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Sterol regulatory element-binding protein (SREBP)-1c is involved in cellular lipid homeostasis and cholesterol biosynthesis and is highly increased in nonalcoholic steatohepatitis (NASH). However, the molecular mechanism by which SREBP-1c regulates hepatic stellate cells (HSCs) activation in NASH animal models and patients have not been fully elucidated. In this study, we examined the role of SREBP-1c in NASH and the regulation of LCN2 gene expression. Wild-type and SREBP-1c knockout (1cKO) mice were fed a high-fat/high-sucrose diet, treated with carbon tetrachloride (CCl4), and subjected to lipocalin-2 (LCN2) overexpression. The role of LCN2 in NASH progression was assessed using mouse primary hepatocytes, Kupffer cells, and HSCs. LCN2 expression was examined in samples from normal patients and those with NASH. LCN2 gene expression and secretion increased in CCl4-induced liver fibrosis mice model, and SREBP-1c regulated LCN2 gene transcription. Moreover, treatment with holo-LCN2 stimulated intracellular iron accumulation and fibrosis-related gene expression in mouse primary HSCs, but these effects were not observed in 1cKO HSCs, indicating that SREBP-1c-induced LCN2 expression and secretion could stimulate HSCs activation through iron accumulation. Furthermore, LCN2 expression was strongly correlated with inflammation and fibrosis in patients with NASH. Our findings indicate that SREBP-1c regulates Lcn2 gene expression, contributing to diet-induced NASH. Reduced Lcn2 expression in 1cKO mice protects against NASH development. Therefore, the activation of Lcn2 by SREBP-1c establishes a new connection between iron and lipid metabolism, affecting inflammation and HSCs activation. These findings may lead to new therapeutic strategies for NASH.
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Ferro , Lipocalina-2 , Cirrose Hepática , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica , Proteína de Ligação a Elemento Regulador de Esterol 1 , Animais , Humanos , Masculino , Camundongos , Tetracloreto de Carbono/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Ferro/metabolismo , Lipocalina-2/metabolismo , Lipocalina-2/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Cirrose Hepática/induzido quimicamente , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genéticaRESUMO
Adipose-derived stem cells (ADSCs) play an important role in the differential capacity for excess energy storage between upper body abdominal (ABD) adipose tissue (AT) and lower body gluteofemoral (GF) AT. We cultured ADSCs from subcutaneous ABD AT and GF AT isolated from eight women with differential body fat distribution and performed single-cell RNA sequencing. Six populations of ADSCs were identified and segregated according to their anatomical origin. The three ADSC subpopulations in GF AT were characterized by strong cholesterol/fatty acid (FA) storage and proliferation signatures. The two ABD subpopulations, differentiated by higher expression of committed preadipocyte marker genes, were set apart by differential expression of extracellular matrix and ribosomal genes. The last population, identified in both depots, was similar to smooth muscle cells and when individually isolated and cultured in vitro they differentiated less than the other subpopulations. This work provides important insight into the use of ADSC as an in vitro model of adipogenesis and suggests that specific subpopulations of GF-ADSCs contribute to the more robust capacity for GF-AT to expand and grow compared with ABD-AT in women.NEW & NOTEWORTHY Identification of distinct subpopulations of adipose-derived stem cells (ADSCs) in upper body abdominal subcutaneous (ABD) and lower body gluteofemoral subcutaneous (GF) adipose tissue depots. In ABD-ADSCs, subpopulations are more committed to adipocyte lineage. GF-ADSC subpopulations are enriched for genes involved in lipids and cholesterol metabolism. Similar depot differences were found in stem cell population identified in freshly isolated stoma vascular fraction. The repertoire of ADSCs subpopulations was different in apple-shaped versus pear-shaped women.
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Tecido Adiposo , Gordura Subcutânea , Humanos , Feminino , Tecido Adiposo/metabolismo , Adipócitos/metabolismo , Análise de Sequência de RNA , Colesterol/metabolismoRESUMO
Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of ß-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to ß-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.
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The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.
