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1.
FASEB J ; 38(1): e23369, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38100642

RESUMEN

The human cardiovascular system has evolved to accommodate the gravity of Earth. Microgravity during spaceflight has been shown to induce vascular remodeling, leading to a decline in vascular function. The underlying mechanisms are not yet fully understood. Our previous study demonstrated that miR-214 plays a critical role in angiotensin II-induced vascular remodeling by reducing the levels of Smad7 and increasing the phosphorylation of Smad3. However, its role in vascular remodeling evoked by microgravity is not yet known. This study aimed to determine the contribution of miR-214 to the regulation of microgravity-induced vascular remodeling. The results of our study revealed that miR-214 expression was increased in the forebody arteries of both mice and monkeys after simulated microgravity treatment. In vitro, rotation-simulated microgravity-induced VSMC migration, hypertrophy, fibrosis, and inflammation were repressed by miR-214 knockout (KO) in VSMCs. Additionally, miR-214 KO increased the level of Smad7 and decreased the phosphorylation of Smad3, leading to a decrease in downstream gene expression. Furthermore, miR-214 cKO protected against simulated microgravity induced the decline in aorta function and the increase in stiffness. Histological analysis showed that miR-214 cKO inhibited the increases in vascular medial thickness that occurred after simulated microgravity treatment. Altogether, these results demonstrate that miR-214 has potential as a therapeutic target for the treatment of vascular remodeling caused by simulated microgravity.


Asunto(s)
MicroARNs , Ingravidez , Humanos , Ratones , Animales , Músculo Liso Vascular/metabolismo , MicroARNs/metabolismo , Remodelación Vascular/genética , Aorta/metabolismo , Miocitos del Músculo Liso/metabolismo
2.
J Biol Chem ; 299(4): 103059, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36841479

RESUMEN

Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation, glucolipid metabolism, and inflammation. Thiazolidinediones are PPARγ full agonists with potent insulin-sensitizing effects, whereas their oral usage is restricted because of unwanted side effects, including obesity and cardiovascular risks. Here, via virtual screening, microscale thermophoresis analysis, and molecular confirmation, we demonstrate that diosmin, a natural compound of wide and long-term clinical use, is a selective PPARγ modulator that binds to PPARγ and blocks PPARγ phosphorylation with weak transcriptional activity. Local diosmin administration in subcutaneous fat (inguinal white adipose tissue [iWAT]) improved insulin sensitivity and attenuated obesity via enhancing browning of white fat and energy expenditure. Besides, diosmin ameliorated inflammation in WAT and liver and reduced hepatic steatosis. Of note, we determined that iWAT local administration of diosmin did not exhibit obvious side effects. Taken together, the present study demonstrated that iWAT local delivery of diosmin protected mice from diet-induced insulin resistance, obesity, and fatty liver by blocking PPARγ phosphorylation, without apparent side effects, making it a potential therapeutic agent for the treatment of metabolic diseases.


Asunto(s)
Tejido Adiposo Pardo , Tejido Adiposo Blanco , Diosmina , Hígado Graso , Resistencia a la Insulina , PPAR gamma , Animales , Ratones , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Dieta Alta en Grasa , Diosmina/farmacología , Diosmina/metabolismo , Diosmina/uso terapéutico , Hígado Graso/metabolismo , Inflamación/metabolismo , Ratones Endogámicos C57BL , Obesidad/metabolismo , PPAR gamma/metabolismo , Tejido Adiposo Pardo/metabolismo
3.
Circulation ; 144(9): 694-711, 2021 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-34139860

RESUMEN

BACKGROUND: Without adequate treatment, pathological cardiac hypertrophy induced by sustained pressure overload eventually leads to heart failure. WWP1 (WW domain-containing E3 ubiquitin protein ligase 1) is an important regulator of aging-related pathologies, including cancer and cardiovascular diseases. However, the role of WWP1 in pressure overload-induced cardiac remodeling and heart failure is yet to be determined. METHODS: To examine the correlation of WWP1 with hypertrophy, we analyzed WWP1 expression in patients with heart failure and mice subjected to transverse aortic constriction (TAC) by Western blotting and immunohistochemical staining. TAC surgery was performed on WWP1 knockout mice to assess the role of WWP1 in cardiac hypertrophy, heart function was examined by echocardiography, and related cellular and molecular markers were examined. Mass spectrometry and coimmunoprecipitation assays were conducted to identify the proteins that interacted with WWP1. Pulse-chase assay, ubiquitination assay, reporter gene assay, and an in vivo mouse model via AAV9 (adeno-associated virus serotype 9) were used to explore the mechanisms by which WWP1 regulates cardiac remodeling. AAV9 carrying cardiac troponin T (cTnT) promoter-driven small hairpin RNA targeting WWP1 (AAV9-cTnT-shWWP1) was administered to investigate its rescue role in TAC-induced cardiac dysfunction. RESULTS: The WWP1 level was significantly increased in the hypertrophic hearts from patients with heart failure and mice subjected to TAC. The results of echocardiography and histology demonstrated that WWP1 knockout protected the heart from TAC-induced hypertrophy. There was a direct interaction between WWP1 and DVL2 (disheveled segment polarity protein 2). DVL2 was stabilized by WWP1-mediated K27-linked polyubiquitination. The role of WWP1 in pressure overload-induced cardiac hypertrophy was mediated by the DVL2/CaMKII/HDAC4/MEF2C signaling pathway. Therapeutic targeting WWP1 almost abolished TAC induced heart dysfunction, suggesting WWP1 as a potential target for treating cardiac hypertrophy and failure. CONCLUSIONS: We identified WWP1 as a key therapeutic target for pressure overload induced cardiac remodeling. We also found a novel mechanism regulated by WWP1. WWP1 promotes atypical K27-linked ubiquitin multichain assembly on DVL2 and exacerbates cardiac hypertrophy by the DVL2/CaMKII/HDAC4/MEF2C pathway.


