RESUMEN
Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the limiters of energy expenditure are largely unknown. Here, we show that ablation of the anti-inflammatory cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to differentiation, obesity, and aging. Assay for transposase-accessible chromatin sequencing (ATAC-seq), ChIP-seq, and RNA-seq reveal that IL-10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and C/EBPß recruitment to key enhancer regions. These findings expand our understanding of the relationship between inflammatory signaling pathways and adipose tissue function and provide insight into the physiological control of thermogenesis that could inform future therapy.
Asunto(s)
Adipocitos/metabolismo , Ensamble y Desensamble de Cromatina , Metabolismo Energético , Interleucina-10/metabolismo , Termogénesis , Factores de Transcripción Activadores/metabolismo , Animales , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Línea Celular , Células Cultivadas , Interleucina-10/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de SeñalRESUMEN
The mechanisms underlying sterol transport in mammalian cells are poorly understood. In particular, how cholesterol internalized from HDL is made available to the cell for storage or modification is unknown. Here, we describe three ER-resident proteins (Aster-A, -B, -C) that bind cholesterol and facilitate its removal from the plasma membrane. The crystal structure of the central domain of Aster-A broadly resembles the sterol-binding fold of mammalian StARD proteins, but sequence differences in the Aster pocket result in a distinct mode of ligand binding. The Aster N-terminal GRAM domain binds phosphatidylserine and mediates Aster recruitment to plasma membrane-ER contact sites in response to cholesterol accumulation in the plasma membrane. Mice lacking Aster-B are deficient in adrenal cholesterol ester storage and steroidogenesis because of an inability to transport cholesterol from SR-BI to the ER. These findings identify a nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals.
Asunto(s)
HDL-Colesterol/metabolismo , Proteínas de la Membrana/fisiología , Proteínas de la Membrana/ultraestructura , Células 3T3 , Animales , Transporte Biológico/fisiología , Antígenos CD36/metabolismo , Células CHO , Proteínas Portadoras/metabolismo , Línea Celular , Membrana Celular/metabolismo , Membrana Celular/fisiología , Colesterol/metabolismo , Cricetulus , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/fisiología , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Membranas Mitocondriales/metabolismo , Alineación de Secuencia , Esteroles/metabolismoRESUMEN
Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore-forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, the mechanisms by which these cells evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages without changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host defense strategy.
Asunto(s)
Infecciones Bacterianas/inmunología , Toxinas Bacterianas/inmunología , Hidroxicolesteroles/metabolismo , Interferones/aislamiento & purificación , Fagocitos/inmunología , Estreptolisinas/inmunología , Animales , Bacterias/inmunología , Bacterias/metabolismo , Proteínas Bacterianas/administración & dosificación , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/metabolismo , Membrana Celular/metabolismo , Permeabilidad de la Membrana Celular/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inmunología , Femenino , Interacciones Microbiota-Huesped/inmunología , Humanos , Microscopía Intravital , Masculino , Ratones , Ratones Transgénicos , Fagocitos/citología , Fagocitos/metabolismo , Cultivo Primario de Células , Esteroide Hidroxilasas/genética , Esteroide Hidroxilasas/metabolismo , Estreptolisinas/administración & dosificación , Estreptolisinas/metabolismoRESUMEN
GATA4 is a transcription factor known for its crucial role in the development of many tissues, including the liver; however, its role in adult liver metabolism is unknown. Here, using high-throughput sequencing technologies, we identified GATA4 as a transcriptional regulator of metabolism in the liver. GATA4 expression is elevated in response to refeeding, and its occupancy is increased at enhancers of genes linked to fatty acid and lipoprotein metabolism. Knocking out GATA4 in the adult liver (Gata4LKO) decreased transcriptional activity at GATA4 binding sites, especially during feeding. Gata4LKO mice have reduced plasma HDL cholesterol and increased liver triglyceride levels. The expression of a panel of GATA4 binding genes involved in hepatic cholesterol export and triglyceride hydrolysis was down-regulated in Gata4LKO mice. We further demonstrate that GATA4 collaborates with LXR nuclear receptors in the liver. GATA4 and LXRs share a number of binding sites, and GATA4 was required for the full transcriptional response to LXR activation. Collectively, these results show that hepatic GATA4 contributes to the transcriptional control of hepatic and systemic lipid homeostasis.