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Proteína Quinase C , Transdução de Sinais , Animais , Humanos , Camundongos , Transformação Celular Neoplásica/genética , Colesterol , Células Epiteliais/metabolismo , Proteína Quinase C/genética , Proteína Quinase C/metabolismoRESUMO
In mammals, O2 and CO2 levels are tightly regulated and are altered under various pathological conditions. While the molecular mechanisms that participate in O2 sensing are well characterized, little is known regarding the signaling pathways that participate in CO2 signaling and adaptation. Here, we show that CO2 levels control a distinct cellular transcriptional response that differs from mere pH changes. Unexpectedly, we discovered that CO2 regulates the expression of cholesterogenic genes in a SREBP2-dependent manner and modulates cellular cholesterol accumulation. Molecular dissection of the underlying mechanism suggests that CO2 triggers SREBP2 activation through changes in endoplasmic reticulum (ER) membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO2 signaling and that cellular cholesterol levels can be modulated by CO2 through SREBP2.
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Dióxido de Carbono , Colesterol , Animais , Colesterol/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Mamíferos/metabolismoRESUMO
Trabecular meshwork (TM) cells are contractile and mechanosensitive, and they aid in maintaining intraocular pressure (IOP) homeostasis. Lipids are attributed to modulating TM contractility, with poor mechanistic understanding. In this study using human TM cells, we identify the mechanosensing role of the transcription factors sterol regulatory element binding proteins (SREBPs) involved in lipogenesis. By constitutively activating SREBPs and pharmacologically inactivating SREBPs, we have mechanistically deciphered the attributes of SREBPs in regulating the contractile properties of TM. The pharmacological inhibition of SREBPs by fatostatin and molecular inactivation of SREBPs ex vivo and in vivo, respectively, results in significant IOP lowering. As a proof of concept, fatostatin significantly decreased the SREBPs responsive genes and enzymes involved in lipogenic pathways as well as the levels of the phospholipid, cholesterol, and triglyceride. Further, we show that fatostatin mitigated actin polymerization machinery and stabilization, and decreased ECM synthesis and secretion. We thus postulate that lowering lipogenesis in the TM outflow pathway can hold the key to lowering IOP by modifying the TM biomechanics.
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Pressão Intraocular , Proteínas de Ligação a Elemento Regulador de Esterol , Humanos , Mecanotransdução Celular , Fatores de Transcrição/genéticaRESUMO
Trabecular meshwork (TM) cells are highly contractile and mechanosensitive to aid in maintaining intraocular pressure (IOP) homeostasis. Lipids are attributed to modulating TM contractility with poor mechanistic understanding. In this study using human TM cells, we identify the mechanosensing role of the transcription factors sterol regulatory element binding proteins (SREBPs) involved in lipogenesis. By constitutively activating SREBPs and pharmacologically inactivating SREBPs, we have mechanistically deciphered the attributes of SREBPs in regulating the contractile properties of TM. The pharmacological inhibition of SREBPs by fatostatin and molecular inactivation of SREBPs ex vivo and in vivo respectively results in significant IOP lowering. As a proof of concept, fatostatin significantly decreased the SREBPs responsive genes and enzymes involved in lipogenic pathways as well as the levels of the phospholipid, cholesterol, and triglyceride. Further, we show that fatostatin mitigated actin polymerization machinery and stabilization, and decreased ECM synthesis and secretion. We thus postulate that lowering lipogenesis in the TM outflow pathway can hold the key to lowering IOP by modifying the TM biomechanics. Synopsis: In this study, we show the role of lipogenic transcription factors sterol regulatory element binding proteins (SREBPs) in the regulation of intraocular pressure (IOP). ( Synopsis Figure - Created using Biorender.com ) SREBPs are involved in the sensing of changes in mechanical stress on the trabecular meshwork (TM). SREBPs aid in transducing the mechanical signals to induce actin polymerization and filopodia/lamellipodia formation.SREBPs inactivation lowered genes and enzymes involved in lipogenesis and modified lipid levels in TM.SREBPs activity is a critical regulator of ECM engagement to the matrix sites.Inactivation of SCAP-SREBP pathway lowered IOP via actin relaxation and decreasing ECM production and deposition in TM outflow pathway signifying a novel relationship between SREBP activation status and achieving IOP homeostasis.
