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1.
Nat Med ; 25(9): 1385-1389, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501613

RESUMO

The worldwide obesity epidemic1 makes it important to understand how lipid turnover (the capacity to store and remove lipids) regulates adipose tissue mass. Cross-sectional studies have shown that excess body fat is associated with decreased adipose lipid removal rates2,3. Whether lipid turnover is constant over the life span or changes during long-term weight increase or loss is unknown. We determined the turnover of fat cell lipids in adults followed for up to 16 years, by measuring the incorporation of nuclear bomb test-derived 14C in adipose tissue triglycerides. Lipid removal rate decreases during aging, with a failure to reciprocally adjust the rate of lipid uptake resulting in weight gain. Substantial weight loss is not driven by changes in lipid removal but by the rate of lipid uptake in adipose tissue. Furthermore, individuals with a low baseline lipid removal rate are more likely to remain weight-stable after weight loss. Therefore, lipid turnover adaptation might be important for maintaining pronounced weight loss. Together these findings identify adipose lipid turnover as an important factor for the long-term development of overweight/obesity and weight loss maintenance in humans.


Assuntos
Envelhecimento/metabolismo , Peso Corporal/genética , Obesidade/metabolismo , Ganho de Peso/genética , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Adolescente , Adulto , Envelhecimento/genética , Envelhecimento/patologia , Peso Corporal/fisiologia , Radioisótopos de Carbono/química , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Masculino , Obesidade/genética , Obesidade/patologia , Sobrepeso/genética , Sobrepeso/metabolismo , Sobrepeso/patologia , Triglicerídeos/metabolismo , Perda de Peso/genética
2.
Adv Exp Med Biol ; 1161: 193-217, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562631

RESUMO

Headache is a common complaint after mild traumatic brain injury (mTBI). Changes in the CNS lipidome were previously associated with acrolein-induced headache in rodents. mTBI caused similar headache-like symptoms in rats; therefore, we tested the hypothesis that mTBI might likewise alter the lipidome. Using a stereotaxic impactor, rats were given either a single mTBI or a series of 4 mTBIs 48 h apart. 72 h later for single mTBI and 7 days later for repeated mTBI, the trigeminal ganglia (TG), trigeminal nucleus (TNC), and cerebellum (CER) were isolated. Using HPLC/MS/MS, ~80 lipids were measured in each tissue and compared to sham controls. mTBI drove widespread alterations in lipid levels. Single mTBI increased arachidonic acid and repeated mTBI increased prostaglandins in all 3 tissue types. mTBI affected multiple TRPV agonists, including N-arachidonoyl ethanolamine (AEA), which increased in the TNC and CER after single mTBI. After repeated mTBI, AEA increased in the TG, but decreased in the TNC. Common to all tissue types in single and repeated mTBI was an increase the AEA metabolite, N-arachidonoyl glycine, a potent activator of microglial migration. Changes in the CNS lipidome associated with mTBI likely play a role in headache and in long-term neurodegenerative effects of repeated mTBI.


Assuntos
Lesões Encefálicas Traumáticas , Sistema Nervoso Central , Cefaleia , Inflamação , Lipídeos , Neoplasias , Animais , Lesões Encefálicas Traumáticas/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Cefaleia/fisiopatologia , Inflamação/fisiopatologia , Lipídeos/química , Lipídeos/genética , Lipídeos/fisiologia , Neoplasias/fisiopatologia , Ratos
3.
Mar Drugs ; 17(6)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31195687

