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1.
Artigo em Inglês | MEDLINE | ID: mdl-38957985

RESUMO

Institutional support is crucial for the successful career advancement of all faculty but in particular those who are women. Evolving from the past, in which gender disparities were prevalent in many institutions, recent decades have witnessed significant progress in supporting the career advancement of women faculty in science and academic medicine. However, continued advancement is necessary as previously unrecognized needs and new opportunities for improvement emerge. To identify the needs, opportunities, and potential challenges encountered by women faculty, the Women's Leadership Committee of the Arteriosclerosis, Thrombosis, and Vascular Biology Council developed an initiative termed GROWTH (Generating Resources and Opportunities for Women in Technology and Health). The committee designed a survey questionnaire and interviewed 19 leaders with roles and responsibilities in faculty development from a total of 12 institutions across various regions of the United States. The results were compiled, analyzed, and discussed. Based on our interviews and analyses, we present the current status of these representative institutions in supporting faculty development, highlighting efforts specific to women faculty. Through the experiences, insights, and vision of these leaders, we identified success stories, challenges, and future priorities. Our article provides a primer and a snapshot of institutional efforts to support the advancement of women faculty. Importantly, this article can serve as a reference and resource for academic entities seeking ideas to gauge their commitment level to women faculty and to implement new initiatives. Additionally, this article can provide guidance and strategies for women faculty as they seek support and resources from their current or prospective institutions when pursuing new career opportunities.

2.
Science ; 381(6658): eabq5693, 2023 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-37561875

RESUMO

Using DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.


Assuntos
Metilação de DNA , Epigênese Genética , Mamíferos , Adulto , Animais , Humanos , Epigenoma , Genoma , Mamíferos/genética , Filogenia
3.
J Lipid Res ; 63(10): 100279, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36100091

RESUMO

The unfolded protein response (UPR) is an elaborate signaling network that evolved to maintain proteostasis in the endoplasmic reticulum (ER) and mitochondria (mt). These organelles are functionally and physically associated, and consequently, their stress responses are often intertwined. It is unclear how these two adaptive stress responses are coordinated during ER stress. The inositol-requiring enzyme-1 (IRE1), a central ER stress sensor and proximal regulator of the UPRER, harbors dual kinase and endoribonuclease (RNase) activities. IRE1 RNase activity initiates the transcriptional layer of the UPRER, but IRE1's kinase substrate(s) and their functions are largely unknown. Here, we discovered that sphingosine 1-phosphate (S1P) lyase (SPL), the enzyme that degrades S1P, is a substrate for the mammalian IRE1 kinase. Our data show that IRE1-dependent SPL phosphorylation inhibits SPL's enzymatic activity, resulting in increased intracellular S1P levels. S1P has previously been shown to induce the activation of mitochondrial UPR (UPRmt) in nematodes. We determined that IRE1 kinase-dependent S1P induction during ER stress potentiates UPRmt signaling in mammalian cells. Phosphorylation of eukaryotic translation initiation factor 2α (eif2α) is recognized as a critical molecular event for UPRmt activation in mammalian cells. Our data further demonstrate that inhibition of the IRE1-SPL axis abrogates the activation of two eif2α kinases, namely double-stranded RNA-activated protein kinase (PKR) and PKR-like ER kinase upon ER stress. These findings show that the IRE1-SPL axis plays a central role in coordinating the adaptive responses of ER and mitochondria to ER stress in mammalian cells.