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BACKGROUND: It has previously been shown that CT scans performed for other indications can be used to identify patients with osteoporosis. This has not yet been tested in a British population. We sought to evaluate the use of vertebral CT attenuation measures for predicting osteoporosis in a British cohort, using dual-energy X-ray absorptiometry (DEXA) as a reference standard. METHODS: Patients who underwent abdominal CT in 2018 and concomitantly underwent DEXA within a six-month interval were retrospectively included. CT attenuation values in Hounsfield units (HU) were measured by placement of a region-of-interest at the central portion of the L1 vertebral body and then compared to their corresponding DEXA score. Receiver operating characteristic (ROC) curves were generated to evaluate the performance of a logistic regression model and to determine sensitivity and specificity thresholds. RESULTS: 536 patients (394 females, mean age 65.8) were included, of which 174 had DEXA-defined osteoporosis. L1 attenuation measures were significantly different (p < 0.01) between the three DEXA-defined groups of osteoporosis (118 HU), osteopenia (143 HU) and normal bone density (178 HU). The area under the ROC curve was 0.74 (95% CI 0.69-0.78). A threshold of 169 HU was 90% sensitive, and a threshold of 104 HU was 90% specific for diagnosing osteoporosis. CONCLUSIONS: Routine abdominal CT can be used to opportunistically screen for osteoporosis without additional cost or radiation exposure. The thresholds identified in this study are comparable with previous studies in other populations. We recommend radiologists engage with primary care and rheumatology providers to determine appropriate cut-off values for further investigation.
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AIM: We look at the effect of introducing the faecal immunochemical test (FIT) in the straight-to-test 2-week pathway for change in bowel habit (CIBH). METHOD: The FIT in primary care triages 2-week wait (2WW) colorectal referrals for patients aged 60 years and above for straight-to-test CT colonography (CTC). We compare the impact of the FIT on numbers of 2WW CTCs, in the year before and after FIT, in both colorectal cancer (CRC) detection and cost-effectiveness at both 4 µg Hb/g faeces and 10 µg Hb/g faeces. RESULTS: At a threshold of 4 µg Hb/g faeces, the positive predictive value of the FIT for diagnosis of CRC is 5.0% with a negative predictive value of 99.8% and a polyp detection rate of 25.5%. The introduction of the FIT resulted in a reduction in the number of CTCs performed through the CIBH pathway from a mean of 143.9 per month prior to the FIT to 66.8 CTCs per month once the FIT was well established. Given a FIT threshold of 10 µg Hb/g the number of CTCs would be predicted to fall by 70.4% to 42.6 CTCs per month resulting in higher CRC and polyp detection rate, and an estimated annual cost saving of £238 258 in our institution. CONCLUSION: The FIT use in primary care improves the yield of 2WW referrals for CIBH alone and reduces the burden and cost of investigations to exclude CRC. Improvements may be possible by increasing the cut-off employed, without adversely affecting the risk of missing a cancer.
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Neoplasias Colorretais , Humanos , Neoplasias Colorretais/diagnóstico , Sensibilidade e Especificidade , Hemoglobinas/análise , Valor Preditivo dos Testes , Colonoscopia , Fezes/química , Sangue Oculto , Detecção Precoce de Câncer/métodos , HábitosRESUMO
Our previous study using systems vaccinology identified an association between the sterol regulatory binding protein (SREBP) pathway and humoral immune response to vaccination in humans. To investigate the role of SREBP signaling in modulating immune responses, we generated mice with B cell- or CD11c+ antigen-presenting cell (APC)-specific deletion of SCAP, an essential regulator of SREBP signaling. Ablation of SCAP in CD11c+ APCs had no effect on immune responses. In contrast, SREBP signaling in B cells was critical for antibody responses, as well as the generation of germinal centers,memory B cells and bone marrow plasma cells. SREBP signaling was required for metabolic reprogramming in activated B cells. Upon mitogen stimulation, SCAP-deficient B cells could not proliferate and had decreased lipid rafts. Deletion of SCAP in germinal center B cells using AID-Cre decreased lipid raft content and cell cycle progression. These studies provide mechanistic insights coupling sterol metabolism with the quality and longevity of humoral immunity.
