RESUMO
Defects in circadian rhythm influence physiology and behavior with implications for the treatment of sleep disorders, metabolic disease, and cancer. Although core regulatory components of clock rhythmicity have been defined, insight into the mechanisms underpinning amplitude is limited. Here, we show that REV-ERBα, a core inhibitory component of clock transcription, is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7. By relieving REV-ERBα-dependent repression, FBXW7 provides an unrecognized mechanism for enhancing the amplitude of clock gene transcription. Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of REV-ERBα is necessary for FBXW7 recognition. Moreover, targeted hepatic disruption of FBXW7 alters circadian expression of core clock genes and perturbs whole-body lipid and glucose levels. This CDK1-FBXW7 pathway controlling REV-ERBα repression defines an unexpected molecular mechanism for re-engaging the positive transcriptional arm of the clock, as well as a potential route to manipulate clock amplitude via small molecule CDK1 inhibition.
Assuntos
Ritmo Circadiano , Proteínas F-Box/metabolismo , Fígado/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Proteína Quinase CDC2/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Relógios Circadianos , Proteínas F-Box/genética , Proteína 7 com Repetições F-Box-WD , Técnicas de Inativação de Genes , Humanos , Metabolismo dos Lipídeos , Camundongos , Fosforilação , Processamento de Proteína Pós-Traducional , Transcriptoma , Ubiquitina-Proteína Ligases/genéticaRESUMO
Tissue-resident and recruited macrophages contribute to both host defense and pathology. Multiple macrophage phenotypes are represented in diseased tissues, but we lack deep understanding of mechanisms controlling diversification. Here, we investigate origins and epigenetic trajectories of hepatic macrophages during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induced significant changes in Kupffer cell enhancers and gene expression, resulting in partial loss of Kupffer cell identity, induction of Trem2 and Cd9 expression, and cell death. Kupffer cell loss was compensated by gain of adjacent monocyte-derived macrophages that exhibited convergent epigenomes, transcriptomes, and functions. NASH-induced changes in Kupffer cell enhancers were driven by AP-1 and EGR that reprogrammed LXR functions required for Kupffer cell identity and survival to instead drive a scar-associated macrophage phenotype. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct gene expression programs and corresponding functions.
Assuntos
Microambiente Celular/genética , Reprogramação Celular/genética , Epigênese Genética , Regulação da Expressão Gênica , Células Mieloides/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Biomarcadores , Sequenciamento de Cromatina por Imunoprecipitação , Dieta , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Células de Kupffer/imunologia , Células de Kupffer/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Ligação Proteica , Transdução de Sinais , Análise de Célula ÚnicaRESUMO
In macrophages, homeostatic and immune signals induce distinct sets of transcriptional responses, defining cellular identity and functional states. The activity of lineage-specific and signal-induced transcription factors are regulated by chromatin accessibility and other epigenetic modulators. Glucocorticoids are potent antiinflammatory drugs; however, the mechanisms by which they selectively attenuate inflammatory genes are not yet understood. Acting through the glucocorticoid receptor (GR), glucocorticoids directly repress inflammatory responses at transcriptional and epigenetic levels in macrophages. A major unanswered question relates to the sequence of events that result in the formation of repressive regions. In this study, we identify bromodomain containing 9 (BRD9), a component of SWI/SNF chromatin remodeling complex, as a modulator of glucocorticoid responses in macrophages. Inhibition, degradation, or genetic depletion of BRD9 in bone marrow-derived macrophages significantly attenuated their responses to both liposaccharides and interferon inflammatory stimuli. Notably, BRD9-regulated genes extensively overlap with those regulated by the synthetic glucocorticoid dexamethasone. Pharmacologic inhibition of BRD9 potentiated the antiinflammatory responses of dexamethasone, while the genetic deletion of BRD9 in macrophages reduced high-fat diet-induced adipose inflammation. Mechanistically, BRD9 colocalized at a subset of GR genomic binding sites, and depletion of BRD9 enhanced GR occupancy primarily at inflammatory-related genes to potentiate GR-induced repression. Collectively, these findings establish BRD9 as a genomic antagonist of GR at inflammatory-related genes in macrophages, and reveal a potential for BRD9 inhibitors to increase the therapeutic efficacies of glucocorticoids.
