RESUMO
Risk factors for nonalcoholic hepatic steatosis include obesity and vitamin D deficiency which commonly coexist. Thus, the role of vitamin D signaling in the prevention of hepatic steatosis in the absence of obesity or a "Western" high-fat diet is unclear. These studies were performed to address the role of the adipocyte vitamin D receptor (VDR) in the prevention of hepatic steatosis in mice fed a chow diet containing 5% fat by weight. Female mice with adipocyte VDR ablation (Adipoq-Cre; VDRflox/flox) exhibited a mild increase in weight gain at age 70 days, accompanied by an increase in visceral white adipose tissue (VAT) weight. While they did not exhibit evidence of hepatic inflammation or fibrosis, an increase in hepatic lipid content was observed. This was accompanied by an increase in the hepatic expression of genes involved in fatty acid transport and synthesis, as well as fatty acid oxidation. Markers of hepatic inflammation and fibrosis were unaffected by adipocyte VDR ablation. Consistent with the increase in VAT weight in the Adipoq-Cre; VDRflox/flox mice, higher levels of transcripts encoding adipogenesis-related genes were observed in VAT. In contrast to other models of impaired vitamin D signaling studied in the setting of a high-fat or "Western" diet, the Adipoq-Cre; VDRflox/flox mice do not exhibit hepatic inflammation or fibrosis. These findings suggest that the adipocyte VDR regulates hepatic lipid accumulation, but in the absence of obesity or a high-fat diet, is not required to prevent hepatic inflammation or fibrosis.
Assuntos
Dieta com Restrição de Gorduras , Gordura Intra-Abdominal/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Receptores de Calcitriol/fisiologia , Adipócitos/química , Animais , Feminino , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Receptores de Calcitriol/deficiência , Receptores de Calcitriol/genética , Transdução de Sinais/fisiologia , Vitamina D/metabolismoRESUMO
Immune cells, including dendritic cells, macrophages, and T and B cells, express the vitamin D receptor and 1α-hydroxylase. In vitro studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, has an anti-inflammatory effect. Recent epidemiological evidence has indicated a significant association between vitamin D deficiency and an increased incidence, or aggravation, of infectious diseases and inflammatory autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. However, the impact of vitamin D on treatment and prevention, particularly in infectious diseases such as the 2019 coronavirus disease (COVID-19), remains controversial. Here, we review recent evidence associated with the relationship between vitamin D and inflammatory diseases and describe the underlying immunomodulatory effect of vitamin D.
Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19/prevenção & controle , Sistema Imunitário/efeitos dos fármacos , Inflamação/tratamento farmacológico , Vitamina D/uso terapêutico , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/prevenção & controle , Doenças Autoimunes/tratamento farmacológico , Linfócitos B/imunologia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/prevenção & controle , Macrófagos/imunologia , Camundongos , Monócitos/imunologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/prevenção & controle , Receptores de Calcitriol/genética , Receptores de Calcitriol/fisiologia , Linfócitos T/imunologia , Deficiência de Vitamina D/complicaçõesRESUMO
Many cell types display the remarkable ability to alter their cellular phenotype in response to specific external or internal signals. Such phenotypic plasticity is apparent in the nematode Caenorhabditis elegans when adverse environmental conditions trigger entry into the dauer diapause stage. This entry is accompanied by structural, molecular, and functional remodeling of a number of distinct tissue types of the animal, including its nervous system. The transcription factor (TF) effectors of 3 different hormonal signaling systems, the insulin-responsive DAF-16/FoxO TF, the TGFß-responsive DAF-3/SMAD TF, and the steroid nuclear hormone receptor, DAF-12/VDR, a homolog of the vitamin D receptor (VDR), were previously shown to be required for entering the dauer arrest stage, but their cellular and temporal focus of action for the underlying cellular remodeling processes remained incompletely understood. Through the generation of conditional alleles that allowed us to spatially and temporally control gene activity, we show here that all 3 TFs are not only required to initiate tissue remodeling upon entry into the dauer stage, as shown before, but are also continuously required to maintain the remodeled state. We show that DAF-3/SMAD is required in sensory neurons to promote and then maintain animal-wide tissue remodeling events. In contrast, DAF-16/FoxO or DAF-12/VDR act cell-autonomously to control anatomical, molecular, and behavioral remodeling events in specific cell types. Intriguingly, we also uncover non-cell autonomous function of DAF-16/FoxO and DAF-12/VDR in nervous system remodeling, indicating the presence of several insulin-dependent interorgan signaling axes. Our findings provide novel perspectives into how hormonal systems control tissue remodeling.
