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1.
Immunity ; 55(4): 623-638.e5, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35385697

RESUMO

The epithelium is an integral component of mucosal barrier and host immunity. Following helminth infection, the intestinal epithelial cells secrete "alarmin" cytokines, such as interleukin-25 (IL-25) and IL-33, to initiate the type 2 immune responses for helminth expulsion and tolerance. However, it is unknown how helminth infection and the resulting cytokine milieu drive epithelial remodeling and orchestrate alarmin secretion. Here, we report that epithelial O-linked N-Acetylglucosamine (O-GlcNAc) protein modification was induced upon helminth infections. By modifying and activating the transcription factor STAT6, O-GlcNAc transferase promoted the transcription of lineage-defining Pou2f3 in tuft cell differentiation and IL-25 production. Meanwhile, STAT6 O-GlcNAcylation activated the expression of Gsdmc family genes. The membrane pore formed by GSDMC facilitated the unconventional secretion of IL-33. GSDMC-mediated IL-33 secretion was indispensable for effective anti-helminth immunity and contributed to induced intestinal inflammation. Protein O-GlcNAcylation can be harnessed for future treatment of type 2 inflammation-associated human diseases.


Assuntos
Alarminas , Mucosa Intestinal , Acilação , Alarminas/imunologia , Anti-Helmínticos/imunologia , Biomarcadores Tumorais , Citocinas , Proteínas de Ligação a DNA , Helmintíase/imunologia , Humanos , Hiperplasia , Inflamação , Interleucina-33 , Mucosa Intestinal/imunologia , Mebendazol , N-Acetilglucosaminiltransferases/imunologia , Proteínas Citotóxicas Formadoras de Poros , Fator de Transcrição STAT6/imunologia
2.
Cell ; 160(4): 745-758, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25662011

RESUMO

Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase. Insulin's ability to suppress hepatic acetyl CoA, PC activity, and lipolysis was lost in high-fat-fed rats, a phenomenon reversible by IL-6 neutralization and inducible by IL-6 infusion. Taken together, these data identify WAT-derived hepatic acetyl CoA as the main regulator of HGP by insulin and link it to inflammation-induced hepatic insulin resistance associated with obesity and T2D.


Assuntos
Acetilcoenzima A/metabolismo , Resistência à Insulina , Fígado/metabolismo , Paniculite/metabolismo , Tecido Adiposo Branco/química , Adolescente , Animais , Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica , Glucose/metabolismo , Humanos , Hiperglicemia , Interleucina-6/análise , Lipólise , Masculino , Camundongos , Obesidade/metabolismo , Ratos Sprague-Dawley
3.
Cell ; 159(2): 306-17, 2014 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-25303527

RESUMO

Induction of beige cells causes the browning of white fat and improves energy metabolism. However, the central mechanism that controls adipose tissue browning and its physiological relevance are largely unknown. Here, we demonstrate that fasting and chemical-genetic activation of orexigenic AgRP neurons in the hypothalamus suppress the browning of white fat. O-linked ß-N-acetylglucosamine (O-GlcNAc) modification of cytoplasmic and nuclear proteins regulates fundamental cellular processes. The levels of O-GlcNAc transferase (OGT) and O-GlcNAc modification are enriched in AgRP neurons and are elevated by fasting. Genetic ablation of OGT in AgRP neurons inhibits neuronal excitability through the voltage-dependent potassium channel, promotes white adipose tissue browning, and protects mice against diet-induced obesity and insulin resistance. These data reveal adipose tissue browning as a highly dynamic physiological process under central control, in which O-GlcNAc signaling in AgRP neurons is essential for suppressing thermogenesis to conserve energy in response to fasting.