Assuntos
RNA de Cadeia Dupla , Resposta a Proteínas não Dobradas , Animais , Fosforilação , Endorribonucleases/genética , Estresse do Retículo Endoplasmático , Proteínas Serina-Treonina Quinases/genética , Aldeído Liases/metabolismo , Ribonucleases/metabolismo , Inositol , Mamíferos/metabolismo
4.
J Biol Chem ; 298(7): 102050, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35598827

RESUMO

The double-stranded RNA-dependent protein kinase activating protein (PACT), an RNA-binding protein that is part of the RNA-induced silencing complex, plays a key role in miR-mediated translational repression. Previous studies showed that PACT regulates the expression of various miRs, selects the miR strand to be loaded onto RNA-induced silencing complex, and determines proper miR length. Apart from PACT's role in mediating the antiviral response in immune cells, what PACT does in other cell types is unknown. Strikingly, it has also been shown that cold exposure leads to marked downregulation of PACT protein in mouse brown adipose tissue (BAT), where mitochondrial biogenesis and metabolism play a central role. Here, we show that PACT establishes a posttranscriptional brake on mitochondrial biogenesis (mitobiogenesis) by promoting the maturation of miR-181c, a key suppressor of mitobiogenesis that has been shown to target mitochondrial complex IV subunit I (Mtco1) and sirtuin 1 (Sirt1). Consistently, we found that a partial reduction in PACT expression is sufficient to enhance mitobiogenesis in brown adipocytes in culture as well as during BAT activation in mice. In conclusion, we demonstrate an unexpected role for PACT in the regulation of mitochondrial biogenesis and energetics in cells and BAT.


Assuntos
Tecido Adiposo Marrom , MicroRNAs , Mitocôndrias , Biogênese de Organelas , Proteínas de Ligação a RNA , Tecido Adiposo Marrom/metabolismo , Animais , Complexo I de Transporte de Elétrons/metabolismo , Camundongos , MicroRNAs/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Complexo de Inativação Induzido por RNA/metabolismo
5.
EMBO Mol Med ; 14(4): e15344, 2022 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-35191199

RESUMO

Fragile X Mental Retardation protein (FMRP), widely known for its role in hereditary intellectual disability, is an RNA-binding protein (RBP) that controls translation of select mRNAs. We discovered that endoplasmic reticulum (ER) stress induces phosphorylation of FMRP on a site that is known to enhance translation inhibition of FMRP-bound mRNAs. We show ER stress-induced activation of Inositol requiring enzyme-1 (IRE1), an ER-resident stress-sensing kinase/endoribonuclease, leads to FMRP phosphorylation and to suppression of macrophage cholesterol efflux and apoptotic cell clearance (efferocytosis). Conversely, FMRP deficiency and pharmacological inhibition of IRE1 kinase activity enhances cholesterol efflux and efferocytosis, reducing atherosclerosis in mice. Our results provide mechanistic insights into how ER stress-induced IRE1 kinase activity contributes to macrophage cholesterol homeostasis and suggests IRE1 inhibition as a promising new way to counteract atherosclerosis.


Assuntos
Aterosclerose , Proteína do X Frágil da Deficiência Intelectual , Proteínas de Membrana , Proteínas Serina-Treonina Quinases , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Estresse do Retículo Endoplasmático , Endorribonucleases/metabolismo , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais
6.
JCI Insight ; 7(6)2022 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-35167493

RESUMO

Kawasaki disease (KD) is the leading cause of noncongenital heart disease in children. Studies in mice and humans propound the NLRP3/IL-1ß pathway as the principal driver of KD pathophysiology. Endoplasmic reticulum (ER) stress can activate the NLRP3 inflammasome, but the potential implication of ER stress in KD pathophysiology has not been investigated to our knowledge. We used human patient data and the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to characterize the impact of ER stress on the development of cardiovascular lesions. KD patient transcriptomics and single-cell RNA sequencing of the abdominal aorta from LCWE-injected mice revealed changes in the expression of ER stress genes. Alleviating ER stress genetically, by conditional deletion of inositol-requiring enzyme 1 (IRE1) in myeloid cells, or pharmacologically, by inhibition of IRE1 endoribonuclease (RNase) activity, led to significant reduction of LCWE-induced cardiovascular lesion formation as well as reduced caspase-1 activity and IL-1ß secretion. These results demonstrate the causal relationship of ER stress to KD pathogenesis and highlight IRE1 RNase activity as a potential new therapeutic target.