Assuntos
Proteínas de Caenorhabditis elegans/fisiologia , Comunicação Celular/genética , Plasticidade Celular/genética , Fatores de Transcrição Forkhead/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento , Sistema Nervoso/crescimento & desenvolvimento , Sistema Nervoso/metabolismo , Especificidade de Órgãos/genética , Organogênese/genética , Comunicação Parácrina/genética , Receptores de Calcitriol/genética , Receptores de Calcitriol/fisiologia , Receptores Citoplasmáticos e Nucleares/genética , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Transdução de Sinais/genéticaRESUMO
Early pregnancy is characterised by elevated circulating levels of vitamin D binding protein (DBP). The impact of this on maternal and fetal health is unclear but DBP is present in the placenta, and DBP gene variants have been linked to malplacentation disorders such as preeclampsia. The functional role of DBP in the placenta was investigated using trophoblastic JEG3, BeWo and HTR8 cells. All three cell lines showed intracellular DBP with increased expression and nuclear localisation of DBP in cells treated with the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D). When cultured in the serum of mice lacking DBP (DBP-/-), JEG3 cells showed no intracellular DBP indicating uptake of exogenous DBP. Inhibition of the membrane receptor for DBP, megalin, also suppressed intracellular DBP. Elimination of intracellular DBP with DBP-/- serum or megalin inhibitor suppressed matrix invasion by trophoblast cells and was associated with increased nuclear accumulation of G-actin. Conversely, treatment with 1,25D enhanced matrix invasion. This was independent of the nuclear vitamin D receptor but was associated with enhanced ERK phosphorylation, and inhibition of ERK kinase suppressed trophoblast matrix invasion. When cultured with serum from pregnant women, trophoblast matrix invasion correlated with DBP concentration, and DBP was lower in first-trimester serum from women who later developed preeclampsia. These data show that the trophoblast matrix invasion involves uptake of serum DBP and associated intracellular actin-binding and homeostasis. DBP is a potential marker of placentation disorders such as preeclampsia and may also provide a therapeutic option for improved placenta and pregnancy health.
Assuntos
Actinas/metabolismo , Trofoblastos/fisiologia , Proteína de Ligação a Vitamina D/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/química , Núcleo Celular/metabolismo , Coriocarcinoma , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Fosforilação , Placentação/fisiologia , Pré-Eclâmpsia/sangue , Gravidez , Receptores de Calcitriol/genética , Receptores de Calcitriol/fisiologia , Neoplasias Uterinas , Vitamina D/análogos & derivados , Vitamina D/sangue , Vitamina D/farmacologia , Proteína de Ligação a Vitamina D/sangue , Proteína de Ligação a Vitamina D/genéticaRESUMO
OBJECTIVE: The purpose of this study was to investigate the effects of vitamin D on adipokine expression and inflammation in human adipose tissues and adipocytes and evaluate the molecular mechanisms involved. METHODS: Omental and abdominal subcutaneous human adipose tissues were treated with 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ), and adipokine levels were measured. Vitamin D effects were measured with or without dexamethasone because glucocorticoids are known to affect vitamin D actions. Using RNA interference, we examined whether the vitamin D receptor (VDR) mediated vitamin D actions on adipokine expression and inflammatory signaling pathways in human adipocytes. RESULTS: mRNA levels and secretion of leptin and IL-6 were suppressed by 1,25(OH)2 D3 in omental adipose tissues. Cotreatment with dexamethasone did not affect these inhibitory actions but partially blocked CYP24A1 induction. Similar results were observed in the subcutaneous depot. In addition, 1,25(OH)2 D3 suppressed leptin and IL-6 expression as well as nuclear factor-κB and extracellular signal-regulated kinase-1/2 phosphorylation in human adipocytes. Adipokine expression also was decreased by 25-hydroxyvitamin D3 (25(OH)D3 ), but not vitamin D3 . Knockdown of VDR increased the inflammatory signaling activity in the control condition and blocked the inhibitory effects of 1,25(OH)2 D3 on adipokine and inflammatory signaling pathways. CONCLUSION: Vitamin D acts through VDR to inhibit inflammatory pathways and adipokine expression in human adipocytes. Increasing vitamin D status may ameliorate obesity-associated metabolic complications by decreasing adipose tissue inflammation.