Assuntos
Montagem e Desmontagem da Cromatina , Dexametasona/farmacologia , Regulação da Expressão Gênica , Macrófagos/imunologia , Receptores de Glucocorticoides/metabolismo , Fatores de Transcrição/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Domínios Proteicos , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/genética , Fatores de Transcrição/genéticaRESUMO
The circadian system regulates numerous physiological processes including immune responses. Here, we show that mice deficient of the circadian clock genes Cry1 and Cry2 [Cry double knockout (DKO)] develop an autoimmune phenotype including high serum IgG concentrations, serum antinuclear antibodies, and precipitation of IgG, IgM, and complement 3 in glomeruli and massive infiltration of leukocytes into the lungs and kidneys. Flow cytometry of lymphoid organs revealed decreased pre-B cell numbers and a higher percentage of mature recirculating B cells in the bone marrow, as well as increased numbers of B2 B cells in the peritoneal cavity of Cry DKO mice. The B cell receptor (BCR) proximal signaling pathway plays a critical role in autoimmunity regulation. Activation of Cry DKO splenic B cells elicited markedly enhanced tyrosine phosphorylation of cellular proteins compared with cells from control mice, suggesting that overactivation of the BCR-signaling pathway may contribute to the autoimmunity phenotype in the Cry DKO mice. In addition, the expression of C1q, the deficiency of which contributes to the pathogenesis of systemic lupus erythematosus, was significantly down-regulated in Cry DKO B cells. Our results suggest that B cell development, the BCR-signaling pathway, and C1q expression are regulated by circadian clock CRY proteins and that their dysregulation through loss of CRY contributes to autoimmunity.
Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/genética , Linfócitos B/imunologia , Relógios Circadianos/imunologia , Criptocromos/imunologia , Animais , Anticorpos Antinucleares/biossíntese , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Relógios Circadianos/genética , Complemento C1q/genética , Criptocromos/deficiência , Criptocromos/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Rim/imunologia , Rim/patologia , Pulmão/imunologia , Pulmão/patologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Baço/patologiaRESUMO
The circadian clock acts at the genomic level to coordinate internal behavioural and physiological rhythms via the CLOCK-BMAL1 transcriptional heterodimer. Although the nuclear receptors REV-ERB-α and REV-ERB-ß have been proposed to form an accessory feedback loop that contributes to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential, we determined the genome-wide cis-acting targets (cistromes) of both REV-ERB isoforms in murine liver, which revealed shared recognition at over 50% of their total DNA binding sites and extensive overlap with the master circadian regulator BMAL1. Although REV-ERB-α has been shown to regulate Bmal1 expression directly, our cistromic analysis reveals a more profound connection between BMAL1 and the REV-ERB-α and REV-ERB-ß genomic regulatory circuits than was previously suspected. Genes within the intersection of the BMAL1, REV-ERB-α and REV-ERB-ß cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb-α and Rev-erb-ß function by creating double-knockout mice profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, double-knockout mice show markedly altered circadian wheel-running behaviour and deregulated lipid metabolism. These data now unite REV-ERB-α and REV-ERB-ß with PER, CRY and other components of the principal feedback loop that drives circadian expression and indicate a more integral mechanism for the coordination of circadian rhythm and metabolism.
Assuntos
Ritmo Circadiano/fisiologia , Metabolismo Energético , Metabolismo dos Lipídeos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Animais , Relógios Biológicos/efeitos dos fármacos , Relógios Biológicos/genética , Ritmo Circadiano/genética , Criptocromos/deficiência , Criptocromos/genética , Criptocromos/metabolismo , Metabolismo Energético/genética , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Redes Reguladoras de Genes/genética , Homeostase/genética , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Atividade Motora/genética , Atividade Motora/fisiologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/deficiência , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Proteínas Circadianas Period/deficiência , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Receptores Citoplasmáticos e Nucleares/deficiência , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Transcriptoma/genéticaRESUMO
Enhancers are critical genomic elements that define cellular and functional identity through the spatial and temporal regulation of gene expression. Recent studies suggest that key genes regulating cell type-specific functions reside in enhancer-dense genomic regions (i.e., super enhancers, stretch enhancers). Here we report that enhancer RNAs (eRNAs) identified by global nuclear run-on sequencing are extensively transcribed within super enhancers and are dynamically regulated in response to cellular signaling. Using Toll-like receptor 4 (TLR4) signaling in macrophages as a model system, we find that transcription of super enhancer-associated eRNAs is dynamically induced at most of the key genes driving innate immunity and inflammation. Unexpectedly, genes repressed by TLR4 signaling are also associated with super enhancer domains and accompanied by massive repression of eRNA transcription. Furthermore, we find each super enhancer acts as a single regulatory unit within which eRNA and genic transcripts are coordinately regulated. The key regulatory activity of these domains is further supported by the finding that super enhancer-associated transcription factor binding is twice as likely to be conserved between human and mouse than typical enhancer sites. Our study suggests that transcriptional activities at super enhancers are critical components to understand the dynamic gene regulatory network.