Assuntos
Tecido Adiposo Marrom/metabolismo , Dieta , N-Acetilglucosaminiltransferases/metabolismo , Neurônios/metabolismo , Tecido Adiposo Branco/metabolismo , Proteína Relacionada com Agouti/metabolismo , Animais , Jejum , Feminino , Grelina/metabolismo , Hipotálamo/citologia , Hipotálamo/metabolismo , Resistência à Insulina , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Acetilglucosaminiltransferases/genética , Obesidade/metabolismo , Obesidade/prevenção & controle
4.
Semin Immunol ; 71: 101865, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38232665

RESUMO

Intestinal homeostasis is achieved by the balance among intestinal epithelium, immune cells, and gut microbiota. Gasdermins (GSDMs), a family of membrane pore forming proteins, can trigger rapid inflammatory cell death in the gut, mainly pyroptosis and NETosis. Importantly, there is increasing literature on the non-cell lytic roles of GSDMs in intestinal homeostasis and disease. While GSDMA is low and PJVK is not expressed in the gut, high GSDMB and GSDMC expression is found almost restrictively in intestinal epithelial cells. Conversely, GSDMD and GSDME show more ubiquitous expression among various cell types in the gut. The N-terminal region of GSDMs can be liberated for pore formation by an array of proteases in response to pathogen- and danger-associated signals, but it is not fully understood what cell type-specific mechanisms activate intestinal GSDMs. The host relies on GSDMs for pathogen defense, tissue tolerance, and cancerous cell death; however, pro-inflammatory milieu caused by pyroptosis and excessive cytokine release may favor the development and progression of inflammatory bowel disease and cancer. Therefore, a thorough understanding of spatiotemporal mechanisms that control gasdermin expression, activation, and function is essential for the development of future therapeutics for intestinal disorders.


Assuntos
Gasderminas , Neoplasias , Humanos , Piroptose/fisiologia , Proteínas de Neoplasias/metabolismo , Citocinas/metabolismo , Neoplasias/metabolismo , Inflamassomos , Biomarcadores Tumorais
6.
PLoS Biol ; 21(12): e3002413, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38048357

RESUMO

Brown adipose tissue (BAT) dissipates energy as heat, contributing to temperature control, energy expenditure, and systemic homeostasis. In adult humans, BAT mainly exists in supraclavicular areas and its prevalence is associated with cardiometabolic health. However, the developmental origin of supraclavicular BAT remains unknown. Here, using genetic cell marking in mice, we demonstrate that supraclavicular brown adipocytes do not develop from the Pax3+/Myf5+ epaxial dermomyotome that gives rise to interscapular BAT (iBAT). Instead, the Tbx1+ lineage that specifies the pharyngeal mesoderm marks the majority of supraclavicular brown adipocytes. Tbx1Cre-mediated ablation of peroxisome proliferator-activated receptor gamma (PPARγ) or PR/SET Domain 16 (PRDM16), components of the transcriptional complex for brown fat determination, leads to supraclavicular BAT paucity or dysfunction, thus rendering mice more sensitive to cold exposure. Moreover, human deep neck BAT expresses higher levels of the TBX1 gene than subcutaneous neck white adipocytes. Taken together, our observations reveal location-specific developmental origins of BAT depots and call attention to Tbx1+ lineage cells when investigating human relevant supraclavicular BAT.


Assuntos
Adipócitos Marrons , Tecido Adiposo Branco , Adulto , Humanos , Camundongos , Animais , Fatores de Transcrição , Tecido Adiposo Marrom/fisiologia , Adipócitos Brancos , Proteínas com Domínio T/genética
7.
Genes Dev ; 31(16): 1655-1665, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28903979

RESUMO

Starvation induces liver autophagy, which is thought to provide nutrients for use by other organs and thereby maintain whole-body homeostasis. Here we demonstrate that O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is required for glucagon-stimulated liver autophagy and metabolic adaptation to starvation. Genetic ablation of OGT in mouse livers reduces autophagic flux and the production of glucose and ketone bodies. Upon glucagon-induced calcium signaling, calcium/calmodulin-dependent kinase II (CaMKII) phosphorylates OGT, which in turn promotes O-GlcNAc modification and activation of Ulk proteins by potentiating AMPK-dependent phosphorylation. These findings uncover a signaling cascade by which starvation promotes autophagy through OGT phosphorylation and establish the importance of O-GlcNAc signaling in coupling liver autophagy to nutrient homeostasis.