Asunto(s)
Hígado , Receptores Nucleares Huérfanos , Ratones , Animales , Receptores Nucleares Huérfanos/metabolismo , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Hígado/metabolismo , Homeostasis/genética , Colesterol , Triglicéridos/metabolismo , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Factor de Transcripción GATA4/genética , Factor de Transcripción GATA4/metabolismoRESUMEN
Subcutaneous white adipose tissue can be induced to undergo "browning" and acquire thermogenic capacity in response to physiological stimuli such as cold exposure or exercise. In this issue of Cell, Qiu et al. and Rao et al. demonstrate that pink-staining eosinophils and alternatively activated macrophages play key roles in an immune cascade mediating this metabolic switch.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Eosinófilos/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Macrófagos/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Transducción de Señal , Animales , MasculinoRESUMEN
Vascular permeability is frequently associated with inflammation and is triggered by a cohort of secreted permeability factors such as vascular endothelial growth factor (VEGF). Here, we show that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and is independent of VEGF. Global or endothelial-specific deletion of PR blocks physiological vascular permeability in the uterus, whereas misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of an endothelial genome-wide transcriptional profile with chromatin immunoprecipitation sequencing revealed that PR induces an NR4A1 (Nur77/TR3)-dependent transcriptional program that broadly regulates vascular permeability in response to progesterone. Silencing of NR4A1 blocks PR-mediated permeability responses, indicating a direct link between PR and NR4A1. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely, and venous-specific regulation of vascular barrier function that is critical for embryo implantation.
Asunto(s)
Permeabilidad Capilar , Endotelio Vascular/metabolismo , Útero/metabolismo , Animales , Endometrio/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Ratones , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genéticaRESUMEN
Multilocular adipocytes are a hallmark of thermogenic adipose tissue1,2, but the factors that enforce this cellular phenotype are largely unknown. Here, we show that an adipocyte-selective product of the Clstn3 locus (CLSTN3ß) present in only placental mammals facilitates the efficient use of stored triglyceride by limiting lipid droplet (LD) expansion. CLSTN3ß is an integral endoplasmic reticulum (ER) membrane protein that localizes to ER-LD contact sites through a conserved hairpin-like domain. Mice lacking CLSTN3ß have abnormal LD morphology and altered substrate use in brown adipose tissue, and are more susceptible to cold-induced hypothermia despite having no defect in adrenergic signalling. Conversely, forced expression of CLSTN3ß is sufficient to enforce a multilocular LD phenotype in cultured cells and adipose tissue. CLSTN3ß associates with cell death-inducing DFFA-like effector proteins and impairs their ability to transfer lipid between LDs, thereby restricting LD fusion and expansion. Functionally, increased LD surface area in CLSTN3ß-expressing adipocytes promotes engagement of the lipolytic machinery and facilitates fatty acid oxidation. In human fat, CLSTN3B is a selective marker of multilocular adipocytes. These findings define a molecular mechanism that regulates LD form and function to facilitate lipid utilization in thermogenic adipocytes.
Asunto(s)
Adipocitos , Proteínas de Unión al Calcio , Metabolismo de los Lípidos , Proteínas de la Membrana , Animales , Femenino , Humanos , Ratones , Adipocitos/citología , Adipocitos/metabolismo , Tejido Adiposo Pardo/citología , Tejido Adiposo Pardo/metabolismo , Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/metabolismo , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/metabolismo , Placenta , Triglicéridos/metabolismo , Retículo Endoplásmico/metabolismo , Gotas Lipídicas/metabolismo , Ácidos Grasos/metabolismo , Hipotermia/metabolismo , TermogénesisRESUMEN
Mammals undergo regular cycles of fasting and feeding that engage dynamic transcriptional responses in metabolic tissues. Here we review advances in our understanding of the gene regulatory networks that contribute to hepatic responses to fasting and feeding. The advent of sequencing and -omics techniques have begun to facilitate a holistic understanding of the transcriptional landscape and its plasticity. We highlight transcription factors, their cofactors, and the pathways that they impact. We also discuss physiological factors that impinge on these responses, including circadian rhythms and sex differences. Finally, we review how dietary modifications modulate hepatic gene expression programs.
Asunto(s)
Ingestión de Alimentos/genética , Ayuno/fisiología , Regulación de la Expresión Génica/fisiología , Hígado/metabolismo , Animales , Ritmo Circadiano , Redes Reguladoras de Genes/genética , Humanos , Factores Sexuales , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional coregulator transducin-like enhancer of split 3 (TLE3) inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes promotes mitochondrial oxidative metabolism and increases energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing, we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these binding sites are also enriched for early B-cell factor (EBF) transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 regulates thermogenic gene expression in beige adipocytes through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.