Asunto(s)
Cardiomegalia/metabolismo , Proteínas Dishevelled/metabolismo , Ubiquitina-Proteína Ligasas/genética , Animales , Biomarcadores , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cardiomegalia/diagnóstico , Cardiomegalia/etiología , Cardiomegalia/prevención & control , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/prevención & control , Histona Desacetilasas/metabolismo , Humanos , Inmunohistoquímica , Factores de Transcripción MEF2/metabolismo , Ratones , Ratones Noqueados , Unión Proteica , Estabilidad Proteica , Proteínas Represoras/metabolismo , Transducción de Señal , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
4.
Hepatology ; 73(1): 91-103, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32150756

RESUMEN

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N6 -methyladenosine (m6 A) RNA methylation is the most common internal modification in eukaryotic mRNA. APPROACH AND RESULTS: In the present study, by m6 A sequencing and RNA sequencing, we found that both m6 A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin-receptor-deficient db/db mice. Importantly, our results showed that YT521-B homology domain-containing 2 (Ythdc2), an m6 A reader, was markedly down-regulated in livers of obese mice and NAFLD patients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression. CONCLUSIONS: Our findings describe an important role of the m6 A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity-related NAFLD.


Asunto(s)
Lipogénesis/genética , Hígado/embriología , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad/complicaciones , ARN Helicasas/metabolismo , Estabilidad del ARN/genética , Animales , Ácido Graso Sintasas/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Enfermedad del Hígado Graso no Alcohólico/enzimología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/enzimología , Obesidad/genética , Obesidad/patología , ARN Helicasas/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/metabolismo
5.
FASEB J ; 35(11): e21947, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34637552

RESUMEN

Vascular remodeling is a prominent trait during the development of hypertension, attributable to the phenotypic transition of vascular smooth muscle cells (VSMCs). Increasing studies demonstrate that microRNA plays an important role in this process. Here, we surprisingly found that smooth muscle cell-specific miR-214 knockout (miR-214 cKO) significantly alleviates angiotensin II (Ang II)-induced hypertension, which has the same effect as that of miR-214 global knockout mice in response to Ang II stimulation. Under the treatment of Ang II, miR-214 cKO mice exhibit substantially reduced systolic blood pressure. The vascular medial thickness and area in miR-214 cKO blood vessels were obviously reduced, the expression of collagen I and proinflammatory factors were also inhibited. VSMC-specific deletion of miR-214 blunts the response of blood vessels to the stimulation of endothelium-dependent and -independent vasorelaxation and phenylephrine and 5-HT induced vasocontraction. In vitro, Ang II-induced VSMC proliferation, migration, contraction, hypertrophy, and stiffness were all repressed with miR-214 KO in VSMC. To further explore the mechanism of miR-214 in the regulation of the VSMC function, it is very interesting to find that the TGF-ß signaling pathway is mostly enriched in miR-214 KO VSMC. Smad7, the potent negative regulator of the TGF-ß/Smad pathway, is identified to be the target of miR-214 in VSMC. By which, miR-214 KO sharply enhances Smad7 levels and decreases the phosphorylation of Smad3, and accordingly alleviates the downstream gene expression. Further, Ang II-induced hypertension and vascular dysfunction were reversed by antagomir-214. These results indicate that miR-214 in VSMC established a crosstalk between Ang II-induced AT1R signaling and TGF-ß induced TßRI /Smad signaling, by which it exerts a pivotal role in vascular remodeling and hypertension and imply that miR-214 has the potential as a therapeutic target for the treatment of hypertension.