Assuntos
Adipócitos/efeitos dos fármacos , Adipocinas/metabolismo , Mediadores da Inflamação/metabolismo , Receptores de Calcitriol/fisiologia , Vitamina D/análogos & derivados , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adulto , Idoso , Células Cultivadas , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/prevenção & controle , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Receptores de Calcitriol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Vitamina D/farmacologiaRESUMO
Vitamin D Receptor (VDR), a nuclear steroid receptor, is a transcription factor with a primary physiologic role in calcium metabolism. It has also a physiologic role in breast tissues during development of the gland and postpartum. In addition, it is commonly expressed in breast cancer and has tumor suppressive effects. Cytochrome enzymes CYP27B1 and CYP24A1 that perform the final conversion of the circulating form of vitamin D, 25-hydroxyvitamin D (25-OHD) to the active VDR ligand, 1a,25-dihydroxyvitamin D and the catabolism of it to inactive 24,25-dihydroxyvitamin D, respectively, are also expressed in breast cancer tissues. Defective regulation of the receptor and the metabolic enzymes of VDR ligand is prevalent in breast cancer and leads to decreased VDR signaling. The expression and molecular defects of VDR, CYP27B1 and CYP24A1 that perturb physiologic function, the implications for breast cancer progression and therapeutic opportunities are discussed in this paper.
Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/fisiologia , Neoplasias da Mama/metabolismo , Receptores de Calcitriol/fisiologia , Vitamina D3 24-Hidroxilase/fisiologia , Animais , Mama/metabolismo , Mama/patologia , Linhagem Celular Tumoral , Feminino , Regulação da Expressão Gênica , Humanos , Vitamina D/análogos & derivados , Vitamina D/metabolismoRESUMO
OBJECTIVE: Adipose tissue inflammation and fibrosis appear to contribute to insulin resistance in obesity. Vitamin D receptor (Vdr) genes are expressed by adipocytes, macrophages, and fibroblasts, all of which could potentially play a role in adipose tissue inflammation and fibrosis. As vitamin D has been shown to have direct anti-inflammatory effects on adipocytes, we determined whether specific vitamin D receptor-mediated effects on adipocytes could impact adipose tissue inflammation and fibrosis and ultimately insulin resistance. METHODS: We examined the effects of repleting vitamin D in 25(OH)D-deficient, insulin resistant, overweight-to-obese human subjects (n = 19). A comprehensive assessment of whole-body insulin action was undertaken with stepped euglycemic (â¼90 mg/dL) hyperinsulinemic clamp studies both before and after the administration of vitamin D or placebo. Adipose tissue fibrosis and inflammation were quantified by real-time rt-PCR and immunofluorescence in subcutaneous abdominal adipose tissue. To determine whether vitamin D's effects are mediated through adipocytes, we conducted hyperinsulinemic clamp studies (4 mU/kg/min) and adipose tissue analysis using an adipocyte-specific vitamin D receptor knockout (VDR-KO) mouse model (adiponectin-Cre + VDR+/fl) following high-fat diet feeding for 12 weeks. RESULTS: 25(OH)D repletion was associated with reductions in adipose tissue expression of pro-inflammatory and pro-fibrotic genes, decreased collagen immunofluorescence, and improved hepatic insulin sensitivity in humans. Worsening trends after six months on placebo suggest progressive metabolic effects of 25(OH)D deficiency. Ad-VDR-KO mice mirrored the vitamin D-deficient humans, displaying increased adipose tissue fibrosis and inflammation and hepatic insulin resistance. CONCLUSIONS: These complementary human and rodent studies support a beneficial role of vitamin D repletion for improving hepatic insulin resistance and reducing adipose tissue inflammation and fibrosis in targeted individuals, likely via direct effects on adipocytes. These studies have far-reaching implications for understanding the role of adipocytes in mediating adipose tissue inflammation and fibrosis and ultimately impacting insulin sensitivity.
