esterification, suppresses chylomicron, and increases HDL secretion by enterocytes. These results identify the intestine as a target organ of PPAR-α ligands with entero-hepatic tropism to reduce atherogenic dyslipidaemia.
Asunto(s)
Lipoproteínas HDL/metabolismo , PPAR alfa/fisiología , Animales , Apolipoproteínas B/metabolismo , Butiratos/farmacología , Células CACO-2 , Células Cultivadas , Chalconas/farmacología , Enterocitos/metabolismo , Esterificación/fisiología , Ácidos Grasos/metabolismo , Femenino , Humanos , Yeyuno/metabolismo , Ratones , Ratones Noqueados , PPAR alfa/antagonistas & inhibidores , Compuestos de Fenilurea/farmacología , Propionatos/farmacologíaRESUMEN
The postprandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium-glucose cotransporter 1 (SGLT1). This study uses Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1,547 subjects with class II/III obesity from the Atlas Biologique de l'Obésité Sévère cohort, the study uses SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype serves as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-min postload glycemia from fasting glycemia (Δ30 glucose) as the outcome. Results show that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean Δ30 glucose reduction of -0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study links a 1-SD decrease in SGLT1 expression to a Δ30 glucose reduction of -0.097 mmol/L. MR analysis parallels these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a Δ30 glucose decrease of -0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early postload glucose response. This finding has a potential translational impact on managing early glucose response to prevent or treat type 2 diabetes.
Asunto(s)
Glucemia , Absorción Intestinal , Análisis de la Aleatorización Mendeliana , Periodo Posprandial , Transportador 1 de Sodio-Glucosa , Humanos , Transportador 1 de Sodio-Glucosa/genética , Transportador 1 de Sodio-Glucosa/metabolismo , Periodo Posprandial/fisiología , Glucemia/metabolismo , Absorción Intestinal/genética , Masculino , Femenino , Prueba de Tolerancia a la Glucosa , Glucosa/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Haplotipos , Adulto , Obesidad/genética , Obesidad/metabolismo , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Yeyuno/metabolismoRESUMEN
Metformin (MET) is the most prescribed antidiabetic drug, but its mechanisms of action remain elusive. Recent data point to the gut as MET's primary target. Here, we explored the effect of MET on the gut glucose transport machinery. Using human enterocytes (Caco-2/TC7 cells) in vitro, we showed that MET transiently reduced the apical density of sodium-glucose transporter 1 (SGLT1) and decreased the absorption of glucose, without changes in the mRNA levels of the transporter. Administered 1 h before a glucose challenge in rats (Wistar, GK), C57BL6 mice and mice pigs, oral MET reduced the post-prandial glucose response (PGR). This effect was abrogated in SGLT1-KO mice. MET also reduced the luminal clearance of 2-(18F)-fluoro-2-deoxy-D-glucose after oral administration in rats. In conclusion, oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of SGLT1 in enterocytes, which may contribute to the clinical effects of the drug.
RESUMEN
A novel series of potent agonists of the bile acid receptor TGR5 bearing a dihydropyridone scaffold was developed from a high-throughput screen. Starting from a micromolar hit compound, we implemented an extensive structure-activity-relationship (SAR) study with the synthesis and biological evaluation of 83 analogues. The project culminated with the identification of the potent nanomolar TGR5 agonist 77A. We report the GLP-1 secretagogue effect of our lead compound ex vivo in mouse colonoids and in vivo. In addition, to identify specific features favorable for TGR5 activation, we generated and optimized a three-dimensional quantitative SAR model that contributed to our understanding of our activity profile and could guide further development of this dihydropyridone series.