Asunto(s)
Angiotensina II/farmacología , Técnicas de Inactivación de Genes/métodos , Hipertensión/inducido químicamente , Hipertensión/metabolismo , MicroARNs/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Transducción de Señal/genética , Proteína smad7/metabolismo , Regulación hacia Arriba/genética , Animales , Presión Sanguínea/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Células Cultivadas , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Remodelación Vascular/genética
6.
Eur Heart J ; 42(36): 3786-3799, 2021 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-34347073

RESUMEN

AIMS: 3' untranslated region (3' UTR) of mRNA is more conserved than other non-coding sequences in vertebrate genomes, and its sequence space has substantially expanded during the evolution of higher organisms, which substantiates their significance in biological regulation. However, the independent role of 3' UTR in cardiovascular disease was largely unknown. METHODS AND RESULTS: Using bioinformatics, RNA fluorescent in situ hybridization and quantitative real-time polymerase chain reaction, we found that 3' UTR and coding sequence regions of Ckip-1 mRNA exhibited diverse expression and localization in cardiomyocytes. We generated cardiac-specific Ckip-1 3' UTR overexpression mice under wild type and casein kinase 2 interacting protein-1 (CKIP-1) knockout background. Cardiac remodelling was assessed by histological, echocardiography, and molecular analyses at 4 weeks after transverse aortic constriction (TAC) surgery. The results showed that cardiac Ckip-1 3' UTR significantly inhibited TAC-induced cardiac hypertrophy independent of CKIP-1 protein. To determine the mechanism of Ckip-1 3' UTR in cardiac hypertrophy, we performed transcriptome and metabolomics analyses, RNA immunoprecipitation, biotin-based RNA pull-down, and reporter gene assays. We found that Ckip-1 3' UTR promoted fatty acid metabolism through AMPK-PPARα-CPT1b axis, leading to its protection against pathological cardiac hypertrophy. Moreover, Ckip-1 3' UTR RNA therapy using adeno-associated virus obviously alleviates cardiac hypertrophy and improves heart function. CONCLUSIONS: These findings disclose that Ckip-1 3' UTR inhibits cardiac hypertrophy independently of its cognate protein. Ckip-1 3' UTR is an effective RNA-based therapy tool for treating cardiac hypertrophy and heart failure.


Asunto(s)
Cardiomegalia , Insuficiencia Cardíaca , Regiones no Traducidas 3'/genética , Animales , Cardiomegalia/genética , Cardiomegalia/prevención & control , Proteínas Portadoras , Insuficiencia Cardíaca/genética , Hibridación Fluorescente in Situ , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos
7.
J Hepatol ; 75(1): 150-162, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33548387

RESUMEN

BACKGROUND & AIMS: Chronic endoplasmic reticulum (ER) stress in the liver has been shown to play a causative role in non-alcoholic fatty liver disease (NAFLD) progression, yet the underlying molecular mechanisms remain to be elucidated. Forkhead box A3 (FOXA3), a member of the FOX family, plays critical roles in metabolic homeostasis, although its possible functions in ER stress and fatty liver progression are unknown. METHODS: Adenoviral delivery, siRNA delivery, and genetic knockout mice were used to crease FOXA3 gain- or loss-of-function models. Tunicamycin (TM) and a high-fat diet (HFD) were used to induce acute or chronic ER stress in mice. Chromatin immunoprecipiation (ChIP)-seq, luciferase assay, and adenoviral-mediated downstream gene manipulations were performed to reveal the transcriptional axis involved. Key axis protein levels in livers from healthy donors and patients with NAFLD were assessed via immunohistochemical staining. RESULTS: FOXA3 transcription is specifically induced by XBP1s upon ER stress. FOXA3 exacerbates the excessive lipid accumulation caused by the acute ER-inducer TM, whereas FOXA3 deficiency in hepatocytes and mice alleviates it. Importantly, FOXA3 deficiency in mice reduced diet-induced chronic ER stress, fatty liver, and insulin resistance. In addition, FOXA3 suppression via siRNA or adeno-associated virus delivery ameliorated the fatty liver phenotype in HFD-fed and db/db mice. Mechanistically, ChIP-Seq analysis revealed that FOXA3 directly regulates Period1 (Per1) transcription, which in turn promotes the expression of lipogenic genes, including Srebp1c, thus enhancing lipid synthesis. Of pathophysiological significance, FOXA3, PER1, and SREBP1c levels were increased in livers of obese mice and patients with NAFLD. CONCLUSION: The present study identified FOXA3 as the bridging molecule that links ER stress and NAFLD progression. Our results highlighted the role of the XBP1s-FOXA3-PER1/Srebp1c transcriptional axis in the development of NAFLD and identified FOXA3 as a potential therapeutic target for fatty liver disease. LAY SUMMARY: The molecular mechanisms linking endoplasmic reticulum stress to non-alcoholic fatty liver disease (NAFLD) progression remain undefined. Herein, via in vitro and in vivo analysis, we identified Forkhead box A3 (FOXA3) as a key bridging molecule. Of pathophysiological significance, FOXA3 protein levels were increased in livers of obese mice and patients with NAFLD, indicating that FOXA3 could be a potential therapeutic target in fatty liver disease.