Assuntos
Adipócitos/metabolismo , Receptores de Calcitriol/metabolismo , Deficiência de Vitamina D/metabolismo , Tecido Adiposo/metabolismo , Adulto , Animais , Dieta Hiperlipídica , Feminino , Glucose/metabolismo , Humanos , Inflamação/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Fígado/fisiologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/metabolismo , Sobrepeso/metabolismo , Receptores de Calcitriol/fisiologia , Vitamina D/metabolismo , Vitamina D/farmacologia , Deficiência de Vitamina D/fisiopatologiaRESUMO
We previously reported that daily administration of a pharmacological dose of eldecalcitol, an analog of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], increased bone mass by suppressing bone resorption. These antiresorptive effects were found to be mediated by the vitamin D receptor (VDR) in osteoblast-lineage cells. Using osteoblast-lineage-specific VDR conditional knockout (Ob-VDR-cKO) mice, we examined whether proresorptive activity induced by the high-dose 1α,25(OH)2D3 was also mediated by VDR in osteoblast-lineage cells. Administration of 1α,25(OH)2D3 (5 µg/kg body weight/day) to wild-type mice for 4 days increased the number of osteoclasts in bone and serum concentrations of C-terminal crosslinked telopeptide of type I collagen (CTX-I, a bone resorption marker). The stimulation of bone resorption was concomitant with the increase in serum calcium (Ca) and fibroblast growth factor 23 (FGF23) levels, and decrease in body weight. This suggests that a toxic dose of 1α,25(OH)2D3 can induce bone resorption and hypercalcemia. In contrast, pretreatment of wild-type mice with neutralizing anti-receptor activator of NF-κB ligand (RANKL) antibody inhibited the 1α,25(OH)2D3-induced increase of osteoclast numbers in bone, and increase of CTX-I, Ca, and FGF23 levels in serum. The pretreatment with anti-RANKL antibody also inhibited the 1α,25(OH)2D3-induced decrease in body weight. Consistent with observations in mice conditioned with anti-RANKL antibody, the high-dose administration of 1α,25(OH)2D3 to Ob-VDR-cKO mice failed to significantly increase bone osteoclast numbers, serum CTX-I, Ca, or FGF23 levels, and failed to reduce the body weight. Taken together, this study demonstrated that the proresorptive, hypercalcemic, and toxic actions of high-dose 1α,25(OH)2D3 are mediated by VDR in osteoblast-lineage cells.
Assuntos
Reabsorção Óssea/genética , Linhagem da Célula/genética , Osteoblastos/metabolismo , Receptores de Calcitriol/fisiologia , Vitamina D/análogos & derivados , Animais , Reabsorção Óssea/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Feminino , Fator de Crescimento de Fibroblastos 23 , Hipercalcemia/genética , Hipercalcemia/metabolismo , Hipercalcemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Osteoblastos/citologia , Receptores de Calcitriol/genética , Vitamina D/farmacologiaRESUMO
Vitamin D is well known for its important roles in maintaining calcium homeostasis and bone mineralization via the regulation of calcium mobilization and renal reabsorption, and the intestinal absorption of both calcium and phosphorus [...].
Assuntos
Osso e Ossos/metabolismo , Epigênese Genética , Nutrigenômica , Fenômenos Fisiológicos da Nutrição/fisiologia , Vitamina D/fisiologia , Calcificação Fisiológica , Cálcio/metabolismo , Homeostase , Humanos , Absorção Intestinal , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/fisiologia , Reabsorção Renal , Elemento de Resposta à Vitamina DRESUMO
BACKGROUND: CKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of action are poorly understood. METHODS: Modulation of the noncanonical NF-κB2 pathway and its component TNF receptor-associated factor 3 (TRAF3) by the VDRA paricalcitol was studied in PBMCs from patients with ESKD, cytokine-stimulated cells, and preclinical kidney injury models. RESULTS: In PBMCs isolated from patients with ESKD, TRAF3 protein levels were lower than in healthy controls. This finding was associated with evidence of noncanonical NF-κB2 activation and a proinflammatory state. However, PBMCs from patients with ESKD treated with paricalcitol did not exhibit these features. Experiments in cultured cells confirmed the link between TRAF3 and NF-κB2/inflammation. Decreased TRAF3 ubiquitination in K48-linked chains and cIAP1-TRAF3 interaction mediated the mechanisms of paricalcitol action.TRAF3 overexpression by CRISPR/Cas9 technology mimicked VDRA's effects. In a preclinical model of kidney injury, paricalcitol inhibited renal NF-κB2 activation and decreased renal inflammation. In VDR knockout mice with renal injury, paricalcitol prevented TRAF3 downregulation and NF-κB2-dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol. CONCLUSIONS: These data suggest the anti-inflammatory actions of paricalcitol depend on TRAF3 modulation and subsequent inhibition of the noncanonical NF-κB2 pathway, identifying a novel mechanism for VDRA's effects. Circulating TRAF3 levels could be a biomarker of renal damage associated with the inflammatory state.