Asunto(s)
Adipocitos Beige/metabolismo , Proteínas Co-Represoras/genética , Proteínas Co-Represoras/metabolismo , Glucosa/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Cultivadas , Dieta Alta en Grasa , Metabolismo Energético/genética , Eliminación de Gen , Regulación de la Expresión Génica/genética , Estudio de Asociación del Genoma Completo , Resistencia a la Insulina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/genética , Mitocondrias/metabolismo , Termogénesis/genéticaRESUMEN
Lipoprotein lipase (LPL), the enzyme that carries out the lipolytic processing of triglyceride-rich lipoproteins (TRLs), is synthesized by adipocytes and myocytes and secreted into the interstitial spaces. The LPL is then bound by GPIHBP1, a GPI-anchored protein of endothelial cells (ECs), and transported across ECs to the capillary lumen. The assumption has been that the LPL that is moved into capillaries remains attached to GPIHBP1 and that GPIHBP1 serves as a platform for TRL processing. In the current studies, we examined the validity of that assumption. We found that an LPL-specific monoclonal antibody (mAb), 88B8, which lacks the ability to detect GPIHBP1-bound LPL, binds avidly to LPL within capillaries. We further demonstrated, by confocal microscopy, immunogold electron microscopy, and nanoscale secondary ion mass spectrometry analyses, that the LPL detected by mAb 88B8 is located within the EC glycocalyx, distant from the GPIHBP1 on the EC plasma membrane. The LPL within the glycocalyx mediates the margination of TRLs along capillaries and is active in TRL processing, resulting in the delivery of lipoprotein-derived lipids to immediately adjacent parenchymal cells. Thus, the LPL that GPIHBP1 transports into capillaries can detach and move into the EC glycocalyx, where it functions in the intravascular processing of TRLs.
Asunto(s)
Lipoproteína Lipasa , Receptores de Lipoproteína , Anticuerpos Monoclonales/metabolismo , Capilares/metabolismo , Células Endoteliales/metabolismo , Glicocálix/metabolismo , Lipoproteína Lipasa/metabolismo , Lipoproteínas/metabolismo , Receptores de Lipoproteína/metabolismo , Triglicéridos/metabolismo , Humanos , AnimalesRESUMEN
Aberrant increase of arachidonic acid (ARA) has long been implicated in the pathology of Alzheimer's disease (AD), while the underlying causal mechanism remains unclear. In this study, we revealed a link between ARA mobilization and microglial dysfunction in Aß pathology. Lipidomic analysis of primary microglia from AppNL-GF mice showed a marked increase in free ARA and lysophospholipids (LPLs) along with a decrease in ARA-containing phospholipids, suggesting increased ARA release from phospholipids (PLs). To manipulate ARA-containing PLs in microglia, we genetically deleted lysophosphatidylcholine acyltransferase 3 (Lpcat3), the main enzyme catalyzing the incorporation of ARA into PLs. Loss of microglial Lpcat3 reduced the levels of ARA-containing PLs, free ARA and LPLs, leading to a compensatory increase in monounsaturated fatty acid (MUFA)-containing PLs in both male and female App NL-GF mice. Notably, the reduction of ARA in microglia significantly ameliorated oxidative stress and inflammatory responses while enhancing the phagocytosis of Aß plaques and promoting the compaction of Aß deposits. Mechanistically, scRNA seq suggested that LPCAT3 deficiency facilitates phagocytosis by facilitating de novo lipid synthesis while protecting microglia from oxidative damage. Collectively, our study reveals a novel mechanistic link between ARA mobilization and microglial dysfunction in AD. Lowering brain ARA levels through pharmacological or dietary interventions may be a potential therapeutic strategy to slow down AD progression.
Asunto(s)
1-Acilglicerofosfocolina O-Aciltransferasa , Péptidos beta-Amiloides , Ácido Araquidónico , Microglía , Animales , Microglía/metabolismo , Ratones , Ácido Araquidónico/metabolismo , Masculino , Femenino , Péptidos beta-Amiloides/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferasa/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferasa/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Ratones Transgénicos , Peroxidación de Lípido , Ratones Endogámicos C57BL , Estrés Oxidativo/fisiología , Fosfolípidos/metabolismoRESUMEN
Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXRα was essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR-deficient mice were defective in the generation of MZ and metallophilic macrophages, which resulted in abnormal responses to blood-borne antigens. Myeloid-specific expression of LXRα or adoptive transfer of wild-type monocytes restored the MZ microenvironment in LXRα-deficient mice. Our results demonstrate that signaling via LXRα in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets.