Assuntos
Elementos Facilitadores Genéticos , Inflamação/metabolismo , RNA/genética , Animais , Células Cultivadas , Humanos , Camundongos , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Transcrição GênicaRESUMO
Lipid homeostasis and inflammation are key determinants in atherogenesis, exemplified by the requirement of lipid-laden, foam cell macrophages for atherosclerotic lesion formation. Although the nuclear receptor PPARdelta has been implicated in both systemic lipid metabolism and macrophage inflammation, its role as a therapeutic target in vascular disease is unclear. We show here that orally active PPARdelta agonists significantly reduce atherosclerosis in apoE(-/-) mice. Metabolic and gene expression studies reveal that PPARdelta attenuates lesion progression through its HDL-raising effect and anti-inflammatory activity within the vessel wall, where it suppresses chemoattractant signaling by down-regulation of chemokines. Activation of PPARdelta also induces the expression of regulator of G protein signaling (RGS) genes, which are implicated in blocking the signal transduction of chemokine receptors. Consistent with this, PPARdelta ligands repress monocyte transmigration and macrophage inflammatory responses elicited by atherogenic cytokines. These results reveal that PPARdelta antagonizes multiple proinflammatory pathways and suggest PPARdelta-selective drugs as candidate therapeutics for atherosclerosis.
Assuntos
Aterosclerose/metabolismo , PPAR delta/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/genética , Aterosclerose/prevenção & controle , Linhagem Celular , Quimiocinas/metabolismo , HDL-Colesterol/sangue , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , PPAR delta/genética , Transdução de SinaisRESUMO
Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Regulation of osteoclast function is central to the understanding of bone diseases such as osteoporosis, rheumatoid arthritis and osteopetrosis. Although peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to inhibit osteoblast differentiation, its role, if any, in osteoclasts is unknown. This is a clinically crucial question because PPAR-gamma agonists, "such as thiazolidinediones-" a class of insulin-sensitizing drugs, have been reported to cause a higher rate of fractures in human patients. Here we have uncovered a pro-osteoclastogenic effect of PPAR-gamma by using a Tie2Cre/flox mouse model in which PPAR-gamma is deleted in osteoclasts but not in osteoblasts. These mice develop osteopetrosis characterized by increased bone mass, reduced medullary cavity space and extramedullary hematopoiesis in the spleen. These defects are the result of impaired osteoclast differentiation and compromised receptor activator of nuclear factor-kappaB ligand signaling and can be rescued by bone marrow transplantation. Moreover, ligand activation of PPAR-gamma by rosiglitazone exacerbates osteoclast differentiation in a receptor-dependent manner. Our examination of the underlying mechanisms suggested that PPAR-gamma functions as a direct regulator of c-fos expression, an essential mediator of osteoclastogenesis. Therefore, PPAR-gamma and its ligands have a previously unrecognized role in promoting osteoclast differentiation and bone resorption.