Assuntos
Lacticaseibacillus casei , Síndrome de Linfonodos Mucocutâneos , Vasculite , Animais , Modelos Animais de Doenças , Endorribonucleases/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas Serina-Treonina Quinases/genética , Ribonucleases
7.
Hepatology ; 75(2): 280-296, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34449924

RESUMO

BACKGROUND AND AIMS: Methionine adenosyltransferase 1A (MAT1A) is responsible for S-adenosylmethionine (SAMe) biosynthesis in the liver. Mice lacking Mat1a have hepatic SAMe depletion and develop NASH and HCC spontaneously. Several kinases are activated in Mat1a knockout (KO) mice livers. However, characterizing the phospho-proteome and determining whether they contribute to liver pathology remain open for study. Our study aimed to provide this knowledge. APPROACH AND RESULTS: We performed phospho-proteomics in Mat1a KO mice livers with and without SAMe treatment to identify SAMe-dependent changes that may contribute to liver pathology. Our studies used Mat1a KO mice at different ages treated with and without SAMe, cell lines, in vitro translation and kinase assays, and human liver specimens. We found that the most striking change was hyperphosphorylation and increased content of La-related protein 1 (LARP1), which, in the unphosphorylated form, negatively regulates translation of 5'-terminal oligopyrimidine (TOP)-containing mRNAs. Consistently, multiple TOP proteins are induced in KO livers. Translation of TOP mRNAs ribosomal protein S3 and ribosomal protein L18 was enhanced by LARP1 overexpression in liver cancer cells. We identified LARP1-T449 as a SAMe-sensitive phospho-site of cyclin-dependent kinase 2 (CDK2). Knocking down CDK2 lowered LARP1 phosphorylation and prevented LARP1-overexpression-mediated increase in translation. LARP1-T449 phosphorylation induced global translation, cell growth, migration, invasion, and expression of oncogenic TOP-ribosomal proteins in HCC cells. LARP1 expression is increased in human NASH and HCC. CONCLUSIONS: Our results reveal a SAMe-sensitive mechanism of LARP1 phosphorylation that may be involved in the progression of NASH to HCC.


Assuntos
Autoantígenos/metabolismo , Oligonucleotídeos/genética , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/metabolismo , Ribonucleoproteínas/antagonistas & inibidores , Ribonucleoproteínas/metabolismo , S-Adenosilmetionina/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/imunologia , Quinase 2 Dependente de Ciclina/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Metionina Adenosiltransferase/genética , Camundongos , Camundongos Knockout , Mutação , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosforilação/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Proteômica , RNA Mensageiro/metabolismo , Proteínas Ribossômicas/genética , S-Adenosilmetionina/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Antígeno SS-B
8.
EMBO Rep ; 21(12): e51462, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33140520

RESUMO

The ER-bound kinase/endoribonuclease (RNase), inositol-requiring enzyme-1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1's one known, specific RNA target, X box-binding protein-1 (XBP1) or the RNA substrates of IRE1-dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P3 ) 5-phosphatase-2 (INPPL1) is a direct target of miR-2137, which controls PI(3,4,5)P3 levels in macrophages. The modulation of cellular PI(3,4,5)P3 /PIP2 ratio and anabolic mTOR signaling by the IRE1-induced miR-2137 demonstrates how the ER can provide a critical input into cell growth decisions.


Assuntos
Estresse do Retículo Endoplasmático , Fosfatidilinositóis , Endorribonucleases/genética , Endorribonucleases/metabolismo , Humanos , Inositol , Macrófagos/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Resposta a Proteínas não Dobradas
9.
Mol Metab ; 28: 58-72, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31422082