Asunto(s)
Hematopoyesis/inmunología , Macrófagos/inmunología , Receptores Nucleares Huérfanos/inmunología , Bazo/inmunología , Animales , Benzoatos/farmacología , Bencilaminas/farmacología , Diferenciación Celular/inmunología , Citometría de Flujo , Inmunidad Celular/inmunología , Inmunohistoquímica , Receptores X del Hígado , Macrófagos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía Fluorescente , Receptores Nucleares Huérfanos/agonistas , Transducción de Señal/inmunología , Organismos Libres de Patógenos Específicos , Bazo/citologíaRESUMEN
BACKGROUND AND AIMS: The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction-associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear. APPROACH AND RESULTS: We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity and increased IHH mRNA. CONCLUSIONS: This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis, adds new insight into an established genetic locus for MASH, and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7.
RESUMEN
Liver X receptors (LXRs) are regulators of cholesterol metabolism that also modulate immune responses. Inactivation of LXR α and ß in mice leads to autoimmunity; however, how the regulation of cholesterol metabolism contributes to autoimmunity is unclear. Here we found that cholesterol loading of CD11c+ cells triggered the development of autoimmunity, whereas preventing excess lipid accumulation by promoting cholesterol efflux was therapeutic. LXRß-deficient mice crossed to the hyperlipidemic ApoE-deficient background or challenged with a high-cholesterol diet developed autoantibodies. Cholesterol accumulation in lymphoid organs promoted T cell priming and stimulated the production of the B cell growth factors Baff and April. Conversely, B cell expansion and the development of autoantibodies in ApoE/LXR-ß-deficient mice was reversed by ApoA-I expression. These findings implicate cholesterol imbalance as a contributor to immune dysfunction and suggest that stimulating HDL-dependent reverse cholesterol transport could be beneficial in the setting of autoimmune disease.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Enfermedades Autoinmunes/inmunología , Colesterol/metabolismo , Hipercolesterolemia/metabolismo , Animales , Enfermedades Autoinmunes/metabolismo , Antígeno CD11c/inmunología , Colesterol/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Perfilación de la Expresión Génica , Hipercolesterolemia/inmunología , Receptores X del Hígado/inmunología , Receptores X del Hígado/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , TranscriptomaRESUMEN
The nuclear receptors liver X receptor (LXR) α and ß play crucial roles in hepatic metabolism. Many genes induced in response to pharmacologic LXR agonism have been defined; however, the transcriptional consequences of loss of LXR binding to its genomic targets are less well characterized. Here, we addressed how deletion of both LXRα and LXRß from mouse liver (LXR double knockout [DKO]) affects the transcriptional regulatory landscape by integrating changes in LXR binding, chromatin accessibility, and gene expression. Many genes involved in fatty acid metabolism showed reduced expression and chromatin accessibility at their intergenic and intronic regions in LXRDKO livers. Genes that were up-regulated with LXR deletion had increased chromatin accessibility at their promoter regions and were enriched for functions not linked to lipid metabolism. Loss of LXR binding in liver reduced the activity of a broad set of hepatic transcription factors, inferred through changes in motif accessibility. By contrast, accessibility at promoter nuclear factor Y (NF-Y) motifs was increased in the absence of LXR. Unexpectedly, we also defined a small set of LXR targets for direct ligand-dependent repression. These genes have LXR-binding sites but showed increased expression in LXRDKO liver and reduced expression in response to the LXR agonist. In summary, the binding of LXRs to the hepatic genome has broad effects on the transcriptional landscape that extend beyond its canonical function as an activator of lipid metabolic genes.
Asunto(s)
Benzoatos/farmacología , Bencilaminas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Receptores X del Hígado/metabolismo , Hígado/metabolismo , Animales , Regulación de la Expresión Génica/fisiología , Receptores X del Hígado/agonistas , Receptores X del Hígado/genética , Ratones , Ratones NoqueadosRESUMEN
Regulation of hepatocyte proliferation and liver morphology is of critical importance to tissue and whole-body homeostasis. However, the molecular mechanisms that underlie this complex process are incompletely understood. Here, we describe a role for the ubiquitin ligase BRCA1-associated protein (BRAP) in regulation of hepatocyte morphology and turnover via regulation of MST2, a protein kinase in the Hippo pathway. The Hippo pathway has been implicated in the control of liver morphology, inflammation, and fibrosis. We demonstrate here that liver-specific ablation of Brap in mice results in gross and cellular morphological alterations of the liver. Brap-deficient livers exhibit increased hepatocyte proliferation, cell death, and inflammation. We show that loss of BRAP protein alters Hippo pathway signaling, causing a reduction in phosphorylation of YAP and increased expression of YAP target genes, including those regulating cell growth and interactions with the extracellular environment. Finally, increased Hippo signaling in Brap knockout mice alters the pattern of liver lipid accumulation in dietary models of obesity. These studies identify a role for BRAP as a modulator of the hepatic Hippo pathway with relevance to human liver disease.
