Asunto(s)
Trastornos Mentales/diagnóstico , Trastornos Mentales/terapia , Servicios de Salud Mental/organización & administración , Guías de Práctica Clínica como Asunto , Telemedicina/organización & administración , Adolescente , Adulto , Niño , Preescolar , Accesibilidad a los Servicios de Salud/normas , Humanos , Lactante , Servicios de Salud Mental/normas , Aplicaciones Móviles , Evaluación de Necesidades , Sociedades Médicas , Telemedicina/normas , Estados Unidos , Comunicación por Videoconferencia/normas , Adulto JovenRESUMEN
During the acute phase response, cytokines induce marked alterations in lipid metabolism including an increase in serum triglyceride levels and a decrease in hepatic fatty acid oxidation, in bile acid synthesis, and in high-density lipoprotein levels. Here we demonstrate that tumor necrosis factor (TNF) and interleukin 1 (IL-1), but not IL-6, decrease the expression of retinoid X receptor alpha (RXRalpha), peroxisome proliferator-activated receptor alpha (PPARalpha), PPARgamma, liver X receptor alpha (LXRalpha), and coactivators PPARgamma coactivator 1alpha (PGC-1alpha), PGC-1beta, and steroid receptor coactivator 1 (SRC-1) in Hep3B human hepatoma cells. In addition, treatment of mice with TNF and IL-1 also decreased RXRalpha, PPARalpha, PPARgamma, LXRalpha, and PGC-1alpha messenger RNA (mRNA) levels in the liver. These decreases were accompanied by reduced binding of nuclear extracts to RXR, PPAR, and LXR response elements and decreased luciferase activity driven by PPAR and LXR response elements. In addition, the mRNA levels of proteins regulated by PPARalpha (carnitine palmitoyltransferase 1alpha) and LXR (sterol regulatory element binding protein) were decreased in Hep3B cells treated with TNF or IL-1. Finally, using constructs of the LXRalpha promoter or the PGC-1alpha promoter linked to luciferase, we were able to demonstrate that a decrease in transcription contributes to the reduction in mRNA levels of nuclear hormone receptors and coactivators. Thus, our results suggest that decreased expression of nuclear hormone receptors RXRalpha, PPARalpha, PPARgamma, and LXRalpha, as well as coactivators PGC-1alpha, PGC-1beta, and SRC-1 may contribute to the cytokine-induced alterations in hepatic lipid metabolism during the acute phase response.
Asunto(s)
Interleucina-1/farmacología , Hígado/metabolismo , Receptores de Superficie Celular/metabolismo , Factores de Necrosis Tumoral/farmacología , Reacción de Fase Aguda/metabolismo , Animales , Northern Blotting , Western Blotting , Núcleo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Histona Acetiltransferasas/metabolismo , Hígado/efectos de los fármacos , Receptores X del Hígado , Ratones , Ratones Endogámicos C57BL , Coactivador 1 de Receptor Nuclear , Receptores Nucleares Huérfanos , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , ARN Mensajero/biosíntesis , ARN Mensajero/aislamiento & purificación , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptor alfa X Retinoide/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , TransfecciónRESUMEN
Carbohydrate response element binding protein (ChREBP) is a recently discovered transcription factor whose levels and activity are increased by glucose leading to the activation of target genes, which include acetyl-CoA carboxylase, fatty acid synthase, and liver-type pyruvate kinase. Here, we demonstrate that lipopolysaccharide (LPS) treatment causes a marked decrease in ChREBP mRNA and protein levels in the liver of mice fed a normal chow diet or in mice fasted for 24 h and then re-fed a high carbohydrate diet. This decrease occurs rapidly and is a sensitive response (half-maximal dose 0.1 µg/mouse). The decrease in ChREBP is accompanied by a decrease in the expression of ChREBP target genes. Zymosan and turpentine treatment also decrease hepatic ChREBP levels and the expression of its target genes. Additionally, tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) decrease liver ChREBP expression both in vivo and in Hep3B cells in culture. Finally, LPS decreased ChREBP expression in muscle and adipose tissue. These studies demonstrate that ChREBP is down-regulated during the acute phase response resulting in alterations in the expression of ChREBP regulated target genes. Thus, ChREBP joins a growing list of transcription factors that are regulated during the acute phase response.
Asunto(s)
Regulación de la Expresión Génica , Hígado/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Línea Celular , Carbohidratos de la Dieta/administración & dosificación , Endotoxinas/inmunología , Endotoxinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Trementina/metabolismo , Zimosan/inmunología , Zimosan/metabolismoRESUMEN
Activation of macrophages by TLR agonists enhances foam cell formation, but the underlying mechanisms are not understood. We examined the effects of TLR agonists on ADRP/ADFP, a protein associated with forming lipid droplets, and Mal1 a fatty acid-binding protein, in two mouse macrophage cell lines and human monocytes. Low doses of LPS, a TLR4 agonist increased both mRNA and protein levels of ADRP/ADFP and Mal1 in RAW 264.7 macrophages. Following pretreatment with Intralipid, fatty acids, or acetyl-LDL to increase triglyceride or cholesterol ester storage, LPS treatment still increased ADRP/ADFP and Mal1 mRNA levels. LPS also induced ADRP/ADFP and Mal1 in J774 macrophages and ADRP/ADFP in human monocytes. Zymosan, a fungal product that activates TLR2, poly-I:C, a viral mimetic that activates TLR3, and imiquimod, a TLR7 agonist, also increased ADRP/ADFP. Zymosan, but not poly-I:C or imiquimod, induced Mal1. In contrast, neither gene was induced by TNFalpha, IL-1beta, IL-6, or interferon-gamma. Thus TLR agonists induce ADRP/ADFP and Mal1, which likely contributes to macrophage triglyceride and cholesterol ester storage leading to foam cell formation.
Asunto(s)
Aterosclerosis/inmunología , Proteínas de Unión a Ácidos Grasos/biosíntesis , Macrófagos/inmunología , Proteínas de la Membrana/biosíntesis , Proteínas de Neoplasias/biosíntesis , Receptores Toll-Like/agonistas , Aminoquinolinas/farmacología , Animales , Ésteres del Colesterol/metabolismo , Humanos , Imiquimod , Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Activación de Macrófagos , Macrófagos/efectos de los fármacos , Ratones , Perilipina-2 , Poli I-C/farmacología , Receptores Toll-Like/inmunología , Triglicéridos/metabolismo , Zimosan/farmacologíaRESUMEN
Inflammation can produce abnormalities that could increase the risk for atherosclerosis including alterations in lipid and lipoprotein metabolism. Apolipoprotein M is a recently described HDL-associated apoprotein expressed mainly in the liver and kidney with protective effects against atherosclerosis. In this study, we describe the regulation of apolipoprotein M during the acute phase response. Stimuli that produce systemic inflammation, LPS, zymosan, or turpentine, decrease apolipoprotein M mRNA levels in the liver and kidney. Treatment of Hep3B hepatoma cells with TNF or IL-1 also decreased apolipoprotein M mRNA levels. The decrease in apolipoprotein M mRNA leads to a decrease in apolipoprotein M secretion into the media in Hep3B cells and a decrease in mouse serum following LPS administration. Moreover, in humans with acute bacterial infections or chronic HIV infection, serum apolipoprotein M levels are decreased. Apolipoprotein M is a negative acute response protein that decreases during infection and inflammation. These results are consistent with the finding that infections and inflammatory disorders accompanied by systemic inflammation are associated with an increased risk of atherosclerosis.