Assuntos
Autofagia , Sinalização do Cálcio , Fígado/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Fenômenos Fisiológicos da Nutrição , Adaptação Biológica , Animais , Proteína 5 Relacionada à Autofagia/fisiologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Glucagon/farmacologia , Células HEK293 , Células HeLa , Humanos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos Endogâmicos C57BL , N-Acetilglucosaminiltransferases/fisiologia
8.
Int J Mol Sci ; 23(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36232438

RESUMO

Dynamic regulation of intestinal epithelial cell (IEC) proliferation and differentiation is crucial for maintaining mucosa homeostasis and the response to helminth infection. O-GlcNAc transferase (OGT), an enzyme catalyzing the transfer of GlcNAc from the donor substrate UDP-GlcNAc onto acceptor proteins, has been proposed to promote intestinal epithelial remodeling for helminth expulsion by modifying and activating epithelial STAT6, but whether the IEC intrinsic OGT-STAT6 axis is involved in anti-helminth responses has not been tested in vivo. Here, we show that the inducible deletion of Ogt in IECs of adult mice leads to reduced tuft and goblet cell differentiation, increased crypt cell proliferation, and aberrant Paneth cell localization. By using a mouse model with concurrent Ogt deletion and STAT6 overexpression in IECs, we provide direct in vivo evidence that STAT6 acts downstream of OGT to control tuft and goblet cell differentiation in IECs. However, epithelial OGT regulates crypt cell proliferation and Paneth cell differentiation in a STAT6-independent pathway. Our results verify that protein O-GlcNAcylation in IECs is crucial for maintaining epithelial homeostasis and anti-helminthic type 2 immune responses.


Assuntos
Mebendazol , N-Acetilglucosaminiltransferases , Células Caliciformes/metabolismo , Intestinos , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Celulas de Paneth/metabolismo , Difosfato de Uridina
9.
Nature ; 510(7506): 547-51, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24870244

RESUMO

Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis; dysregulation of this axis causes diabetes. PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1α) links insulin signalling to the expression of glucose and lipid metabolic genes. The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1α and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1α. Although insulin is a mitogenic signal in proliferative cells, whether components of the cell cycle machinery contribute to its metabolic action is poorly understood. Here we report that in mice insulin activates cyclin D1-cyclin-dependent kinase 4 (Cdk4), which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, we identify a Cdk4 inhibitor that potently decreases PGC-1α acetylation. Insulin/GSK-3ß (glycogen synthase kinase 3-beta) signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger RNA transcripts. Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1α activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycaemia. In diabetic models, cyclin D1-Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycaemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division.


Assuntos
Ciclo Celular , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Transdução de Sinais , Acetilação , Aminoácidos/farmacologia , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Células Cultivadas , Ciclina D1/deficiência , Ciclina D1/genética , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Diabetes Mellitus/metabolismo , Ativação Enzimática , Jejum , Deleção de Genes , Gluconeogênese/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Histona Acetiltransferases/metabolismo , Homeostase , Humanos , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Masculino , Camundongos , Fosforilação , RNA Mensageiro/análise , RNA Mensageiro/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica/efeitos dos fármacos
10.
Mol Cell ; 48(6): 900-13, 2012 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-23142079

RESUMO

Hepatic glucose production (HGP) maintains blood glucose levels during fasting but can also exacerbate diabetic hyperglycemia. HGP is dynamically controlled by a signaling/transcriptional network that regulates the expression/activity of gluconeogenic enzymes. A key mediator of gluconeogenic gene transcription is PGC-1α. PGC-1α's activation of gluconeogenic gene expression is dependent upon its acetylation state, which is controlled by the acetyltransferase GCN5 and the deacetylase Sirt1. Nevertheless, whether other chromatin modifiers-particularly other sirtuins-can modulate PGC-1α acetylation is currently unknown. Herein, we report that Sirt6 strongly controls PGC-1α acetylation. Surprisingly, Sirt6 induces PGC-1α acetylation and suppresses HGP. Sirt6 depletion decreases PGC-1α acetylation and promotes HGP. These acetylation effects are GCN5 dependent: Sirt6 interacts with and modifies GCN5, enhancing GCN5's activity. Lepr(db/db) mice, an obese/diabetic animal model, exhibit reduced Sirt6 levels; ectopic re-expression suppresses gluconeogenic genes and normalizes glycemia. Activation of hepatic Sirt6 may therefore be therapeutically useful for treating insulin-resistant diabetes.