Asunto(s)
Vía de Señalización Hippo , Transducción de Señal , Hepatocitos/metabolismo , Hígado/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Membrane contact sites (MCS), close membrane apposition between organelles, are platforms for interorganellar transfer of lipids including cholesterol, regulation of lipid homeostasis, and co-ordination of endocytic trafficking. Sphingosine kinases (SphKs), two isoenzymes that phosphorylate sphingosine to the bioactive sphingosine-1-phosphate (S1P), have been implicated in endocytic trafficking. However, the physiological functions of SphKs in regulation of membrane dynamics, lipid trafficking and MCS are not known. Here, we report that deletion of SphKs decreased S1P with concomitant increases in its precursors sphingosine and ceramide, and markedly reduced endoplasmic reticulum (ER) contacts with late endocytic organelles. Expression of enzymatically active SphK1, but not catalytically inactive, rescued the deficit of these MCS. Although free cholesterol accumulated in late endocytic organelles in SphK null cells, surprisingly however, cholesterol transport to the ER was not reduced. Importantly, deletion of SphKs promoted recruitment of the ER-resident cholesterol transfer protein Aster-B (also called GRAMD1B) to the plasma membrane (PM), consistent with higher accessible cholesterol and ceramide at the PM, to facilitate cholesterol transfer from the PM to the ER. In addition, ceramide enhanced in vitro binding of the Aster-B GRAM domain to phosphatidylserine and cholesterol liposomes. Our study revealed a previously unknown role for SphKs and sphingolipid metabolites in governing diverse MCS between the ER network and late endocytic organelles versus the PM to control the movement of cholesterol between distinct cell membranes.
Asunto(s)
Fosfatidilserinas , Esfingosina , Ceramidas/metabolismo , Colesterol/metabolismo , Retículo Endoplásmico/metabolismo , Isoenzimas/metabolismo , Liposomas/metabolismo , Lisofosfolípidos , Fosfatidilserinas/metabolismo , Esfingolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismoRESUMEN
In this issue of Genes & Development, Shapira and colleagues (pp. 660-673) outline mechanisms by which the brown fat transcription factor early B-cell factor 2 (EBF2) selectively activates brown lineage-specific gene expression. The investigators show that EBF2 interacts with and recruits a tissue-specific BAF chromatin remodeling complex to brown fat gene enhancers, thereby regulating chromatin accessibility. Their findings provide important insight into epigenetic regulation of adipocyte fate and thermogenic gene expression.
Asunto(s)
Tejido Adiposo Pardo , Cromatina , Adipocitos Marrones , Linfocitos B , Epigénesis Genética , TermogénesisRESUMEN
Nuclear receptors are integrators of hormonal and nutritional signals, mediating changes to metabolic pathways within the body. Given that modulation of lipid and glucose metabolism has been linked to diseases including type 2 diabetes, obesity and atherosclerosis, a greater understanding of pathways that regulate metabolism in physiology and disease is crucial. The liver X receptors (LXRs) and the farnesoid X receptors (FXRs) are activated by oxysterols and bile acids, respectively. Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid metabolism but also in the integration of sterol, fatty acid and glucose metabolism.
Asunto(s)
Metabolismo de los Lípidos/fisiología , Receptores Nucleares Huérfanos/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Aterosclerosis/metabolismo , Ácidos y Sales Biliares/metabolismo , Colesterol/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Regulación de la Expresión Génica , Glucosa/metabolismo , Humanos , Receptores X del Hígado , Obesidad/metabolismo , Receptores Nucleares Huérfanos/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Esteroles/metabolismo , Transcripción GenéticaRESUMEN
Mutations in the gene encoding the orphan nuclear receptor Nurr1 are linked to a rare familial form of Parkinson's disease. By examining the function of its mouse homolog, Saijo et al. (2009) provide evidence that Nurr1 protects dopaminergic neurons by suppressing inflammatory gene expression in astrocytes and microglia.