RESUMO

OBJECTIVE: Saturated and trans fat consumption is associated with increased cardiovascular disease (CVD) risk. Current dietary guidelines recommend low fat and significantly reduced trans fat intake. Full fat dairy can worsen dyslipidemia, but recent epidemiological studies show full-fat dairy consumption may reduce diabetes and CVD risk. This dairy paradox prompted a reassessment of the dietary guidelines. The beneficial metabolic effects in dairy have been claimed for a ruminant-derived, trans fatty acid, trans-C16:1n-7 or trans-palmitoleate (trans-PAO). A close relative, cis-PAO, is produced by de novo lipogenesis and mediates inter-organ crosstalk, improving insulin-sensitivity and alleviating atherosclerosis in mice. These findings suggest trans-PAO may be a useful substitute for full fat dairy, but a metabolic function for trans-PAO has not been shown to date. METHODS: Using lipidomics, we directly investigated trans-PAO's impact on plasma and tissue lipid profiles in a hypercholesterolemic atherosclerosis mouse model. Furthermore, we investigated trans-PAO's impact on hyperlipidemia-induced inflammation and atherosclerosis progression in these mice. RESULTS: Oral trans-PAO supplementation led to significant incorporation of trans-PAO into major lipid species in plasma and tissues. Unlike cis-PAO, however, trans-PAO did not prevent organelle stress and inflammation in macrophages or atherosclerosis progression in mice. CONCLUSIONS: A significant, inverse correlation between circulating trans-PAO levels and diabetes incidence and cardiovascular mortality has been reported. Our findings show that trans-PAO can incorporate efficiently into the same pools that its cis counterpart is known to incorporate into. However, we found trans-PAO's anti-inflammatory and anti-atherosclerotic effects are muted due to its different structure from cis-PAO.


Assuntos
Aterosclerose/prevenção & controle , Ácidos Graxos Monoinsaturados/química , Ácidos Graxos Monoinsaturados/farmacologia , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Masculino , Camundongos , Camundongos Knockout
10.
J Am Coll Cardiol ; 73(10): 1149-1169, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30871699

RESUMO

BACKGROUND: Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2α) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2α phosphorylation is observed in mouse and human atheroma. OBJECTIVES: Potent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated the potential benefits of intercepting ISR in a chronic metabolic and inflammatory disease, atherosclerosis. METHODS: The authors investigated ISR's role in lipid-induced inflammasome activation and atherogenesis by taking advantage of 3 different small molecules and the ATP-analog sensitive kinase allele technology to intercept ISR at multiple molecular nodes. RESULTS: The results show lipid-activated eIF2α signaling induces a mitochondrial protease, Lon protease 1 (LONP1), that degrades phosphatase and tensin-induced putative kinase 1 and blocks Parkin-mediated mitophagy, resulting in greater mitochondrial oxidative stress, inflammasome activation, and interleukin-1ß secretion in macrophages. Furthermore, ISR inhibitors suppress hyperlipidemia-induced inflammasome activation and inflammation, and reduce atherosclerosis. CONCLUSIONS: These results reveal endoplasmic reticulum controls mitochondrial clearance by activating eIF2α-LONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1ß secretion by dietary fats. These findings underscore the intricate exchange of information and coordination of both organelles' responses to lipids is important for metabolic health. Modulation of ISR to alleviate organelle stress can prevent inflammasome activation by dietary fats and may be a strategy to reduce lipid-induced inflammation and atherosclerosis.


Assuntos
Aterosclerose/imunologia , Gorduras na Dieta/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Estresse Fisiológico/imunologia , Animais , Retículo Endoplasmático/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Mitocôndrias/metabolismo , Estresse Oxidativo , Fosforilação , Transdução de Sinais
11.
Cell Metab ; 28(3): 432-448.e4, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-29937375