Assuntos
Anti-Inflamatórios/farmacologia , Ergocalciferóis/farmacologia , Falência Renal Crônica/tratamento farmacológico , Receptores de Calcitriol/agonistas , Fator 3 Associado a Receptor de TNF/fisiologia , Animais , Células Cultivadas , Citocina TWEAK/farmacologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , NF-kappa B/fisiologia , Receptores de Calcitriol/fisiologia , Transdução de Sinais/efeitos dos fármacos , Fator 3 Associado a Receptor de TNF/análiseRESUMO
A lack of vitamin D has been linked to autoimmune diseases including type 1 diabetes, autoimmune thyroiditis and to obesity. The prevalence of vitamin D deficiency is higher in diabetic or obese children and patients with thyroiditis compared to healthy controls. Moreover, low vitamin D values seem to be associated with major complications and poor glycemic control, in particular in obese children. Supplementation with vitamin D, which has immune-regulatory properties, may support our therapies and improve the outcomes in different diseases. Although some studies suggest a possible role of vitamin D in the etiology of autoimmune diseases and obesity, data on supplementation benefits are inconclusive and further studies are needed. In this paper, we focus on the current evidence regarding vitamin D function in endocrine diseases and possible benefits of its supplementation in pediatric age.
Assuntos
Diabetes Mellitus Tipo 1/etiologia , Doenças do Sistema Endócrino/etiologia , Tireoidite Autoimune/etiologia , Deficiência de Vitamina D/complicações , Vitamina D/fisiologia , Criança , Diabetes Mellitus Tipo 1/terapia , Doenças do Sistema Endócrino/terapia , Humanos , Imunidade Celular , Obesidade Infantil/metabolismo , Receptores de Calcitriol/fisiologia , Vitamina D/administração & dosagem , Deficiência de Vitamina D/terapia , Vitaminas/administração & dosagemRESUMO
The last couple of decades have seen an explosion in our interest and understanding of the role of vitamin D in the regulation of immunity. At the molecular level, the hormonal form of vitamin D signals through the nuclear vitamin D receptor (VDR), a ligand-regulated transcription factor. The VDR and vitamin D metabolic enzymes are expressed throughout the innate and adaptive arms of the immune system. The advent of genome-wide approaches to gene expression profiling have led to the identification of numerous VDR-regulated genes implicated in the regulation of innate and adaptive immunity. The molecular data infer that vitamin D signaling should boost innate immunity against pathogens of bacterial or viral origin. Vitamin D signaling also suppresses inflammatory immune responses that underlie autoimmunity and regulate allergic responses. These findings have been bolstered by clinical studies linking vitamin D deficiency to increased rates of infections, autoimmunity, and allergies. Our goals here are to provide an overview of the molecular basis for immune system regulation and to survey the clinical data from pediatric populations, using randomized placebo-controlled trials and meta-analyses where possible, linking vitamin D deficiency to increased rates of infections, autoimmune conditions, and allergies, and addressing the impact of supplementation on these conditions.
Assuntos
Imunidade Adaptativa , Autoimunidade , Fenômenos Fisiológicos da Nutrição Infantil/imunologia , Suplementos Nutricionais , Imunidade Inata , Fatores Imunológicos , Vitamina D/farmacologia , Vitamina D/fisiologia , Fatores Etários , Doenças Autoimunes/etiologia , Criança , Pré-Escolar , Doenças Transmissíveis/etiologia , Feminino , Humanos , Hipersensibilidade/etiologia , Lactente , Masculino , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/fisiologia , Transdução de Sinais/fisiologia , Vitamina D/metabolismo , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/imunologiaRESUMO
The biologically active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), modulates innate and adaptive immunity via genes regulated by the transcription factor vitamin D receptor (VDR). In order to identify the key vitamin D target genes involved in these processes, transcriptome-wide datasets were compared, which were obtained from a human monocytic cell line (THP-1) and peripheral blood mononuclear cells (PBMCs) treated in vitro by 1,25(OH)2D3, filtered using different approaches, as well as from PBMCs of individuals supplemented with a vitamin D3 bolus. The led to the genes ACVRL1, CAMP, CD14, CD93, CEBPB, FN1, MAPK13, NINJ1, LILRB4, LRRC25, SEMA6B, SRGN, THBD, THEMIS2 and TREM1. Public epigenome- and transcriptome-wide data from THP-1 cells were used to characterize these genes based on the level of their VDR-driven enhancers as well as the level of the dynamics of their mRNA production. Both types of datasets allowed the categorization of the vitamin D target genes into three groups according to their role in (i) acute response to infection, (ii) infection in general and (iii) autoimmunity. In conclusion, 15 genes were identified as major mediators of the action of vitamin D in innate and adaptive immunity and their individual functions are explained based on different gene regulatory scenarios.