Asunto(s)
Estrés del Retículo Endoplásmico , Factor Nuclear 3-gamma del Hepatocito/metabolismo , Animales , Descubrimiento de Drogas , Hepatocitos/metabolismo , Humanos , Lipogénesis/genética , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Proteínas Circadianas Period/metabolismo , Transducción de Señal , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a la X-Box/metabolismo
8.
Rheumatology (Oxford) ; 59(5): 1159-1169, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-31846044

RESUMEN

OBJECTIVE: Bone loss is common in AS, and miR-214 plays an important role in regulating bone formation. The aim of this study was to investigate the effect of miR-214, the production of which is stimulated by IL-17A, on bone loss in AS. METHODS: Peripheral blood was obtained from 32 patients with AS and 24 healthy controls. Levels of IL-17A, soluble RANK ligand (RANKL) and osteoprotegerin in serum were evaluated by ELISA, and the relative level of miR-214 in serum was detected by real-time quantitative PCR. In addition, we assessed the relationship between levels of miR-214, IL-17A and bone loss in primary murine osteoblasts and mouse bone marrow cells. RESULTS: The expression of RANKL and miR-214 in osteoblasts was increased following stimulation by IL-17A, and osteoblasts stimulated by IL-17A promoted the expression of miR-214 in osteoclasts and the activity of osteoclasts. We showed that osteoblast-derived miR-214 could be transferred to osteoclasts and could then regulate their activity. The levels of IL-17A and miR-214 were much higher in the serum of patients with AS than in that of healthy controls, and the relative level of miR-214 was positively correlated with the level of IL-17A in the serum and synovial fluid of the patients with AS, not healthy controls. The level of miR-214 in the serum of AS patients has potential diagnostic value. CONCLUSION: The production of miR-214 in osteoblasts is stimulated by IL-17A. It is an important inhibitor of bone formation in AS, and the serum level of miR-214 might be of potential diagnostic value for AS.


Asunto(s)
Interleucina-17/metabolismo , Osteogénesis , Ligando RANK/metabolismo , Espondilitis Anquilosante/sangre , Espondilitis Anquilosante/metabolismo , Animales , Resorción Ósea , Estudios de Casos y Controles , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Ratones , MicroARNs/metabolismo , Osteoclastos/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Valores de Referencia , Investigación Biomédica Traslacional
9.
FASEB J ; 33(6): 6904-6918, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30811956

RESUMEN

Spaceflight leads to health risks including bone demineralization, skeletal muscle atrophy, cardiovascular dysfunction, and disorders of almost all physiologic systems. However, the impacts of microgravity on blood lineage cells and hematopoietic stem cells (HSCs) in vivo are largely unknown. In this study, we analyzed peripheral blood samples from 6 astronauts who had participated in spaceflight missions and found significant changes in several cell populations at different time points. These dynamic alterations of lineage cells and the role of HSCs were further studied in a mouse model, using hindlimb unloading (HU) to simulate microgravity. Large reductions in the frequency of NK cells, B cells, and erythrocyte precursors in the bone marrow of the HU mice were observed, together with an increased frequency of T cells, neutrophils, and HSCs. T cell levels recovered faster than those of B cells and erythrocyte precursors, whereas the recovery rates of NK cells and granulocytes were slow. In addition, competitive reconstitution experiments demonstrated the impaired function of HSCs, although these changes were reversible. Deep sequencing showed changes in the expression of regulatory molecules important for the differentiation of HSCs. This study provides the first determination of altered HSC function under simulated microgravity in vivo. The impairment of HSC function and differentiation provides an explanation for the immune disorders that occur under simulated microgravity. Thus, our findings demonstrated that spaceflight and simulated microgravity disrupt the homeostasis of immune system and cause dynamic alterations on both HSCs and lineage cells.-Cao, D., Song, J., Ling, S., Niu, S., Lu, L., Cui, Z., Li, Y., Hao, S., Zhong, G., Qi, Z., Sun, W., Yuan, X., Li, H., Zhao, D., Jin, X., Liu, C., Wu, X., Kan, G., Cao, H., Kang, Y., Yu, S., Li, Y. Hematopoietic stem cells and lineage cells undergo dynamic alterations under microgravity and recovery conditions.


Asunto(s)
Diferenciación Celular , Linaje de la Célula , Células Madre Hematopoyéticas/citología , Suspensión Trasera/fisiología , Homeostasis , Recuperación de la Función , Simulación de Ingravidez , Animales , Astronautas , Eritrocitos/citología , Humanos , Linfocitos/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/citología , Vuelo Espacial
10.
J Exp Biol ; 221(Pt 10)2018 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-29650756

RESUMEN

Insulin-like growth factor-1 (IGF-1) plays a crucial role in regulating growth in vertebrates whereas suppressors of cytokine signaling (SOCS) act as feedback inhibitors of the GH/IGF-1 axis. Although SOCS-2 binds the IGF-1 receptor and inhibits IGF-1-induced STAT3 activation, presently there is no clear evidence as to whether IGF-1 could induce SOCS gene expression. The current study aimed to determine whether IGF-1 could induce the transcription of SOCS in juvenile Nile tilapia (Oreochromis niloticus). We show that there is a common positive relationship between the mRNA expression of IGF-I and SOCS-2 under different nutritional statuses and stimulants, but not the mRNA expression of SOCS-1 and SOCS-3 Furthermore, rhIGF-1 treatment and transcriptional activity assay confirmed the hypothesis that IGF-1 could induce SOCS-2 expression, whereas it had no effect or even decreased the expression of SOCS-1 and SOCS-3 Overall, we obtained evidence that the transcription of SOCS-2, but not SOCS-1 or SOCS-3, could be induced by IGF signaling, suggesting that SOCS-2 serves as a feedback suppressor of the IGF-1 axis in juvenile Nile tilapia.