RESUMO

Pathogen burden accelerates atherosclerosis, but the mechanisms remain unresolved. Activation of the NLRP3 inflammasome is linked to atherogenesis. Here we investigated whether Chlamydia pneumoniae (C.pn) infection engages NLRP3 in promoting atherosclerosis. C.pn potentiated hyperlipidemia-induced inflammasome activity in cultured macrophages and in foam cells in atherosclerotic lesions of Ldlr-/- mice. C.pn-induced acceleration of atherosclerosis was significantly dependent on NLRP3 and caspase-1. We discovered that C.pn-induced extracellular IL-1ß triggers a negative feedback loop to inhibit GPR109a and ABCA1 expression and cholesterol efflux, leading to accumulation of intracellular cholesterol and foam cell formation. Gpr109a and Abca1 were both upregulated in plaque lesions in Nlrp3-/- mice in both hyperlipidemic and C.pn infection models. Mature IL-1ß and cholesterol may compete for access to the ABCA1 transporter to be exported from macrophages. C.pn exploits this metabolic-immune crosstalk, which can be modulated by NLRP3 inhibitors to alleviate atherosclerosis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Aterosclerose/microbiologia , Chlamydophila pneumoniae/patogenicidade , Colesterol/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Aterosclerose/imunologia , Aterosclerose/patologia , Transporte Biológico , Caspase 1/metabolismo , Feminino , Células Espumosas/imunologia , Células Espumosas/patologia , Interações entre Hospedeiro e Microrganismos , Inflamassomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/microbiologia , Transdução de Sinais
12.
Nat Immunol ; 19(6): 526-537, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29777212

RESUMO

After activation, cells of the myeloid lineage undergo robust metabolic transitions, as well as discrete epigenetic changes, that can dictate both ongoing and future inflammatory responses. In atherosclerosis, in which macrophages play central roles in the initiation, growth, and ultimately rupture of arterial plaques, altered metabolism is a key feature that dictates macrophage function and subsequent disease progression. This Review explores how factors central to the plaque microenvironment (for example, altered cholesterol metabolism, oxidative stress, hypoxia, apoptotic and necrotic cells, and hyperglycemia) shape the metabolic rewiring of macrophages in atherosclerosis as well as how these metabolic shifts in turn alter macrophage immune-effector and tissue-reparative functions. Finally, this overview offers insight into the challenges and opportunities of harnessing metabolism to modulate aberrant macrophage responses in disease.


Assuntos
Aterosclerose/imunologia , Aterosclerose/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Animais , Humanos
13.
J Am Coll Cardiol ; 71(14): 1553-1570, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29622163

RESUMO

BACKGROUND: Recent studies indicate that Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) signaling promote the development of high fat diet-induced atherosclerosis in hypercholesterolemic mice. OBJECTIVES: The authors investigated the role of TLR4/MyD88 signaling in hematopoietic and stromal cells in the development and infection-mediated acceleration of atherosclerosis. METHODS: The authors generated bone marrow chimeras between wild-type and Tlr4-/- mice, as well as wild-type and Myd88-/- mice. All mice were on the Apoe-/- background and fed high fat diet. The authors infected the chimeric mice with C. pneumoniae (CP) and fed them high fat diet. RESULTS: Aortic sinus plaques and lipid content were significantly reduced in Apoe-/- mice that received Tlr4-/-or Myd88-/- bone marrow compared with control animals despite similar cholesterol levels. Similarly, Tlr4 or Myd88 deficiency in stromal cells also led to a reduction in the lesion area and lipid in aortic sinus plaques. MyD88 expression only in CD11c+ dendritic cells (myeloid cells) in cells was sufficient in otherwise MyD88-deficient mice to induce CP infection-mediated acceleration of atherosclerosis, underlining the key role of MyD88 in CD11c+ dendritic cells (myeloid cells). Whereas CP infection markedly accelerated atherosclerosis in TLR4- or MyD88-positive chimeras, CP infection had a minimal effect on atherosclerosis in TLR4- or MyD88-deficient mice (either in the hematopoietic or stromal cell compartments). CONCLUSIONS: The authors show that both CP infection and metabolic stress associated with dyslipidemia use the same innate immune response pathway, utilizing TLR4/MyD88 signaling, with similar relative contributions in bone marrow-derived hematopoietic cells and in stromal cells. Further studies are required to understand this intricate and complex cross talk among innate and adaptive immune systems in various conditions to more effectively design dendritic cell-mediated atheroprotective vaccines and other therapeutic strategies.