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Proteínas de Transporte , Linfoma de Células B , Esteróis , Animais , Humanos , Camundongos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Esteróis/metabolismo , Linfoma de Células B/metabolismoRESUMO
INTRODUCTION: Sterol regulatory element binding protein (SREBP) cleavage-associating protein (SCAP) is a sterol-regulated escort protein that translocates SREBPs from the endoplasmic reticulum to the Golgi apparatus, thereby activating lipid metabolism and cholesterol synthesis. Although SCAP regulates lipid metabolism in metabolic tissues, such as the liver and muscle, the effect of macrophage-specific SCAP deficiency in adipose tissue macrophages (ATMs) of patients with metabolic diseases is not completely understood. OBJECTIVES: Here, we examined the function of SCAP in high-fat/high-sucrose diet (HFHS)-fed mice and investigated its role in the polarization of classical activated macrophages in adipose tissue. METHODS: Macrophage-specific SCAP knockout (mKO) mice were generated through crossbreeding lysozyme 2-cre mice with SCAP floxed mice which were then fed HFHS for 12 weeks. Primary macrophages were derived from bone marrow cells and analyzed further. RESULTS: We found that fat accumulation and the appearance of proinflammatory M1 macrophages were both higher in HFHS-fed SCAP mKO mice relative to floxed control mice. We traced the effect to a defect in the lipopolysaccharide-mediated increase in SREBP-1a that occurs in control but not SCAP mKO mice. Mechanistically, SREBP-1a increased expression of cholesterol 25-hydroxylase transcription, resulting in an increase in the production of 25-hydroxycholesterol (25-HC), an endogenous agonist of liver X receptor alpha (LXRα) which increased expression of cholesterol efflux to limit cholesterol accumulation and M1 polarization. In the absence of SCAP mediated activation of SREBP-1a, increased M1 macrophage polarization resulted in reduced cholesterol efflux downstream from 25-HC-dependent LXRα activation. CONCLUSION: Overall, the activation of the SCAP-SREBP-1a pathway in macrophages may provide a novel therapeutic strategy that ameliorates obesity by controlling cholesterol homeostasis in ATMs.
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Resistência à Insulina , Camundongos , Animais , Proteína de Ligação a Elemento Regulador de Esterol 1 , Peptídeos e Proteínas de Sinalização Intracelular , Colesterol , ObesidadeRESUMO
Determining the mechanism driving body fat distribution will provide insights into obesity-related health risks. We used functional genomics tools to profile the epigenomic landscape to help infer the differential transcriptional potential of apple- and pear-shaped women's subcutaneous adipose-derived stem cells (ADSCs). We found that CCCTC-binding factor (CTCF) expression and its chromatin binding were increased in ADSCs from pear donors compared to those from apple donors. Interestingly, the pear enriched CTCF binding sites were located predominantly at the active transcription start sites (TSSs) of genes with active histone marks and YY1 motifs and were also associated with pear enriched RNAPII binding. In contrast, apple enriched CTCF binding sites were mainly found at intergenic regions and when identified at TSS, they were enriched with the bivalent chromatin signatures. Altogether, we provide evidence that CTCF plays an important role in differential regulation of subcutaneous ADSCs gene expression and may influence the development of apple vs. pear body shape.
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Regulação da Expressão Gênica , Fatores de Transcrição , Feminino , Humanos , Fator de Ligação a CCCTC , Cromatina , Gordura SubcutâneaRESUMO
The genome of human adipose-derived stem cells (ADSCs) from abdominal and gluteofemoral adipose tissue depots are maintained in depot-specific stable epigenetic conformations that influence cell-autonomous gene expression patterns and drive unique depot-specific functions. The traditional approach to explore tissue-specific transcriptional regulation has been to correlate differential gene expression to the nearest-neighbor linear-distance regulatory region defined by associated chromatin features including open chromatin status, histone modifications, and DNA methylation. This has provided important information; nonetheless, the approach is limited because of the known organization of eukaryotic chromatin into a topologically constrained three-dimensional network. This network positions distal regulatory elements in spatial proximity with gene promoters which are not predictable based on linear genomic distance. In this work, we capture long-range chromatin interactions using HiChIP to identify remote genomic regions that influence the differential regulation of depot-specific genes in ADSCs isolated from different adipose depots. By integrating these data with RNA-seq results and histone modifications identified by ChIP-seq, we uncovered distal regulatory elements that influence depot-specific gene expression in ADSCs. Interestingly, a subset of the HiChIP-defined chromatin loops also provide previously unknown connections between waist-to-hip ratio GWAS variants with genes that are known to significantly influence ADSC differentiation and adipocyte function.
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Adipócitos , Ascomicetos , Humanos , Regiões Promotoras Genéticas , Tecido Adiposo , Cromatina/genética , Células-TroncoRESUMO
The biosynthesis of host lipids and/or lipid droplets (LDs) has been studied extensively as a putative therapeutic target in diverse viral infections. However, directly targeting the LD lipolytic catabolism in virus-infected cells has not been widely investigated. Here, we show the linkage of the LD-associated lipase activation to the breakdown of LDs for the generation of free fatty acids (FFAs) at the late stage of diverse RNA viral infections, which represents a broad-spectrum antiviral target. Dysfunction of membrane transporter systems due to virus-induced cell injury results in intracellular malnutrition at the late stage of infection, thereby making the virus more dependent on the FFAs generated from LD storage for viral morphogenesis and as a source of energy. The replication of SARS-CoV-2 and influenza A virus (IAV), which is suppressed by the treatment with LD-associated lipases inhibitors, is rescued by supplementation with FFAs. The administration of lipase inhibitors, either individually or in a combination with virus-targeting drugs, protects mice from lethal IAV infection and mitigates severe lung lesions in SARS-CoV-2-infected hamsters. Moreover, the lipase inhibitors significantly reduce proinflammatory cytokine levels in the lungs of SARS-CoV-2- and IAV-challenged animals, a cause of a cytokine storm important for the critical infection or mortality of COVID-19 and IAV patients. In conclusion, the results reveal that lipase-mediated intracellular LD lipolysis is commonly exploited to facilitate RNA virus replication and furthermore suggest that pharmacological inhibitors of LD-associated lipases could be used to curb current COVID-19- and future pandemic outbreaks of potentially troublesome RNA virus infection in humans.