Asunto(s)
Cíclidos/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Alimentación Animal/análisis , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Cíclidos/genética , Cíclidos/microbiología , Dieta/veterinaria , Regulación de la Expresión Génica , Factor I del Crecimiento Similar a la Insulina/genética , Masculino , ARN Mensajero , Receptor IGF Tipo 1/metabolismo , Transducción de Señal/efectos de los fármacos
11.
Fish Shellfish Immunol ; 50: 160-7, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26820103

RESUMEN

Suppressor of cytokine signaling (SOCS) proteins are inverse feedback regulators of cytokine and hormone signaling mediated by the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway that are involved in immunity, growth and development of organisms. In the present study, three SOCS genes, SOCS-1, SOCS-2 and SOCS-3, were identified in an economically important fish, Nile tilapia (Oreochromis niloticus) referred to as NtSOCS-1, NtSOCS-2 and NtSOCS-3. Multiple alignments showed that, the three SOCS molecules share highly conserved functional domains, including the SRC homology 2 (SH2) domain, the extended SH2 subdomain (ESS) and the SOCS box with others vertebrate counterparts. Phylogenetic analysis indicated that NtSOCS-1, 2 and 3 belong to the SOCS type II subfamily. Whereas NtSOCS-1 and 3 showed close evolutionary relationship with Perciformes, NtSOCS-2 was more related to Salmoniformes. Tissue specific expression results showed that, NtSOCS-1, 2 and 3 were constitutively expressed in all nine tissues examined. NtSOCS-1 and 3 were highly expressed in immune-related tissues, such as gills, foregut and head kidney. However, NtSOCS-2 was superlatively expressed in liver, brain and heart. In vivo, NtSOCS-1 and 3 mRNA levels were up-regulated after lipopolysaccharide (LPS) challenge while NtSOCS-2 was down-regulated. In vitro, LPS stimulation increased NtSOCS-3 mRNA expression, however it inhibited the transcription of NtSOCS-1 and 2. Collectively, our findings suggest that, the NtSOCS-1 and 3 might play significant role(s) in innate immune response, while NtSOCS-2 may be more involved in metabolic regulation.


Asunto(s)
Cíclidos/genética , Proteínas de Peces/genética , Inmunidad Innata , Proteínas Supresoras de la Señalización de Citocinas/genética , Secuencia de Aminoácidos , Animales , Cíclidos/metabolismo , Clonación Molecular , ADN Complementario/genética , ADN Complementario/metabolismo , Escherichia coli/química , Proteínas de Peces/química , Proteínas de Peces/metabolismo , Inmunidad Innata/efectos de los fármacos , Lipopolisacáridos/farmacología , Conformación Molecular , Especificidad de Órganos , Filogenia , ARN Mensajero/genética , ARN Mensajero/metabolismo , Alineación de Secuencia/veterinaria , Proteínas Supresoras de la Señalización de Citocinas/química , Proteínas Supresoras de la Señalización de Citocinas/metabolismo
12.
Biochim Biophys Acta ; 1843(11): 2775-83, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24983770

RESUMEN

Ferritin light chain (FTL) reduces the free iron concentration by forming ferritin complexes with ferritin heavy chain (FTH). Thus, FTL competes with the Fenton reaction by acting as an antioxidant. In the present study, we determined that FTL influences the lipopolysaccharide (LPS)-induced inflammatory response. FTL protein expression was regulated by LPS stimulation in RAW264.7 cells. To investigate the role of FTL in LPS-activated murine macrophages, we established stable FTL-expressing cells and used shRNA to silence FTL expression in RAW264.7 cells. Overexpression of FTL significantly decreased the LPS-induced production of tumor necrosis factor alpha (TNF-α), interleukin 1ß (IL-1ß), nitric oxide (NO) and prostaglandin E2 (PGE2). Additionally, overexpression of FTL decreased the LPS-induced increase of the intracellular labile iron pool (LIP) and reactive oxygen species (ROS). Moreover, FTL overexpression suppressed the LPS-induced activation of MAPKs and nuclear factor-κB (NF-κB). In contrast, knockdown of FTL by shRNA showed the reverse effects. Therefore, our results indicate that FTL plays an anti-inflammatory role in response to LPS in murine macrophages and may have therapeutic potential for treating inflammatory diseases.