Assuntos
Imunidade Adaptativa/genética , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Receptores de Calcitriol/fisiologia , Vitamina D/genética , Vitamina D/imunologia , Receptores de Activinas Tipo II , Peptídeos Catiônicos Antimicrobianos , Autoimunidade/genética , Autoimunidade/imunologia , Proteína beta Intensificadora de Ligação a CCAAT , Conjuntos de Dados como Assunto , Fibronectinas , Humanos , Leucócitos Mononucleares/imunologia , Receptores de Lipopolissacarídeos , Glicoproteínas de Membrana , Receptores de Complemento , Células THP-1/imunologia , Transcriptoma , CatelicidinasRESUMO
Molecular endocrinology of vitamin D is based on the activation of the transcription factor vitamin D receptor (VDR) by the vitamin D metabolite 1α,25-dihydroxyvitamin D3. This nuclear vitamin D-sensing process causes epigenome-wide effects, such as changes in chromatin accessibility as well as in the contact of VDR and its supporting pioneer factors with thousands of genomic binding sites, referred to as vitamin D response elements. VDR binding enhancer regions loop to transcription start sites of hundreds of vitamin D target genes resulting in changes of their expression. Thus, vitamin D signaling is based on epigenome- and transcriptome-wide shifts in VDR-expressing tissues. Monocytes are the most responsive cell type of the immune system and serve as a paradigm for uncovering the chromatin model of vitamin D signaling. In this review, an alternative approach for selecting vitamin D target genes is presented, which are most relevant for understanding the impact of vitamin D endocrinology on innate immunity. Different scenarios of the regulation of primary upregulated vitamin D target genes are presented, in which vitamin D-driven super-enhancers comprise a cluster of persistent (constant) and/or inducible (transient) VDR-binding sites. In conclusion, the spatio-temporal VDR binding in the context of chromatin is most critical for the regulation of vitamin D target genes.
Assuntos
Cromatina/fisiologia , Vitamina D/metabolismo , Vitamina D/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , Cromatina/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Genoma Humano/efeitos dos fármacos , Genoma Humano/fisiologia , Humanos , Ligação Proteica/genética , Receptores de Calcitriol/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ativação Transcricional/efeitos dos fármacos , Vitamina D/análogos & derivados , Vitamina D/fisiologiaRESUMO
Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity; however, the mechanistic bases of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) to the vitamin D receptor (VDR). Recent evidence has linked 1α,25(OH)2D3 to the regulation of skeletal muscle mitochondrial function in vitro; however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we used lentivirus-mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared with an shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes (P < 0.001). VDR-KD myoblasts displayed a 30%, 30%, and 36% reduction in basal, coupled, and maximal respiration, respectively (P < 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33%, and 48% reduction in basal, coupled, and maximal respiration (P < 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATPOx) was reduced by 20%, suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content, as well as markers of mitochondrial fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro, providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.