Asunto(s)
Relación Estructura-Actividad Cuantitativa , Factores de Transcripción , Animales , Ratones , Péptido 1 Similar al Glucagón , Ácidos y Sales BiliaresRESUMEN
BACKGROUND & AIMS: Glucagon-like peptide (GLP)-1, an intestinal incretin produced by L cells through proglucagon processing, is secreted after nutrient ingestion and acts on endocrine pancreas beta cells to enhance insulin secretion. Peroxisome proliferator-activated receptor (PPAR) ß/δ is a nuclear receptor that improves glucose homeostasis and pancreas islet function in diabetic animal models. Here, we investigated whether PPARß/δ activation regulates L cell GLP-1 production. METHODS: Proglucagon regulation and GLP-1 release were evaluated in murine GLUTag and human NCI-H716 L cells and in vivo using wild-type, PPARß/δ-null, and ob/ob C57Bl/6 mice treated with the PPARß/δ synthetic agonists GW501516 or GW0742. RESULTS: PPARß/δ activation increased proglucagon expression and enhanced glucose- and bile acid-induced GLP-1 release by intestinal L cells in vitro and ex vivo in human jejunum. In vivo treatment with GW0742 increased proglucagon messenger RNA levels in the small intestine in wild-type but not in PPARß/δ-deficient mice. Treatment of wild-type and ob/ob mice with GW501516 enhanced the increase in plasma GLP-1 level after an oral glucose load and improved glucose tolerance. Concomitantly, proglucagon and GLP-1 receptor messenger RNA levels increased in the small intestine and pancreas, respectively. Finally, PPARß/δ agonists activate the proglucagon gene transcription by interfering with the ß-catenin/TCF-4 pathway. CONCLUSIONS: Our data show that PPARß/δ activation potentiates GLP-1 production by the small intestine. Pharmacologic targeting of PPARß/δ is a promising approach in the treatment of patients with type 2 diabetes mellitus, especially in combination with dipeptidyl peptidase IV inhibitors.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Células Enteroendocrinas/metabolismo , Regulación de la Expresión Génica , Péptido 1 Similar al Glucagón/biosíntesis , PPAR-beta/metabolismo , ARN Mensajero/genética , Animales , Glucemia/metabolismo , Western Blotting , Células Cultivadas , Diabetes Mellitus Experimental/patología , Modelos Animales de Enfermedad , Células Enteroendocrinas/patología , Péptido 1 Similar al Glucagón/genética , Humanos , Masculino , Ratones , Reacción en Cadena de la Polimerasa , ARN Mensajero/biosíntesis , RatasRESUMEN
Several studies have demonstrated that high protein diets improve glucose homeostasis. Nevertheless, the mechanisms underlying this effect remain elusive. This exploratory study aims to screen and compare the acute effects of dietary proteins from different sources on intestinal glucose absorption. Six dietary proteins from various sources were thus selected and digested thanks to the INFOGEST static gastrointestinal digestion protocol. The digested proteins were able to decrease intestinal glucose absorption in vitro and ex vivo. Moreover, acute ingestion of casein and fish gelatin led to improved glucose tolerance in Wistar rats without significant effect on insulin secretion. In parallel, GLUT2 mRNA expression in enterocytes was decreased following short-term incubation with some of the digested proteins. These results strengthen the evidence that digested protein-derived peptides and amino acids are key regulators of glucose homeostasis and highlight their role in intestinal glucose absorption.
RESUMEN
The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.
Asunto(s)
Colon/metabolismo , Ácidos Grasos Volátiles/farmacología , Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Microbiota , Receptores Citoplasmáticos y Nucleares/fisiología , Animales , Colon/efectos de los fármacos , Péptido 1 Similar al Glucagón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
A qualitative study is presented, where the main question was whether food-derived hemorphins, i.e., originating from digested alimentary hemoglobin, could pass the intestinal barrier and/or the blood-brain barrier (BBB). Once absorbed, hemorphins are opioid receptor (OR) ligands that may interact with peripheral and central OR and have effects on food intake and energy balance regulation. LLVV-YPWT (LLVV-H4), LVV-H4, VV-H4, VV-YPWTQRF (VV-H7), and VV-H7 hemorphins that were previously identified in the 120 min digest resulting from the simulated gastrointestinal digestion of hemoglobin have been synthesized to be tested in in vitro models of passage of IB and BBB. LC-MS/MS analyses yielded that all hemorphins, except the LLVV-H4 sequence, were able to cross intact the human intestinal epithelium model with Caco-2 cells within 5-60 min when applied at 5 mM. Moreover, all hemorphins crossed intact the human BBB model with brain-like endothelial cells (BLEC) within 30 min when applied at 100 µM. Fragments of these hemorphins were also detected, especially the YPWT common tetrapeptide that retains OR-binding capacity. A cAMP assay performed in Caco-2 cells indicates that tested hemorphins behave as OR agonists in these cells by reducing cAMP production. We further provide preliminary results regarding the effects of hemorphins on tight junction proteins, specifically here the claudin-4 that is involved in paracellular permeability. All hemorphins at 100 µM, except the LLVV-H4 peptide, significantly decreased claudin-4 mRNA levels in the Caco-2 intestinal model. This in vitro study is a first step toward demonstrating food-derived hemorphins bioavailability which is in line with the growing body of evidence supporting physiological functions for food-derived peptides.