Assuntos
Aterosclerose/metabolismo , Infecções por Chlamydophila/complicações , Chlamydophila pneumoniae/patogenicidade , Imunidade Inata , Metabolismo dos Lipídeos , Lipídeos , Animais , Aterosclerose/etiologia , Aterosclerose/imunologia , Infecções por Chlamydophila/imunologia , Infecções por Chlamydophila/metabolismo , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
14.
Proc Natl Acad Sci U S A ; 114(8): E1395-E1404, 2017 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-28137856

RESUMO

Metaflammation, an atypical, metabolically induced, chronic low-grade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ER-resident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenic genes, including several important cytokines and chemokines. We show that IRE1 inhibitors uncouple lipid-induced ER stress from inflammasome activation in both mouse and human macrophages. In vivo, these IRE1 inhibitors led to a significant decrease in hyperlipidemia-induced IL-1ß and IL-18 production, lowered T-helper type-1 immune responses, and reduced atherosclerotic plaque size without altering the plasma lipid profiles in apolipoprotein E-deficient mice. These results show that pharmacologic modulation of IRE1 counteracts metaflammation and alleviates atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Apolipoproteínas E/metabolismo , Células Cultivadas , Progressão da Doença , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
15.
Sci Transl Med ; 8(358): 358ra126, 2016 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-27683551

RESUMO

De novo lipogenesis (DNL), the conversion of glucose and other substrates to lipids, is often associated with ectopic lipid accumulation, metabolic stress, and insulin resistance, especially in the liver. However, organ-specific DNL can also generate distinct lipids with beneficial metabolic bioactivity, prompting a great interest in their use for the treatment of metabolic diseases. Palmitoleate (PAO), one such bioactive lipid, regulates lipid metabolism in liver and improves glucose utilization in skeletal muscle when it is generated de novo from the obese adipose tissue. We show that PAO treatment evokes an overall lipidomic remodeling of the endoplasmic reticulum (ER) membranes in macrophages and mouse tissues, which is associated with resistance of the ER to hyperlipidemic stress. By preventing ER stress, PAO blocks lipid-induced inflammasome activation in mouse and human macrophages. Chronic PAO supplementation also lowers systemic interleukin-1ß (IL-1ß) and IL-18 concentrations in vivo in hyperlipidemic mice. Moreover, PAO prevents macrophage ER stress and IL-1ß production in atherosclerotic plaques in vivo, resulting in a marked reduction in plaque macrophages and protection against atherosclerosis in mice. These findings demonstrate that oral supplementation with a product of DNL such as PAO can promote membrane remodeling associated with metabolic resilience of intracellular organelles to lipid stress and limit the progression of atherosclerosis. These findings support therapeutic PAO supplementation as a potential preventive approach against complex metabolic and inflammatory diseases such as atherosclerosis, which warrants further studies in humans.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/uso terapêutico , Inflamassomos/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Apoptose/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Ácidos Graxos Monoinsaturados/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Membranas Intracelulares/metabolismo , Lipídeos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Placa Aterosclerótica/patologia
16.
Arterioscler Thromb Vasc Biol ; 36(6): 1122-31, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27102962