Assuntos
Gluconeogênese , Hepatócitos/metabolismo , Sirtuínas/fisiologia , Transativadores/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Animais , Glicemia , Linhagem Celular , Ativação Enzimática , Expressão Gênica , Gluconeogênese/genética , Hepatócitos/enzimologia , Humanos , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Obesos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fosforilação , Processamento de Proteína Pós-Traducional , Sirtuína 1/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Fatores de Transcrição
11.
J Biol Chem ; 293(36): 13989-14000, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30037904

RESUMO

Many intracellular proteins are reversibly modified by O-linked GlcNAc (O-GlcNAc), a post-translational modification that dynamically regulates fundamental cellular processes in response to diverse environmental cues. Accumulating evidence indicates that both excess and deficiency of protein O-GlcNAcylation can have deleterious effects on the cell, suggesting that maintenance of O-GlcNAc homeostasis is essential for proper cellular function. However, the mechanisms through which O-GlcNAc homeostasis is maintained in the physiologic state and altered in the disease state have not yet been investigated. Here, we demonstrate the existence of a homeostatic mechanism involving mutual regulation of the O-GlcNAc-cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) at the transcriptional level. Specifically, we found that OGA promotes Ogt transcription through cooperation with the histone acetyltransferase p300 and transcription factor CCAAT/enhancer-binding protein ß (C/EBPß). To examine the role of mutual regulation of OGT and OGA in the disease state, we analyzed gene expression data from human cancer data sets, which revealed that OGT and OGA expression levels are highly correlated in numerous human cancers, particularly in pancreatic adenocarcinoma. Using a KrasG12D -driven primary mouse pancreatic ductal adenocarcinoma (PDAC) cell line, we found that inhibition of extracellular signal-regulated kinase (ERK) signaling decreases OGA glycosidase activity and reduces OGT mRNA and protein levels, suggesting that ERK signaling may alter O-GlcNAc homeostasis in PDAC by modulating OGA-mediated Ogt transcription. Our study elucidates a transcriptional mechanism that regulates cellular O-GlcNAc homeostasis, which may lay a foundation for exploring O-GlcNAc signaling as a therapeutic target for human disease.


Assuntos
Acetilglucosamina/metabolismo , Regulação Neoplásica da Expressão Gênica , Homeostase , Neoplasias Pancreáticas/metabolismo , Animais , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Glicosídeo Hidrolases , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , N-Acetilglucosaminiltransferases , Neoplasias Pancreáticas/genética , Processamento de Proteína Pós-Traducional , Transdução de Sinais
12.
Haematologica ; 104(9): 1731-1743, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30792196

RESUMO

Hematopoiesis is dynamically regulated by metabolic cues in homeostatic and stressed conditions; however, the cellular and molecular mechanisms mediating the metabolic sensing and regulation remain largely obscure. Bone marrow adipose tissue remodels in various metabolic conditions and has been recently proposed as a niche for hematopoietic stem cells after irradiation. Here, we investigated the role of marrow adipose tissue-derived hematopoietic cytokine stem cell factor in unperturbed hematopoiesis by selectively ablating the Kitl gene from adipocytes and bone marrow stroma cells using Adipoq-Cre and Osx1-Cre, respectively. We found that both Adipoq-Kitl knockout (KO) and Osx1-Kitl KO mice diminished hematopoietic stem and progenitor cells and myeloid progenitors in the bone marrow and developed macrocytic anemia at the steady-state. The composition and differentiation of hematopoietic progenitor cells in the bone marrow dynamically responded to metabolic challenges including high fat diet, ß3-adrenergic activation, thermoneutrality, and aging. However, such responses, particularly within the myeloid compartment, were largely impaired in Adipoq-Kitl KO mice. Our data demonstrate that marrow adipose tissue provides stem cell factor essentially for hematopoiesis both at the steady state and upon metabolic stresses.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Medula Óssea/metabolismo , Hematopoese , Fator de Transcrição Sp7/metabolismo , Fator de Células-Tronco/metabolismo , Adipócitos/metabolismo , Animais , Células da Medula Óssea/metabolismo , Citocinas/metabolismo , Dieta Hiperlipídica , Feminino , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Receptores Adrenérgicos beta 3/metabolismo , Células-Tronco/citologia
13.
Int J Mol Sci ; 20(5)2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30818760