Assuntos
Mitocôndrias/fisiologia , Mioblastos/fisiologia , Receptores de Calcitriol/fisiologia , Animais , Técnicas de Silenciamento de Genes/métodos , Células HEK293 , Humanos , Camundongos , Receptores de Calcitriol/deficiência , Deficiência de Vitamina D/metabolismoRESUMO
The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (VD3), exerts its tissue-specific actions through binding to its intracellular vitamin D receptor (VDR) which functions as a heterodimer with retinoid X receptor (RXR) to recognize vitamin D response elements (VDRE) and activate target genes. Upregulation of VDR in murine skeletal muscle cells occurs concomitantly with transcriptional regulation of key myogenic factors upon VD3 administration, reinforcing the notion that VD3 exerts beneficial effects on muscle. Herein we elucidated the regulatory role of VD3/VDR axis on the expression of dystrobrevin alpha (DTNA), a member of dystrophin-associated protein complex (DAPC). In C2C12 cells, Dtna and VDR gene and protein expression were upregulated by 1-50 nM of VD3 during all stages of myogenic differentiation. In the dystrophic-derived H2K-mdx52 cells, upregulation of DTNA by VD3 occurred upon co-transfection of VDR and RXR expression vectors. Silencing of MyoD1, an E-box binding myogenic transcription factor, did not alter the VD3-mediated Dtna induction, but Vdr silencing abolished this effect. We also demonstrated that VD3 administration enhanced the muscle-specific Dtna promoter activity in presence of VDR/RXR only. Through site-directed mutagenesis and chromatin immunoprecipitation assays, we have validated a VDRE site in Dtna promoter in myogenic cells. We have thus proved that the positive regulation of Dtna by VD3 observed during in vitro murine myogenic differentiation is VDR mediated and specific. The current study reveals a novel mechanism of VDR-mediated regulation for Dtna, which may be positively explored in treatments aiming to stabilize the DAPC in musculoskeletal diseases.
Assuntos
Proteínas Associadas à Distrofina/genética , Músculos/metabolismo , Neuropeptídeos/genética , Receptores de Calcitriol/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculos/efeitos dos fármacos , Músculos/fisiologia , Mioblastos Esqueléticos/efeitos dos fármacos , Mioblastos Esqueléticos/fisiologia , Ativação Transcricional/efeitos dos fármacos , Vitamina D/análogos & derivados , Vitamina D/farmacologia , Elemento de Resposta à Vitamina D/efeitos dos fármacos , Elemento de Resposta à Vitamina D/genéticaRESUMO
Epidemiological studies highlight the negative correlation between vitamin D levels and the incidence of many non-skeletal diseases including inflammatory diseases, cancer, and metabolic and neurological disorders. However, most randomized controlled trials (RCTs) with oral vitamin D supplementation give mixed results or are inconclusive. It has been said that "discovery commences with the awareness of anomaly". The "anomaly" between our preclinical and clinical data provides the opportunity to propose an alternative paradigm to the vitamin D endocrine system: the vitamin D autacoid paradigm. In the vitamin D autacoid paradigm, the extra-skeletal effects of vitamin D depend on the tissue reserves of vitamin D metabolites. These vitamin D autacoid systems are inducible oscillatory ecosystems in which 1,25D is produced, acts and is inactivated locally. In the vitamin D autacoid paradigm, attaining adequacy of vitamin D in the systemic circulation is necessary but not sufficient; we must also ensure the repletion of the tissue stores. The co-existence of two different vitamin D systems, endocrine and autacoid, with different functions and regulations leads to "significant shifts in the criteria determining the legitimacy both of problems and of proposed solutions". With respect to our clinical trials of vitamin D supplementation for unconventional effects, the proposed solution is administering and quantifying vitamin D metabolites directly to the target tissue.
Assuntos
Autacoides/uso terapêutico , Modelos Biológicos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Vitamina D/uso terapêutico , Tecido Adiposo/metabolismo , Administração Oral , Autacoides/administração & dosagem , Autacoides/farmacocinética , Encéfalo/metabolismo , Calcitriol/sangue , Microambiente Celular , Humanos , Inflamação , Rim/metabolismo , Fígado/metabolismo , Especificidade de Órgãos , Receptores de Calcitriol/fisiologia , Projetos de Pesquisa , Pele/metabolismo , Pele/efeitos da radiação , Raios Ultravioleta , Vitamina D/administração & dosagem , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Vitamina D/farmacocinéticaRESUMO
BACKGROUND AND AIMS: Obesity-induced chronic inflammation is a key component in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and insulin resistance. Increased secretion of proinflammatory cytokines by macrophages in metabolic tissues promotes disease progression. In the diet-induced obesity (DIO) mouse model, activation of liver resident macrophages, or Kupffer cells (KCs), drives inflammatory responses, which recruits circulating macrophages and promotes fatty liver development, and ultimately contributes to impaired hepatic insulin sensitivity. Hepatic macrophages express the highest level of vitamin D receptors (VDRs) among nonparenchymal cells, whereas VDR expression is very low in hepatocytes. VDR activation exerts anti-inflammatory effects in immune cells. APPROACH AND RESULTS: Here we found that VDR activation exhibits strong anti-inflammatory effects in mouse hepatic macrophages, including those isolated from DIO livers, and mice with genetic loss of Vdr developed spontaneous hepatic inflammation at 6 months of age. Under the chronic inflammation conditions of the DIO model, VDR activation by the vitamin D analog calcipotriol reduced liver inflammation and hepatic steatosis, significantly improving insulin sensitivity. The hyperinsulinemic euglycemic clamp revealed that VDR activation greatly increased the glucose infusion rate, while hepatic glucose production was remarkably decreased. Glucose uptake in muscle and adipose did not show similar effects, suggesting that improved hepatic insulin sensitivity is the primary contributor to the beneficial effects of VDR activation. Finally, specifically ablating liver macrophages by treatment with clodronate liposomes largely abolished the beneficial metabolic effects of calcipotriol, confirming that VDR activation in liver macrophages is required for the antidiabetic effect. CONCLUSIONS: Activation of liver macrophage VDRs by vitamin D ligands ameliorates liver inflammation, steatosis and insulin resistance. Our results suggest therapeutic paradigms for treatment of NAFLD and type 2 diabetes mellitus.