RESUMO

OBJECTIVE: The c-Jun NH2-terminal kinases (JNK) are regulated by a wide variety of cellular stresses and have been implicated in apoptotic signaling. Macrophages express 2 JNK isoforms, JNK1 and JNK2, which may have different effects on cell survival and atherosclerosis. APPROACH AND RESULTS: To dissect the effect of macrophage JNK1 and JNK2 on early atherosclerosis, Ldlr(-/-) mice were reconstituted with wild-type, Jnk1(-/-), and Jnk2(-/-) hematopoietic cells and fed a high cholesterol diet. Jnk1(-/-)→Ldlr(-/-) mice have larger atherosclerotic lesions with more macrophages and fewer apoptotic cells than mice transplanted with wild-type or Jnk2(-/-) cells. Moreover, genetic ablation of JNK to a single allele (Jnk1(+/-)/Jnk2(-/-) or Jnk1(-/-)/Jnk2(+/-)) in marrow of Ldlr(-/-) recipients further increased atherosclerosis compared with Jnk1(-/-)→Ldlr(-/-) and wild-type→Ldlr(-/-) mice. In mouse macrophages, anisomycin-mediated JNK signaling antagonized Akt activity, and loss of Jnk1 gene obliterated this effect. Similarly, pharmacological inhibition of JNK1, but not JNK2, markedly reduced the antagonizing effect of JNK on Akt activity. Prolonged JNK signaling in the setting of endoplasmic reticulum stress gradually extinguished Akt and Bad activity in wild-type cells with markedly less effects in Jnk1(-/-) macrophages, which were also more resistant to apoptosis. Consequently, anisomycin increased and JNK1 inhibitors suppressed endoplasmic reticulum stress-mediated apoptosis in macrophages. We also found that genetic and pharmacological inhibition of phosphatase and tensin homolog abolished the JNK-mediated effects on Akt activity, indicating that phosphatase and tensin homolog mediates crosstalk between these pathways. CONCLUSIONS: Loss of Jnk1, but not Jnk2, in macrophages protects them from apoptosis, increasing cell survival, and this accelerates early atherosclerosis.


Assuntos
Aorta/enzimologia , Doenças da Aorta/enzimologia , Apoptose , Aterosclerose/enzimologia , Células da Medula Óssea/enzimologia , Macrófagos/enzimologia , Proteína Quinase 8 Ativada por Mitógeno/deficiência , Receptores de LDL/deficiência , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apoptose/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/patologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Transplante de Medula Óssea , Sobrevivência Celular , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Predisposição Genética para Doença , Hipercolesterolemia/enzimologia , Hipercolesterolemia/genética , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/deficiência , Proteína Quinase 9 Ativada por Mitógeno/genética , PTEN Fosfo-Hidrolase/antagonistas & inibidores , PTEN Fosfo-Hidrolase/metabolismo , Fenótipo , Placa Aterosclerótica , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de LDL/genética , Transdução de Sinais , Proteína de Morte Celular Associada a bcl/metabolismo
17.
Arterioscler Thromb Vasc Biol ; 31(6): 1283-90, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21474828

RESUMO

OBJECTIVE: The adipocyte/macrophage fatty acid-binding proteins aP2 (FABP4) and Mal1 (FABP5) are intracellular lipid chaperones that modulate systemic glucose metabolism, insulin sensitivity, and atherosclerosis. Combined deficiency of aP2 and Mal1 has been shown to reduce the development of atherosclerosis, but the independent role of macrophage Mal1 expression in atherogenesis remains unclear. METHODS AND RESULTS: We transplanted wild-type (WT), Mal1(-/-), or aP2(-/-) bone marrow into low-density lipoprotein receptor-null (LDLR(-/-)) mice and fed them a Western diet for 8 weeks. Mal1(-/-)→LDLR(-/-) mice had significantly reduced (36%) atherosclerosis in the proximal aorta compared with control WT→LDLR(-/-) mice. Interestingly, peritoneal macrophages isolated from Mal1-deficient mice displayed increased peroxisome proliferator-activated receptor-γ (PPARγ) activity and upregulation of a PPARγ-related cholesterol trafficking gene, CD36. Mal1(-/-) macrophages showed suppression of inflammatory genes, such as COX2 and interleukin 6. Mal1(-/-)→LDLR(-/-) mice had significantly decreased macrophage numbers in the aortic atherosclerotic lesions compared with WT→LDLR(-/-) mice, suggesting that monocyte recruitment may be impaired. Indeed, blood monocytes isolated from Mal1(-/-)→LDLR(-/-) mice on a high-fat diet had decreased CC chemokine receptor 2 gene and protein expression levels compared with WT monocytes. CONCLUSION: Taken together, our results demonstrate that Mal1 plays a proatherogenic role by suppressing PPARγ activity, which increases expression of CC chemokine receptor 2 by monocytes, promoting their recruitment to atherosclerotic lesions.