RESUMO

O-GlcNAcylation is a post-translational modification that influences tyrosine phosphorylation in healthy and malignant cells. O-GlcNAc is a product of the hexosamine biosynthetic pathway, a side pathway of glucose metabolism. It is essential for cell survival and proper gene regulation, mirroring the metabolic status of a cell. STAT3 and STAT5 proteins are essential transcription factors that can act in a mutational context-dependent manner as oncogenes or tumor suppressors. They regulate gene expression for vital processes such as cell differentiation, survival, or growth, and are also critically involved in metabolic control. The role of STAT3/5 proteins in metabolic processes is partly independent of their transcriptional regulatory role, but is still poorly understood. Interestingly, STAT3 and STAT5 are modified by O-GlcNAc in response to the metabolic status of the cell. Here, we discuss and summarize evidence of O-GlcNAcylation-regulating STAT function, focusing in particular on hyperactive STAT5A transplant studies in the hematopoietic system. We emphasize that a single O-GlcNAc modification is essential to promote development of neoplastic cell growth through enhancing STAT5A tyrosine phosphorylation. Inhibition of O-GlcNAcylation of STAT5A on threonine 92 lowers tyrosine phosphorylation of oncogenic STAT5A and ablates malignant transformation. We conclude on strategies for new therapeutic options to block O-GlcNAcylation in combination with tyrosine kinase inhibitors to target neoplastic cancer cell growth and survival.


Assuntos
Metabolismo Energético , Neoplasias/metabolismo , Neoplasias/patologia , Fator de Transcrição STAT5/metabolismo , Animais , Proliferação de Células , Sobrevivência Celular , Glicosilação , Humanos , Transdução de Sinais
14.
Curr Opin Clin Nutr Metab Care ; 21(4): 260-266, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29697540

RESUMO

PURPOSE OF REVIEW: Ketone body metabolism is a dynamic and integrated metabolic node in human physiology, whose roles include but extend beyond alternative fuel provision during carbohydrate restriction. Here we discuss the most recent observations suggesting that ketosis coordinates cellular function via epigenomic regulation. RECENT FINDINGS: Ketosis has been linked to covalent modifications, including lysine acetylation, methylation, and hydroxybutyrylation, to key histones that serve as dynamic regulators of chromatin architecture and gene transcription. Although it remains to be fully established whether these changes to the epigenome are attributable to ketone bodies themselves or other aspects of ketotic states, the regulated genes mediate classical responses to carbohydrate restriction. SUMMARY: Direct regulation of gene expression may occur in-vivo via through ketone body-mediated histone modifications during adherence to low-carbohydrate diets, fasting ketosis, exogenous ketone body therapy, and diabetic ketoacidosis. Additional convergent functional genomics, metabolomics, and proteomics studies are required in both animal models and in humans to identify the molecular mechanisms through which ketosis regulates nuclear signaling events in a myriad of conditions relevant to disease, and the contexts in which the benefits of ketosis might outweigh the risks.


Assuntos
Dieta Cetogênica , Epigênese Genética , Corpos Cetônicos/metabolismo , Cetose , Acetilação , Animais , Cromatina/metabolismo , Cetoacidose Diabética , Jejum , Histonas/metabolismo , Humanos , Corpos Cetônicos/uso terapêutico , Metilação
15.
Am J Physiol Endocrinol Metab ; 313(6): E731-E736, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28851733

RESUMO

Loss of body weight and fat mass is one of the nonmotor symptoms of Parkinson's disease (PD). Weight loss is due primarily to reduced energy intake and increased energy expenditure. Whereas inadequate energy intake in PD patients is caused mainly by appetite loss and impaired gastrointestinal absorption, the underlying mechanisms for increased energy expenditure remain largely unknown. Brown adipose tissue (BAT), a key thermogenic tissue in humans and other mammals, plays an important role in thermoregulation and energy metabolism; however, it has not been tested whether BAT is involved in the negative energy balance in PD. Here, using the 6-hydroxydopamine (6-OHDA) rat model of PD, we found that the activity of sympathetic nerve (SN), the expression of Ucp1 in BAT, and thermogenesis were increased in PD rats. BAT sympathetic denervation blocked sympathetic activity and decreased UCP1 expression in BAT and attenuated the loss of body weight in PD rats. Interestingly, sympathetic denervation of BAT was associated with decreased sympathetic tone and lipolysis in retroperitoneal and epididymal white adipose tissue. Our data suggeste that BAT-mediated thermogenesis may contribute to weight loss in PD.