RESUMEN
OBJECTIVE: The activity of the antitumoral agent bexarotene (Targretin, Bexarotene) depends on its binding to the nuclear retinoid-X receptor (RXR) and subsequent transcriptional regulation of target genes. Through RXR activation, bexarotene may modulate numerous metabolic pathways involved in atherosclerosis. Here, we investigated the effect of bexarotene on atherosclerosis progression in a dyslipidemic murine model, the human apolipoprotein E2 knockin mouse, that develops essentially macrophage-laden lesions. METHODS AND RESULTS: Atherosclerotic lesions together with different metabolic pathways involved in atherosclerosis were investigated in mice treated or not with bexarotene. Bexarotene protects from atherosclerosis development in mice, at least in part by improving the circulating cholesterol distribution profile likely via a marked decrease of dietary cholesterol absorption caused by modulation of intestinal expression of genes recently identified as major players in this process, Niemann-Pick-C1-Like1 (NPC1L1) and CD13. This atheroprotection appears despite a strong hypertriglyceridemia. Moreover, bexarotene treatment only modestly modulates inflammatory gene expression in the vascular wall, but markedly enhanced the capacity of macrophages to efflux cellular lipids. CONCLUSIONS: These data provide evidence of a favorable pharmacological effect of bexarotene on atherosclerosis despite the induction of hypertriglyceridemia, likely via a beneficial action on intestinal absorption and macrophage efflux.
Asunto(s)
Aterosclerosis/tratamiento farmacológico , Aterosclerosis/etiología , Colesterol/metabolismo , Dislipidemias/complicaciones , Homeostasis/efectos de los fármacos , Receptores X Retinoide/agonistas , Tetrahidronaftalenos/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Apolipoproteína E2/genética , Apolipoproteína E2/metabolismo , Aterosclerosis/metabolismo , Bexaroteno , Antígenos CD13/genética , Antígenos CD13/metabolismo , Modelos Animales de Enfermedad , Dislipidemias/tratamiento farmacológico , Dislipidemias/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Homeostasis/fisiología , Absorción Intestinal/efectos de los fármacos , Lipoproteínas/genética , Lipoproteínas/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Tetrahidronaftalenos/uso terapéutico , Triglicéridos/sangreRESUMEN
AIMS: The dyslipidemia associated with type 2 diabetes is a major risk factor for the development of atherosclerosis. Trans-intestinal cholesterol excretion (TICE) has recently been shown to contribute, together with the classical hepatobiliary route, to fecal cholesterol excretion and cholesterol homeostasis. The aim of this study was to develop an in vitro cell model to investigate enterocyte-related processes of TICE. METHODS: Differentiated Caco-2/TC7 cells were grown on transwells and incubated basolaterally (blood side) with human plasma and apically (luminal side) with lipid micelles. Radioactive and fluorescent cholesterol tracers were used to investigate cholesterol uptake at the basolateral membrane, intracellular distribution and apical excretion. RESULTS: Our results show that cholesterol is taken up at the basolateral membrane, accumulates intracellularly as lipid droplets and undergoes a cholesterol acceptor-facilitated and progressive excretion through the apical membrane of enterocytes. The overall process is abolished at 4 °C, suggesting a biologically active phenomenon. Moreover, this trans-enterocytic retrograde cholesterol transport displays some TICE features like modulation by PCSK9 and an ABCB1 inhibitor. Finally, we highlight the involvement of microtubules in the transport of plasma cholesterol from basolateral to apical pole of enterocytes. CONCLUSIONS: The human Caco-2/TC7 cell line appears a good in vitro model to investigate the enterocytic molecular mechanisms of TICE, which may help to identify intestinal molecular targets to enhance reverse cholesterol transport and fight against dyslipidemia.