13.
Biochem Biophys Res Commun ; 465(2): 305-11, 2015 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-26277391

RESUMEN

To examine the role of the intracellular labile iron pool (LIP) in the induction of inflammatory responses, we investigated the anti-inflammatory effect of the iron chelator deferoxamine (DFO) on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 macrophage cells and endotoxic shock in mice in the present study. Our data showed that DFO significantly decreased LPS-induced LIP and ROS upregulation. We then found that DFO inhibited phosphorylation of MAP kinases such as ERK and p38 and also inhibited the activation of NF-κB induced by LPS. Furthermore, the production of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), nitric oxide (NO) and prostaglandin E2 (PGE2) induced by LPS was inhibited by DFO in RAW264.7 macrophages. Administration of DFO significantly decreased the mortality and improved the survival of septic mice with lethal endotoxemia in LPS-injected mice. These results demonstrate that iron plays a pivotal role in the induction of inflammatory responses and against septic shock. DFO has effective inhibitory effect on the production of inflammatory mediators via suppressing activation of MAPKs and NF-κB signaling pathways; it also has a protective effect on LPS-induced endotoxic shock in mice. Our findings open doors to further studies directed at exploring a new class of drugs against septic shock or other inflammatory diseases by modulating cellular chelatable iron.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Deferoxamina/farmacología , Quelantes del Hierro/farmacología , Hierro/metabolismo , Choque Séptico/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/metabolismo , Línea Celular , Deferoxamina/metabolismo , Dinoprostona/antagonistas & inhibidores , Dinoprostona/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación de la Expresión Génica , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Quelantes del Hierro/metabolismo , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Choque Séptico/inducido químicamente , Choque Séptico/metabolismo , Choque Séptico/mortalidad , Transducción de Señal , Análisis de Supervivencia , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
14.
Gen Comp Endocrinol ; 223: 139-47, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-26002036

RESUMEN

Peroxisome proliferator activated receptor gamma (PPARγ) is a master regulator in lipid metabolism and widely exists in vertebrates. However, the molecular structure and transcriptional activity of PPARγ in fish are still unclear. This study cloned PPARγ from Nile tilapia (Oreochromis niloticus) referred as NtPPARγ and transfected the NtPPARγ plasmids into HEK-293 cells to explore its mechanism of transcriptional regulation in fish. The expression of NtPPARγ was compared in fed and fasted fish. Two transcripts of NtPPARγ varied at the 5'-untranslated region and the DNA binding domain was highly conserved. Thirty-nine amino acid residues in the ligand binding domain in Nile tilapia were different from those in human. Two transcripts showed different expression profiles in 11 tissues, but both were highly expressed in liver, intestine and kidney. The transcriptional activity assay showed that NtPPARγ collaborates with retinoid X-receptor α (NtRXRα) to regulate the expression of Nile tilapia fatty acid binding protein 4 (FABP4), the compartment of which have been identified as the target gene of PPARγ in human. In the fish fasting trial, the mRNA expression of NtPPARγ1 and NtPPARγ2 in intestine and liver at 3h post-feeding (HPF) was lower than those at 8 HPF, 24 HPF and in fish fasted for 36h, but was relatively stable in kidney among different feeding treatments. In conclusion, the DNA binding domain in PPARγ was highly conserved, while the ligand binding domain was moderately conserved. In Nile tilapia, the PPARγ collaborates with RXRα to perform transcriptional regulation of FABP4 at least in vitro. The plasmid system established in this study along with a cell line from Nile tilapia will be useful tools for the further functional study of PPARγ in fish.


Asunto(s)
Cíclidos/metabolismo , Ingestión de Alimentos/fisiología , Ayuno/fisiología , Proteínas de Unión a Ácidos Grasos/genética , Proteínas de Peces/metabolismo , Regulación de la Expresión Génica , PPAR gamma/metabolismo , Receptor alfa X Retinoide/metabolismo , Secuencia de Aminoácidos , Animales , Células Cultivadas , Cíclidos/genética , Cíclidos/crecimiento & desarrollo , Clonación Molecular , ADN Complementario/genética , Proteínas de Peces/genética , Células HEK293 , Humanos , Datos de Secuencia Molecular , PPAR gamma/química , PPAR gamma/genética , Filogenia , Conformación Proteica , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor alfa X Retinoide/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Aminoácido , Activación Transcripcional
15.
J Diabetes ; 16(1): e13467, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37646182