Assuntos
Tecido Adiposo Marrom/metabolismo , Doença de Parkinson Secundária/metabolismo , Tecido Adiposo Marrom/inervação , Tecido Adiposo Marrom/fisiopatologia , Animais , Temperatura Baixa , Denervação , Masculino , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/fisiopatologia , Ratos , Ratos Sprague-Dawley , Simpatectomia Química , Sistema Nervoso Simpático/fisiopatologia , Termogênese , Proteína Desacopladora 1/metabolismo , Regulação para Cima , Redução de Peso
16.
J Lipid Res ; 56(4): 771-85, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25724563

RESUMO

Liver X receptor (LXR)α and LXRß play key roles in hepatic de novo lipogenesis through their regulation of lipogenic genes, including sterol regulatory element-binding protein (SREBP)-1c and carbohydrate responsive element-binding protein (ChREBP). LXRs activate lipogenic gene transcription in response to feeding, which is believed to be mediated by insulin. We have previously shown that LXRs are targets for glucose-hexosamine-derived O-linked ß-N-acetylglucosamine (O-GlcNAc) modification enhancing their ability to regulate SREBP-1c promoter activity in vitro. To elucidate insulin-independent effects of feeding on LXR-mediated lipogenic gene expression in vivo, we subjected control and streptozotocin-treated LXRα/ß(+/+) and LXRα/ß(-/-) mice to a fasting-refeeding regime. We show that under hyperglycemic and hypoinsulinemic conditions, LXRs maintain their ability to upregulate the expression of glycolytic and lipogenic enzymes, including glucokinase (GK), SREBP-1c, ChREBPα, and the newly identified shorter isoform ChREBPß. Furthermore, glucose-dependent increases in LXR/retinoid X receptor-regulated luciferase activity driven by the ChREBPα promoter was mediated, at least in part, by O-GlcNAc transferase (OGT) signaling in Huh7 cells. Moreover, we show that LXR and OGT interact and colocalize in the nucleus and that loss of LXRs profoundly reduced nuclear O-GlcNAc signaling and ChREBPα promoter binding activity in vivo. In summary, our study provides evidence that LXRs act as nutrient and glucose metabolic sensors upstream of ChREBP by modulating GK expression, nuclear O-GlcNAc signaling, and ChREBP expression and activity.


Assuntos
Acetilglucosamina/metabolismo , Núcleo Celular/metabolismo , Fígado/citologia , Fígado/metabolismo , Proteínas Nucleares/metabolismo , Receptores Nucleares Órfãos/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Acilação/efeitos dos fármacos , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Ingestão de Alimentos , Jejum , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Humanos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Receptores X do Fígado , Masculino , Camundongos , Proteínas Nucleares/genética , Receptores Nucleares Órfãos/deficiência , Regiões Promotoras Genéticas/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transporte Proteico/efeitos dos fármacos , Piruvato Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/efeitos adversos , Fatores de Transcrição/genética , Ativação Transcricional/efeitos dos fármacos , Triglicerídeos/biossíntese , Triglicerídeos/sangue
17.
Am J Pathol ; 184(1): 122-32, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24211109

RESUMO

Myeloproliferative neoplasms constitute a group of hematopoietic neoplasms at the myeloid stem cell level. Although mutations in the receptor tyrosine kinase KIT have been identified in patients with myeloproliferative neoplasm, the functional causality is unknown because of a lack of animal models. Here, we describe a mouse strain harboring a point mutation in the first Ig-like domain of Kit. Intriguingly, the mutant mice develop a myeloproliferative disorder with typical loss-of-function phenotypes in other tissues. The mutant Kit is incompletely N-glycosylated, shows compromised receptor dimerization, and down-regulates Akt and extracellular signal-regulating kinase 1/2 signaling. However, the mutation increases the association of Kit to Janus kinase (JAK)2 and hence the activation of JAK2. The ß common receptor of the gp140 family interacts and synergizes with Kit to promote JAK2 phosphorylation, which is further enhanced by the Kit mutation. Inhibition of JAK2 suppresses the proliferation of hematopoietic progenitors in vitro and partially rescues myeloproliferation in mice. Our data suggest that overactivation of JAK2 leads to myeloproliferation in Kit mutant mice and provide mechanistic insights for the diagnosis and treatment of myeloproliferative neoplasms in humans.