Assuntos
Hepatite/metabolismo , Resistência à Insulina , Células de Kupffer/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores de Calcitriol/fisiologia , Animais , Modelos Animais de Doenças , Hepatite/etiologia , Inflamação/etiologia , Inflamação/metabolismo , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/imunologia , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicações , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/genética , Vitamina D/farmacologiaRESUMO
Vitamin D plays an important role in maintaining the homeostasis of various biological systems. Beside its well-known function in calcium and phosphate metabolism, it plays a major role in pathophysiology of skin and adnexa. Indeed, vitamin D, through its receptor (VDR), decreases keratinocyte proliferation, improves their differentiation and modulates both cutaneous innate (antimicrobial activity and antigen presentation) and adaptative immunity (T and B lymphocyte function). The maintenance of normal hair is dependant on the integrity of the dermis, epidermis and hair cycles. Beside its effect on epidermal differentiation, VDR plays a vital role in preserving the hair follicle integrity. While the relevance of VDR has been fully elucidated, the real value of vitamin D in the hair follicle cycle still remains uncertain. To date, results in literature remain contradicting and far from definitive; still, the role of vitamin D in the various forms of human alopecia is likely to be significant. The aim of this article is to review evidence about the role of vitamin D and its receptor in trichology, with a focus on scarring and non-scarring alopecia and in particular on the potential therapeutic use of Vitamin D for hair and scalp disorders.
Assuntos
Doenças do Cabelo/etiologia , Receptores de Calcitriol/fisiologia , Dermatoses do Couro Cabeludo/etiologia , Vitamina D/fisiologia , Vitaminas/fisiologia , HumanosRESUMO
BACKGROUND AND AIMS: Hepatic endoplasmic reticulum (ER) stress, whether triggered by intrinsic or extrinsic factors, can be resolved by the unfolded protein response (UPR). Sustained UPR activation leads to cell death and inflammatory response and contributes to liver disease progression. Hepatic tissue macrophages are key players in orchestrating liver inflammation, and ER stress can enhance macrophage activation. However, it is not well defined how the interplay between ER stress and inflammation is regulated during hepatic stress response. APPROACH AND RESULTS: Here we demonstrate that vitamin D receptor (VDR) activation mitigates hepatic ER stress response, whereas VDR knockout mice undergo persistent UPR activation and apoptosis in response to chemical ER stress inducer. Moreover, VDR deficiency promotes hepatic macrophage infiltration and increases gene expression and systematic levels of proinflammatory cytokines, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor α. VDR expression is induced in hepatic macrophages by ER stress, and VDR plays a dual regulatory role in macrophages by protecting against ER stress and promoting anti-inflammatory polarization. Co-culture with VDR-activated bone marrow-derived macrophages suppresses UPR target genes in primary hepatocytes treated with ER stress inducers. Thus, the immunomodulatory functions of VDR in macrophages are critical in hepatic ER stress resolution in mice. CONCLUSIONS: VDR signaling in macrophages regulates a shift between proinflammatory and anti-inflammatory activation during ER stress-induced inflammation to promote hepatic ER stress resolution.