Assuntos
Osteoclastos/metabolismo , PPAR gama/genética , PPAR gama/fisiologia , Animais , Reabsorção Óssea , Feminino , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Transdução de Sinais , Baço/metabolismoRESUMO
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1beta (PGC-1beta) is believed to control mitochondrial oxidative energy metabolism by activating specific target transcription factors including estrogen-related receptors and nuclear respiratory factor 1, yet its physiological role is not yet clearly understood. To define its function in vivo, we generated and characterized mice lacking the functional PGC-1beta protein [PGC-1beta knockout (KO) mice]. PGC-1beta KO mice are viable and fertile and show no overt phenotype under normal laboratory conditions. However, the KO mice displayed an altered expression in a large number of nuclear-encoded genes governing mitochondrial and metabolic functions in multiple tissues including heart, skeletal muscle, brain, brown adipose tissue, and liver. In contrast to PGC-1alpha KO mice that are reportedly hyperactive, PGC-1beta KO mice show greatly decreased activity during the dark cycle. When acutely exposed to cold, the KO mice developed abnormal hypothermia and morbidity. Furthermore, high-fat feeding induced hepatic steatosis and increased serum triglyceride and cholesterol levels in the KO mice. These results suggest that PGC-1beta in mouse plays a nonredundant role in controlling mitochondrial oxidative energy metabolism.
Assuntos
Ritmo Circadiano/fisiologia , Fígado Gorduroso/metabolismo , Mitocôndrias/metabolismo , Termogênese/fisiologia , Transativadores/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Metabolismo Basal , Temperatura Baixa , Dieta , Regulação para Baixo/genética , Fígado Gorduroso/induzido quimicamente , Perfilação da Expressão Gênica , Marcação de Genes , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transativadores/deficiência , Transativadores/genética , Fatores de TranscriçãoRESUMO
Lactation is a highly demanding lipid synthesis and transport process that is crucial for the development of newborn mammals. While PPAR gamma is known to promote adipogenesis and lipogenesis in adipose tissue, its role in the lactating mammary gland is unexplored. Here, we report that a targeted deletion of PPAR gamma in mice results in the production of "toxic milk" containing elevated levels of inflammatory lipids. Surprisingly, ingestion of this "toxic milk" causes inflammation, alopecia, and growth retardation in the nursing neonates. Genomic profiling reveals that PPAR gamma deficiency leads to increased expression of lipid oxidation enzymes in the lactating mammary gland. Consistently, metabolomic profiling detects increased levels of oxidized free fatty acids in the pups nursed by PPAR gamma-deficient mothers. Therefore, maternal PPAR gamma is pivotal for maintaining the quality of milk and protecting the nursing newborns by suppressing the production of inflammatory lipids in the lactating mammary gland.
Assuntos
Mediadores da Inflamação/metabolismo , Leite/metabolismo , PPAR gama/metabolismo , Alopecia/etiologia , Alopecia/patologia , Animais , Animais Recém-Nascidos , Araquidonato 12-Lipoxigenase/metabolismo , Ácidos Graxos não Esterificados/química , Ácidos Graxos não Esterificados/metabolismo , Feminino , Transtornos do Crescimento/etiologia , Inflamação/etiologia , Lactação/metabolismo , Metabolismo dos Lipídeos , Masculino , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Leite/toxicidade , Oxirredução , PPAR gama/deficiência , PPAR gama/genética , GravidezRESUMO
Macrophage activation by the proinflammatory cytokine interferon-gamma (IFN-gamma) is a critical component of the host innate response to bacterial pathogenesis. However, the precise nature of the IFN-gamma-induced activation pathway is not known. Here we show using genome-wide expression and chromatin-binding profiling that IFN-gamma induces the expression of many nuclear genes encoding mitochondrial respiratory chain machinery via activation of the nuclear receptor ERR alpha (estrogen-related receptor alpha, NR3B1). Studies with macrophages lacking ERR alpha demonstrate that it is required for induction of mitochondrial reactive oxygen species (ROS) production and efficient clearance of Listeria monocytogenes (LM) in response to IFN-gamma. As a result, mice lacking ERR alpha are susceptible to LM infection, a phenotype that is localized to bone marrow-derived cells. Furthermore, we found that IFN-gamma-induced activation of ERR alpha depends on coactivator PGC-1 beta (peroxisome proliferator-activated receptor gamma coactivator-1 beta), which appears to be a direct target for the IFN-gamma/STAT-1 signaling cascade. Thus, ERR alpha and PGC-1 beta act together as a key effector of IFN-gamma-induced mitochondrial ROS production and host defense.