Assuntos
Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Mutação Puntual , Proteínas Proto-Oncogênicas c-kit/genética , Animais , Modelos Animais de Doenças , Ativação Enzimática/genética , Citometria de Fluxo , Células HEK293 , Humanos , Immunoblotting , Imunoprecipitação , Camundongos , Camundongos Mutantes , Estrutura Terciária de Proteína , Transfecção
18.
Mol Cell Proteomics ; 12(12): 3489-97, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23824911

RESUMO

The post-translational modification of intracellular proteins by O-linked N-acetylglucosamine (O-GlcNAc) regulates essential cellular processes such as signal transduction, transcription, translation, and protein degradation. Misfolded, damaged, and unwanted proteins are tagged with a chain of ubiquitin moieties for degradation by the proteasome, which is critical for cellular homeostasis. In this review, we summarize the current knowledge of the interplay between O-GlcNAcylation and ubiquitination in the control of protein degradation. Understanding the mechanisms of action of O-GlcNAcylation in the ubiquitin-proteosome system shall facilitate the development of therapeutics for human diseases such as cancer, metabolic syndrome, and neurodegenerative diseases.


Assuntos
Acetilglucosamina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais/genética , Ubiquitinas/metabolismo , Acilação , Regulação da Expressão Gênica , Humanos , Anotação de Sequência Molecular , Fosforilação , Complexo de Endopeptidases do Proteassoma/genética , Biossíntese de Proteínas , Proteólise , Transcrição Gênica , Ubiquitinação , Ubiquitinas/genética
19.
bioRxiv ; 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-39026753

RESUMO

Therapeutic interventions targeting hepatic lipid metabolism in metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) remain elusive. Using mass spectrometry-based stable isotope tracing and shotgun lipidomics, we established a novel link between ketogenesis and MASLD pathophysiology. Our findings show that mouse liver and primary hepatocytes consume ketone bodies to support fatty acid (FA) biosynthesis via both de novo lipogenesis (DNL) and FA elongation. Analysis of 13 C-labeled FAs in hepatocytes lacking mitochondrial D-ß-hydroxybutyrate dehydrogenase (BDH1) revealed a partial reliance on mitochondrial conversion of D-ßOHB to acetoacetate (AcAc) for cytoplasmic DNL contribution, whereas FA elongation from ketone bodies was fully dependent on cytosolic acetoacetyl-CoA synthetase (AACS). Ketone bodies were essential for polyunsaturated FA (PUFA) homeostasis in hepatocytes, as loss of AACS diminished both free and esterified PUFAs. Ketogenic insufficiency depleted liver PUFAs and increased triacylglycerols, mimicking human MASLD, suggesting that ketogenesis supports PUFA homeostasis, and may mitigate MASLD-MASH progression in humans.

20.
J Biol Chem ; 287(16): 12904-12, 2012 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-22371499

RESUMO

Recruitment of O-GlcNAc transferase (OGT) to promoters plays an important role in gene repression. Glucocorticoid signaling represses the transcriptional activities of NF-κB and AP-1 through direct binding, yet the molecular mechanisms remain to be elucidated. Here we report that OGT is an important component of GR-mediated transrepression. OGT associates with ligand-bound GR in a multi-protein repression complex. Overexpression of OGT potentiates the GR transrepression pathway, whereas depletion of endogenous OGT by RNA interference abolishes the repression. The recruitment of OGT by GR leads to increased O-GlcNAcylation and decreased phosphorylation of RNA polymerase II on target genes. Functionally, overexpression of OGT enhances glucocorticoid-induced apoptosis in resistant cell lines while knockdown of OGT prevents sensitive cell lines from apoptosis. These studies identify a molecular mechanism of GR transrepression, and highlight the function of O-GlcNAc in hormone signaling.


Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Acetilglucosamina/metabolismo , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Apoptose/fisiologia , Linhagem Celular Tumoral , Desenho de Fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Hidrocortisona/metabolismo , Hidrocortisona/farmacologia , Neoplasias Pulmonares , NF-kappa B/metabolismo , Coativador 2 de Receptor Nuclear/metabolismo , RNA Polimerase II/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/fisiologia
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