Asunto(s)
Aterosclerosis/complicaciones , Colesterol/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Dislipidemias/metabolismo , Enterocitos/metabolismo , Exocitosis , Células CACO-2 , Dislipidemias/etiología , HumanosRESUMEN
BACKGROUND: Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of functional high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated transcription factor, controls lipid metabolism, cellular cholesterol trafficking in macrophages and influences inflammation. OBJECTIVE: To study whether pharmacological activation of PPARα with a novel highly potent and selective PPARα modulator, pemafibrate, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in vitro and in vivo using human apolipoprotein E2 Knock-In (apoE2KI) and human apoA-I transgenic (hapoA-I tg) mice. APPROACH AND RESULTS: Pemafibrate treatment decreases apoB secretion in chylomicrons by polarized Caco-2/TC7 intestinal epithelium cells and reduces triglyceride levels in apoE2KI mice. Pemafibrate treatment of hapoA-I tg mice increases plasma HDL cholesterol, apoA-I and stimulates RCT to feces. In primary human macrophages, pemafibrate promotes macrophage cholesterol efflux to HDL and exerts anti-inflammatory activities. Pemafibrate also reduces markers of inflammation and macrophages in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apoE2KI mice. CONCLUSIONS: These results demonstrate that the novel selective PPARα modulator pemafibrate exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties.
Asunto(s)
Aterosclerosis/tratamiento farmacológico , Benzoxazoles/farmacología , Butiratos/farmacología , Colesterol/metabolismo , Dislipidemias/tratamiento farmacológico , Inflamación/tratamiento farmacológico , PPAR alfa/antagonistas & inhibidores , Animales , Apolipoproteína A-I/química , Transporte Biológico , Células CACO-2 , Enfermedades Cardiovasculares/sangre , Epitelio/metabolismo , Femenino , Homocigoto , Humanos , Mucosa Intestinal/metabolismo , Ligandos , Metabolismo de los Lípidos , Lipoproteínas HDL/sangre , Lipoproteínas HDL/metabolismo , Macrófagos/metabolismo , Ratones , PPAR alfa/metabolismo , Factores de RiesgoRESUMEN
Bile acids are signalling molecules, which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex bile acids in the intestinal lumen and decrease intestinal FXR activity. The BAS-BA complex also induces glucagon-like peptide-1 (GLP-1) production by L cells which potentiates ß-cell glucose-induced insulin secretion. Whether FXR is expressed in L cells and controls GLP-1 production is unknown. Here, we show that FXR activation in L cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo, FXR deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycaemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes.
Asunto(s)
Células Enteroendocrinas/metabolismo , Péptido 1 Similar al Glucagón/genética , Mucosa Intestinal/metabolismo , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Animales , Anticolesterolemiantes/farmacología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Ácidos y Sales Biliares/metabolismo , Glucemia/metabolismo , Clorhidrato de Colesevelam/farmacología , Colon/citología , Colon/metabolismo , Dieta Alta en Grasa , Péptido 1 Similar al Glucagón/metabolismo , Glucólisis , Humanos , Íleon/citología , Íleon/metabolismo , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Intestinos/citología , Yeyuno/citología , Yeyuno/metabolismo , Ratones , Ratones Noqueados , Ratones Obesos , Proteínas Nucleares/metabolismo , Obesidad/genética , Obesidad/metabolismo , Proglucagón/efectos de los fármacos , Proglucagón/genética , Proglucagón/metabolismo , Receptores Acoplados a Proteínas G/genética , Secuestrantes/farmacología , Transducción de Señal , Factores de Transcripción/metabolismoRESUMEN
Niemann-Pick C1 like 1 (NPC1L1) is a protein critical for intestinal cholesterol absorption. The nuclear receptors peroxisome proliferator-activated receptor alpha (PPARalpha) and liver X receptors (LXRalpha and LXRbeta) are major regulators of cholesterol homeostasis and their activation results in a reduced absorption of intestinal cholesterol. The goal of this study was to define the role of PPARalpha and LXR nuclear receptors in the regulation of NPC1L1 gene expression. We show that LXR activators down-regulate NPC1L1 mRNA levels in the human enterocyte cell line Caco-2/TC7, whereas PPARalpha ligands have no effect. Furthermore, NPC1L1 mRNA levels are decreased in vivo, in duodenum of mice treated with the LXR agonist T0901317. In conclusion, the present study identifies NPC1L1 as a novel LXR target gene further supporting a crucial role of LXR in intestinal cholesterol homeostasis.