RESUMEN

AIM: Iron homeostasis is critical for functional respiratory chain complex of mitochondrial, thus potentially contributing to fat biology and energy homeostasis. Transferrin receptor (Tfrc) binds to transferrin for extracellular iron uptake and is recently reported to be involved in brown fat development and functionality. However, whether TFRC levels and variants are associated with human obesity is unknown. METHODS: To investigate the association of TFRC levels and variants with human obesity, fat biopsies were obtained from surgery. Exon-sequencing and genetic assessments were conducted of a case-control study. For TFRC levels assessment in fat biopsy, 9 overweight and 12 lean subjects were involved. For genetic study, obese (n = 1271) and lean subjects (n = 1455) were involved. TFRC levels were compared in abdominal mesenteric fat of pheochromocytoma patients versus control subjects, and overweight versus lean subjects. For genetic study, whole-exome sequencing of obese and matched control subjects were conducted and analyzed. In addition, the possible disruption in protein stability of TFRC variant was assessed by structural and molecular analysis. RESULTS: TFRC levels are increased in human browning adipose tissue and decreased in fat of overweight patients. Besides, TFRC levels are negatively correlated with body mass index and positively correlated with uncoupling protein 1 levels. Furthermore, a rare heterozygous missense variant p.I337V in TFRC shows a tendency to enrich in obese subjects. Structural and functional study reveals impaired protein stability of the TFRC variant compared to wild-type. CONCLUSIONS: Reduced TFRC levels and its rare variant p.I337V with protein instability are associated with human obesity.


Asunto(s)
Obesidad , Sobrepeso , Humanos , Tejido Adiposo Pardo/metabolismo , Estudios de Casos y Controles , Hierro , Obesidad/metabolismo , Receptores de Transferrina/genética
16.
Diabetes ; 72(4): 467-482, 2023 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-36607240

RESUMEN

The de novo differentiation of hyperplastic adipocytes from adipocyte progenitor cells (APCs) is accompanied by a reduction in adipose tissue fibrosis and inflammation and improvement in insulin sensitivity in obesity and aging. However, the regulators of APC proliferation are poorly understood. Here, we show that fibroblast growth factor 6 (FGF6) acts in an autocrine and/or paracrine manner to control platelet-derived growth factor receptor α-positive APC proliferation via extracellular signal-regulated kinase (ERK) signaling. Specific FGF6 overexpression in inguinal white adipose tissue (iWAT) improved the signs of high-fat diet- or aging-induced adipose hypertrophy and insulin resistance. Conversely, chronic FGF6 expression blockade in iWAT, mediated by a neutralizing antibody or Fgf6 expression deficiency, impaired adipose tissue expansion and glucose tolerance. Overall, our data suggest that FGF6 acts as a proliferative factor for APCs to maintain fat homeostasis and insulin sensitivity.


Asunto(s)
Resistencia a la Insulina , Neoplasias , Animales , Ratones , Factor 6 de Crecimiento de Fibroblastos/metabolismo , Tejido Adiposo/metabolismo , Adipocitos/metabolismo , Tejido Adiposo Blanco/metabolismo , Obesidad/metabolismo , Neoplasias/metabolismo , Proliferación Celular , Homeostasis , Dieta Alta en Grasa , Ratones Endogámicos C57BL
17.
Aging Cell ; 22(10): e13961, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37584432

RESUMEN

Sarcopenia is characterized of muscle mass loss and functional decline in elder individuals which severely affects human physical activity, metabolic homeostasis, and life quality. Physical exercise is considered effective in combating muscle atrophy and sarcopenia, yet it is not feasible to elders with limited mobility. PGC-1α4, a short isoform of PGC-1α, is strongly induced in muscle under resistance training, and promotes muscle hypertrophy. In the present study, we showed that the transcriptional levels and nuclear localization of PGC1α4 was reduced during aging, accompanied with muscle dystrophic morphology, and gene programs. We thus designed NLS-PGC1α4 and ectopically express it in myotubes to enhance PGC1α4 levels and maintain its location in nucleus. Indeed, NLS-PGC1α4 overexpression increased muscle sizes in myotubes. In addition, by utilizing AAV-NLS-PGC1α4 delivery into gastrocnemius muscle, we found that it could improve sarcopenia with grip strength, muscle weights, fiber size and molecular phenotypes, and alleviate age-associated adiposity, insulin resistance and hepatic steatosis, accompanied with altered gene signatures. Mechanistically, we demonstrated that NLS-PGC-1α4 improved insulin signaling and enhanced glucose uptake in skeletal muscle. Besides, via RNA-seq analysis, we identified myokines IGF1 and METRNL as potential targets of NLS-PGC-1α4 that possibly mediate the improvement of muscle and adipose tissue functionality and systemic energy metabolism in aged mice. Moreover, we found a negative correlation between PGC1α4 and age in human skeletal muscle. Together, our results revealed that NLS-PGC1α4 overexpression improves muscle physiology and systematic energy homeostasis during aging and suggested it as a potent therapeutic strategy against sarcopenia and aging-associated metabolic diseases.