Assuntos
Aterosclerose/prevenção & controle , Proteínas de Ligação a Ácido Graxo/fisiologia , Regulação da Expressão Gênica , Macrófagos/fisiologia , Proteínas de Neoplasias/fisiologia , PPAR gama/fisiologia , Receptores de LDL/fisiologia , Animais , Antígenos CD36/fisiologia , Feminino , Lipídeos/sangue , Camundongos , Receptores CCR2/genética
18.
Nat Med ; 15(12): 1383-91, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19966778

RESUMO

Macrophages show endoplasmic reticulum (ER) stress when exposed to lipotoxic signals associated with atherosclerosis, although the pathophysiological importance and the underlying mechanisms of this phenomenon remain unknown. Here we show that mitigation of ER stress with a chemical chaperone results in marked protection against lipotoxic death in macrophages and prevents macrophage fatty acid-binding protein-4 (aP2) expression. Using genetic and chemical models, we show that aP2 is the predominant regulator of lipid-induced macrophage ER stress. The absence of lipid chaperones incites an increase in the production of phospholipids rich in monounsaturated fatty acids and bioactive lipids that render macrophages resistant to lipid-induced ER stress. Furthermore, the impact of aP2 on macrophage lipid metabolism and the ER stress response is mediated by upregulation of key lipogenic enzymes by the liver X receptor. Our results demonstrate the central role for lipid chaperones in regulating ER homeostasis in macrophages in atherosclerosis and show that ER responses can be modified, genetically or chemically, to protect the organism against the deleterious effects of hyperlipidemia.


Assuntos
Aterosclerose/prevenção & controle , Retículo Endoplasmático/metabolismo , Metabolismo dos Lipídeos , Macrófagos/metabolismo , Humanos , Estresse Oxidativo
19.
Nat Rev Immunol ; 8(12): 923-34, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19029988

RESUMO

The proper functioning of the pathways that are involved in the sensing and management of nutrients is central to metabolic homeostasis and is therefore among the most fundamental requirements for survival. Metabolic systems are integrated with pathogen-sensing and immune responses, and these pathways are evolutionarily conserved. This close functional and molecular integration of the immune and metabolic systems is emerging as a crucial homeostatic mechanism, the dysfunction of which underlies many chronic metabolic diseases, including type 2 diabetes and atherosclerosis. In this Review we provide an overview of several important networks that sense and manage nutrients and discuss how they integrate with immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.


Assuntos
Inflamação/metabolismo , Doenças Metabólicas/metabolismo , Animais , Metabolismo Energético , Homeostase , Humanos , Estado Nutricional , Transdução de Sinais
20.
Curr Atheroscler Rep ; 9(3): 222-9, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18241617

RESUMO

The link between inflammation and the development of insulin resistance, type 2 diabetes, and atherosclerosis has been uncovered in the past decade. Although the molecular mechanisms underlying the co-occurrence of these metabolic and inflammatory diseases are not fully understood, several molecular players, integrating stress and inflammatory responses with metabolic homeostasis, were discovered recently. One of these molecular integration sites is through the action of cytosolic lipid chaperones or fatty acid binding proteins (FABPs), which are common to adipocytes and macrophages. Furthermore, studies in a variety of genetic models demonstrated that the FABPs aP2 and mal1 are critical mediators of many components of metabolic syndrome in mice. These exciting findings raise the possibility that FABPs represent desirable therapeutic targets for metabolic syndrome. In this review, we describe the findings demonstrating FABP's role in metabolic and inflammatory diseases and highlight recent advances in understanding the mechanisms of FABP function at the cellular and molecular level.


Assuntos
Proteínas de Ligação a Ácido Graxo/fisiologia , Adipócitos/fisiologia , Animais , Asma/fisiopatologia , Aterosclerose/fisiopatologia , Diabetes Mellitus/fisiopatologia , Hepatócitos/fisiologia , Humanos , Inflamação/fisiopatologia , Resistência à Insulina/fisiologia , Macrófagos/fisiologia , Síndrome Metabólica/metabolismo , Obesidade/fisiopatologia
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