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Tratamento Farmacológico da COVID-19 , Lipólise , Infecções por Orthomyxoviridae , Animais , Humanos , Camundongos , Antivirais/farmacologia , Citocinas , Ácidos Graxos não Esterificados , Vírus da Influenza A , Lipase , Proteínas de Membrana Transportadoras , RNA , SARS-CoV-2 , Infecções por Orthomyxoviridae/tratamento farmacológicoRESUMO
Protein kinase A promotes beige adipogenesis downstream from ß-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1ß (MYPT1-PP1ß) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1ß depletion results in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1ß also dephosphorylates myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ which directly stimulates Ucp1 gene expression. Pre-adipocyte specific Mypt1 deficiency increases cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice, confirming this regulatory mechanism in vivo. Thus, we have uncovered regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of the mechano-sensitive YAP/TAZ transcriptional co-activators.
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Adipogenia , Cromatina , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Actomiosina , Adipogenia/genética , Animais , Proteínas Quinases Dependentes de AMP Cíclico , Epigênese Genética , Histonas , Lisina , Camundongos , Cadeias Leves de Miosina , Fosfatase de Miosina-de-Cadeia-Leve/genética , Monoéster Fosfórico HidrolasesRESUMO
Nonalcoholic fatty liver disease (NAFLD) is a major health concern that often associates with obesity and diabetes. Fatty liver is usually a benign condition, yet a fraction of individuals progress to severe forms of liver damage, including nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Elevated sterol regulatory element-binding protein-driven (SREBP-driven) hepatocyte lipid synthesis is associated with NAFLD in humans and mice. In this issue of the JCI, Kawamura, Matsushita, et al. evaluated the role of SREBP-dependent lipid synthesis in the development of NAFLD, NASH, and HCC in the phosphatase and tensin homolog-knockout (PTEN-knockout) NASH model. Deletion of the gene encoding SREBP cleavage-activating protein (SCAP) from the liver resulted in decreased hepatic lipids, as expected. However, SCAP deletion accelerated progression to more severe liver damage, including NASH and HCC. This study provides a note of caution for those pursuing de novo fat biosynthesis as a therapeutic intervention in human NASH.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Lipídeos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1RESUMO
Accumulation of fat above the waist is an important risk factor in developing obesity-related comorbidities independently of BMI or total fat mass. Deciphering the gene regulatory programs of the adipose tissue precursor cells within upper body or abdominal (ABD) and lower body or gluteofemoral (GF) depots is important to understand their differential capacity for lipid accumulation, maturation, and disease risk. Previous studies identified the HOX transcript antisense intergenic RNA (HOTAIR) as a GF-specific lncRNA; however, its role in adipose tissue biology is still unclear. Using three different approaches (silencing of HOTAIR in GF human adipose-derived stem cells [GF hASCs], overexpression of HOTAIR in ABD hASCs, and ChIRP-seq) to localize HOTAIR binding in GF hASC chromatin, we found that HOTAIR binds and modulates expression, both positively and negatively, of genes involved in adipose tissue-specific pathways, including adipogenesis. We further demonstrate a direct interaction between HOTAIR and genes with high RNAPII binding in their gene bodies, especially at their 3' ends or transcription end sites. Computational analysis suggests HOTAIR binds preferentially to the 3' ends of genes containing predicted strong RNA-RNA interactions with HOTAIR. Together, these results reveal a unique function for HOTAIR in hASC depot-specific regulation of gene expression.