Asunto(s)
Sarcopenia , Ratones , Humanos , Animales , Anciano , Sarcopenia/genética , Sarcopenia/metabolismo , Envejecimiento/metabolismo , Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
18.
Adv Sci (Weinh) ; 10(25): e2300436, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37407508

RESUMEN

N6-methyladenosine (m6 A) modification has been implicated in the progression of obesity and metabolic diseases. However, its impact on beige fat biology is not well understood. Here, via m6 A-sequencing and RNA-sequencing, this work reports that upon beige adipocytes activation, glycolytic genes undergo major events of m6 A modification and transcriptional activation. Genetic ablation of m6 A writer Mettl3 in fat tissues reveals that Mettl3 deficiency in mature beige adipocytes leads to suppressed glycolytic capability and thermogenesis, as well as reduced preadipocytes proliferation via glycolytic product lactate. In addition, specific modulation of Mettl3 in beige fat via AAV delivery demonstrates consistently Mettl3's role in glucose metabolism, thermogenesis, and beige fat hyperplasia. Mechanistically, Mettl3 and m6 A reader Igf2bp2 control mRNA stability of key glycolytic genes in beige adipocytes. Overall, these findings highlight the significance of m6 A on fat biology and systemic energy homeostasis.


Asunto(s)
Tejido Adiposo Beige , Glucólisis , Metilación , Tejido Adiposo Beige/metabolismo , Glucólisis/genética , Homeostasis/genética , ARN/metabolismo
19.
JHEP Rep ; 5(12): 100906, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38023606

RESUMEN

Background & Aims: Liver regeneration is vital for the recovery of liver function after injury, yet the underlying mechanism remains to be elucidated. Forkhead box protein A3 (FOXA3), a member of the forkhead box family, plays important roles in endoplasmic reticulum stress sensing, and lipid and glucose homoeostasis, yet its functions in liver regeneration are unknown. Methods: Here, we explored whether Foxa3 regulates liver regeneration via acute and chronic liver injury mice models. We further characterised the molecular mechanism by chromatin immunoprecipitation sequencing and rescue experiments in vivo and in vitro. Then, we assessed the impact of Foxa3 pharmacological activation on progression and termination of liver regeneration. Finally, we confirmed the Foxa3-Cebpb axis in human liver samples. Results: Foxa3 is dominantly expressed in hepatocytes and cholangiocytes and is induced upon partial hepatectomy (PH) or carbon tetrachloride (CCl4) administration. Foxa3 deficiency in mice decreased cyclin gene levels and delayed liver regeneration after PH, or acute or chronic i.p. CCl4 injection. Conversely, hepatocyte-specific Foxa3 overexpression accelerated hepatocytes proliferation and attenuated liver damage in an CCl4-induced acute model. Mechanistically, Foxa3 directly regulates Cebpb transcription, which is involved in hepatocyte division and apoptosis both in vivo and in vitro. Of note, Cebpb overexpression in livers of Foxa3-deficient mice rescued their defects in cell proliferation and regeneration upon CCl4 treatment. In addition, pharmacological induction of Foxa3 via cardamonin speeded up hepatocyte proliferation after PH, without interfering with liver regeneration termination. Finally, Cebpb and Ki67 levels had a positive correlation with Foxa3 expression in human chronic disease livers. Conclusions: These data characterise Foxa3 as a vital regulator of liver regeneration, which may represent an essential factor to maintain liver mass after liver injury by governing Cebpb transcription. Impact and Implications: Liver regeneration is vital for the recovery of liver function after chemical insults or hepatectomy, yet the underlying mechanism remains to be elucidated. Herein, via in vitro and in vivo models and analysis, we demonstrated that Forkhead box protein A3 (FOXA3), a Forkhead box family member, maintained normal liver regeneration progression by governing Cebpb transcription and proposed cardamonin as a lead compound to induce Foxa3 and accelerate liver repair, which signified that FOXA3 may be a potential therapeutic target for further preclinical study on treating liver injury.

20.
Front Endocrinol (Lausanne) ; 13: 851520, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35265044

RESUMEN

Nonalcoholic fatty liver disease (NAFLD), characterized by extensive triglyceride accumulation in hepatocytes, may progress to nonalcoholic steatohepatitis (NASH) with liver fibrosis and inflammation and increase the risk of cirrhosis, cancer, and death. It has been reported that physical exercise is effective in ameliorating NAFLD and NASH, while skeletal muscle dysfunctions, including lipid deposition and weakness, are accompanied with NAFLD and NASH. However, the molecular characteristics and alterations in skeletal muscle in the progress of NAFLD and NASH remain unclear. In the present study, we provide a comprehensive analysis on the similarity and heterogeneity of quadriceps muscle in NAFLD and NASH mice models by RNA sequencing. Importantly, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway functional enrichment analysis revealed that NAFLD and NASH led to impaired glucose and lipid metabolism and deteriorated functionality in skeletal muscle. Besides this, we identified that myokines possibly mediate the crosstalk between muscles and other metabolic organs in pathological conditions. Overall, our analysis revealed a comprehensive understanding of the molecular signature of skeletal muscles in NAFLD and NASH, thus providing a basis for physical exercise as an intervention against liver diseases.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Perfilación de la Expresión Génica , Inflamación/patología , Cirrosis Hepática , Ratones , Músculo Esquelético/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo
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