Assuntos
Proteínas de Transporte/metabolismo , Interferon gama/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/fisiologia , Receptores de Estrogênio/metabolismo , Animais , Sequência de Bases , Proteínas de Transporte/genética , DNA/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Listeria monocytogenes/imunologia , Listeria monocytogenes/patogenicidade , Ativação de Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Proteínas de Ligação a RNA , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio/deficiência , Receptores de Estrogênio/genética , Proteínas Recombinantes , Transdução de Sinais/efeitos dos fármacos , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
The metabolic syndrome is a collection of obesity-related disorders. The peroxisome proliferator-activated receptors (PPARs) regulate transcription in response to fatty acids and, as such, are potential therapeutic targets for these diseases. We show that PPARdelta (NR1C2) knockout mice are metabolically less active and glucose-intolerant, whereas receptor activation in db/db mice improves insulin sensitivity. Euglycemic-hyperinsulinemic-clamp experiments further demonstrate that a PPARdelta-specific agonist suppresses hepatic glucose output, increases glucose disposal, and inhibits free fatty acid release from adipocytes. Unexpectedly, gene array and functional analyses suggest that PPARdelta ameliorates hyperglycemia by increasing glucose flux through the pentose phosphate pathway and enhancing fatty acid synthesis. Coupling increased hepatic carbohydrate catabolism with its ability to promote beta-oxidation in muscle allows PPARdelta to regulate metabolic homeostasis and enhance insulin action by complementary effects in distinct tissues. The combined hepatic and peripheral actions of PPARdelta suggest new therapeutic approaches to treat type II diabetes.
Assuntos
Glucose/metabolismo , Insulina/metabolismo , PPAR delta/metabolismo , Animais , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Intolerância à Glucose , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Análise de Sequência com Séries de Oligonucleotídeos , PPAR delta/agonistas , PPAR delta/deficiência , PPAR delta/genética , Via de Pentose Fosfato , Transcrição Gênica/genéticaRESUMO
Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, recent advances have identified triglyceride-rich lipoproteins [e.g., very LDL (VLDL)] as independent risk predictors for this disease. We have previously demonstrated peroxisome proliferator-activated receptor (PPAR)delta, but not PPARgamma, is the major nuclear VLDL sensor in the macrophage, which is a crucial component of the atherosclerotic lesion. Here, we show that, in addition to beta-oxidation and energy dissipation, activation of PPARdelta by VLDL particles induces key genes involved in carnitine biosynthesis and lipid mobilization mediated by a recently identified TG lipase, transport secretion protein 2 (also named desnutrin, iPLA2zeta, and adipose triglyceride lipase), resulting in increased fatty acid catabolism. Unexpectedly, deletion of PPARdelta results in derepression of target gene expression, a phenotype similar to that of ligand activation, suggesting that unliganded PPARdelta suppresses fatty acid utilization through active repression, which is reversed upon ligand binding. This unique transcriptional mechanism assures a tight control of the homeostasis of VLDL-derived fatty acid and provides a therapeutic target for other lipid-related disorders, including dyslipidemia and diabetes, in addition to coronary artery disease.
Assuntos
Hidrolases de Éster Carboxílico/genética , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Metabolismo dos Lipídeos/genética , Lipoproteínas VLDL/metabolismo , PPAR delta/metabolismo , Animais , Hidrolases de Éster Carboxílico/metabolismo , Carnitina/biossíntese , Carnitina/genética , Deleção de Genes , Lipase , Lipoproteínas VLDL/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Oxirredução , PPAR delta/genéticaRESUMO
Efficient detoxification and clearance of cholesterol metabolites such as oxysterols, bile alcohols, and bile acids are critical for survival because they can promote liver and cardiovascular disease. We report here that loss of the nuclear xenobiotic receptor PXR (pregnane X receptor), a regulator of enterohepatic drug metabolism and clearance, results in an unexpected acute lethality associated with signs of severe hepatorenal failure when mice are fed with a diet that elicits accumulation of cholesterol and its metabolites. Induction of a distinct drug clearance program by a high-affinity ligand for the related nuclear receptor, the constitutive androstane receptor, does not overcome the lethality, indicating the unique requirement of PXR for detoxification. We propose that the PXR signaling pathway protects the body from toxic dietary cholesterol metabolites, and, by extension, PXR ligands may ameliorate human diseases such as cholestatic liver diseases and the associating acute renal failure.