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RNA Longo não Codificante , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Expressão Gênica , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Células-Tronco/metabolismoRESUMO
Adipocytes play an essential role in the maintenance of whole-body energy homeostasis. White adipocytes regulate energy storage, whereas brown and beige adipocytes regulate energy expenditure and heat production. De novo production of adipocytes (i.e. adipogenesis) and their functions are dynamically controlled by environmental cues. Environmental changes (e.g. temperature, nutrients, hormones, cytokines) are transmitted via intracellular signaling to facilitate short-term responses and long-term adaptation in adipocytes; however, the molecular mechanisms that link the environment and epigenome are poorly understood. Our recent studies have demonstrated that environmental cues dynamically regulate interactions between transcription factors and epigenomic chromatin regulators, which together trigger combinatorial changes in chromatin structure to influence gene expression in adipocytes. Thus, environmental sensing by the concerted action of multiple chromatin-associated protein complexes is a key determinant of the epigenetic regulation of adipocyte functions.
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Adipócitos Bege , Epigênese Genética , Adipócitos/metabolismo , Adipócitos Bege/metabolismo , Adipogenia/fisiologia , Cromatina/metabolismo , Termogênese/genéticaRESUMO
Polycystic ovary syndrome (PCOS) is often associated with metabolic syndrome features, including central obesity, suggesting that adipose tissue (AT) is a key organ in PCOS pathobiology. In this study, we compared both abdominal (ABD) and gluteofemoral (GF) subcutaneous AT in women with and without PCOS. ABD and GF subcutaneous ATs from PCOS and BMI/WHR-matched control women were analyzed by RT-qPCR, FACS and histology. ABD and GF adipose-derived stem cell (ASC) transcriptome and methylome were analyzed by RNA-seq and DNA methylation array. Similar to the control group with abdominal obesity, the GF AT of PCOS women showed lower expression of genes involved in lipid accumulation and angiogenesis compared to ABD depot. FACS analysis revealed an increase in preadipocytes number in both AT depots from PCOS. Further pathway analysis of RNA-seq comparisons demonstrated that the ASCs derived from PCOS are pro-inflammatory and exhibit a hypoxic signature in the ABD depot and have lower expression of adipogenic genes in GF depot. We also found a higher CpG methylation level in PCOS compared to control exclusively in GF-ASCs. Our data suggest that ASCs play an important role in the etiology of PCOS, potentially by limiting expansion of the healthy lower-body AT.
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Síndrome do Ovário Policístico , Tecido Adiposo , Metilação de DNA/genética , Feminino , Humanos , Obesidade/genética , Obesidade Abdominal , Síndrome do Ovário Policístico/genética , Células-Tronco , Gordura SubcutâneaRESUMO
BACKGROUND: The COVID-19 pandemic had direct and indirect effects on health. Indirect effects on long term medical conditions (LTCs) are unclear. We examined trends in recorded incidences of LTCs and quantified differences between expected rates and observed rates from 2020 onwards. METHODS: This is a population data linkage study using primary and secondary care data within the Secure Anonymised Information Linkage Databank. We included data of Welsh residents diagnosed with any of 17 identified LTCs for the first time between Jan 1, 2000, and Dec 31, 2021. LTC's include mental health conditions, respiratory diseases, and heart conditions among others, generally chosen in line with the Quality and Outcomes Framework. The primary outcome was incidence rates (monthly number of new cases per 100â000 population). For each LTC, we did interrupted time series analysis of incidence rates from 2015 to 2021. Expected rates from between Jan 1, 2020, to Dec 31, 2021, were predicted using overall trends and seasonal patterns from the preceding 5 years and compared with observed rates. FINDINGS: We included 5â476â012 diagnoses from 2â257â992 individuals diagnosed with at least one LTC between Jan 1, 2000, to Dec 31, 2021. Across multiple long-term conditions, there was an abrupt reduction in observed incidence of new diagnoses from March to April 2020, followed by a general increase in incidence towards prepandemic rates. The conditions with the largest percentage difference between the observed and expected incidence rates in 2020 and 2021 were chronic obstructive pulmonary disease (38·4% lower than expected), depression (28·3% lower), hypertension (25·5% lower), and anxiety disorders (24·9% lower). The condition with the largest absolute difference between observed and expected incidence rates was anxiety disorders, with 830 per 100â000 less in 2020 and 2021 compared with observed rates. INTERPRETATION: The reduction in incidence rates of LTCs suggests an underreporting of LTCs, especially during 2020 and early 2021. The emergence of these yet undiagnosed cases could result in a surge of new patients in the near future. FUNDING: This work was supported by the Wales COVID-19 Evidence Centre, funded by Health and Care Research Wales.