RESUMO

Bioassay-guided fractionation of marine-derived fungi revealed that the EtOAc fraction from the fermentation broth of a mutated fungal strain Streptomyces nitrosporeus YBH10-5 had lipid-lowering effects in HepG2 cells. Chromatographic separation of the EtOAc fraction resulted in the isolation of 11 PKS-based derivatives, including a structurally unique meroterpenoid namely nitrosporeunol H (1). The structure of compound 1 was determined by the analysis of spectroscopic data. Further bioassay resulted in farnesylquinone (2) and its analogues to exert in vivo fat-reducing effects in C. elegans worm model. The underlying mode of action of compound 2 in the context of live worms was investigated, uncovering that compound 2 enhanced the mitochondrial ß-oxidation rate and changed the transcriptional level of energy metabolism genes. Additional experiments revealed that compound 2 exerted its effects in C. elegans partially through repressing FAT-5, an isoform of stearoyl-CoA desaturase (SCD) which catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids, thereafter leading to the modification of the fatty acid profile. Thus, compound 2 was suggested to be a promising lead for further optimization to treat obesity.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Quinonas/farmacologia , Animais , Caenorhabditis elegans/química , Caenorhabditis elegans/metabolismo , Lipídeos/química , Lipídeos/genética , Oxirredução/efeitos dos fármacos , Quinonas/química , Streptomyces/química , Transcrição Genética/efeitos dos fármacos
4.
Methods Mol Biol ; 1974: 151-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31099001

RESUMO

Systemic delivery of RNA interference (RNAi) payloads for manipulation of gene expression in lymphocytes holds a great potential as a novel therapeutic modality for hematological malignancies and autoimmune disorders. However, lymphocytes are among the most difficult cells to transfect with RNAi, as they are resistant to conventional transfection reagents and are dispersed throughout the body, making it a challenge to successfully deliver these payloads via systemic administration route. We have developed a strategy to target lymphocytes and deliver RNAi payloads in a cell-specific manner to induce therapeutic gene silencing. This approach utilizes antibodies that decorate lipid nanoparticle surfaces to home into lymphocyte subsets. This approach opens new avenues for discovery of new drug targets and potentially for therapeutics.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Inativação Gênica , Lipídeos/genética , RNA Interferente Pequeno/genética , Humanos , Lipídeos/química , Lipídeos/farmacologia , Linfócitos/efeitos dos fármacos , Nanopartículas/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacologia
5.
Biomed Res Int ; 2019: 3102414, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984779

RESUMO

Etifoxine, an 18 kDa translocator protein (TSPO) agonist for the treatment of anxiety disorders in clinic, may be able to cause acute liver injury or cytolytic hepatitis. TSPO has been demonstrated to participate in inflammatory responses in infective diseases as well as to modulate glucose and lipid homeostasis. Hepatitis C virus (HCV) infection disrupts glucose and lipid homoeostasis, leading to insulin resistance (IR). Whether TSPO affects the HCV-induced IR remains unclear. Here, we found that the administration of etifoxine increased the TSPO protein expression and recovered the HCV-mediated lower mitochondrial membrane potential (MMP) without affecting HCV infection. Moreover, etifoxine reversed the HCV-induced lipid accumulation by modulating the expressions of sterol regulatory element-binding protein-1 and apolipoprotein J. On the other hand, in infected cells pretreated with etifoxine, the insulin-mediated insulin receptor substrate-1/Akt signals, forkhead box protein O1 translocation, and glucose uptake were blocked. Taken together, our results pointed out that etifoxine relieved the HCV-retarded MMP and reduced the lipid accumulation but deteriorated the HCV-induced IR by interfering with insulin signal molecules.


Assuntos
Hepatite C/tratamento farmacológico , Inflamação/tratamento farmacológico , Resistência à Insulina/genética , Oxazinas/administração & dosagem , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Hepatite C/genética , Hepatite C/patologia , Hepatite C/virologia , Humanos , Inflamação/genética , Inflamação/patologia , Inflamação/virologia , Proteínas Substratos do Receptor de Insulina/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de GABA/genética
6.
Lipids Health Dis ; 18(1): 89, 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954075

RESUMO

BACKGROUND: Elevation of exogenous free fatty acid (FFA) level leads to insulin resistance (IR) in liver, IR is manifested by elevated hepatic glucose production. We aim to study whether inhibition of endogenous fatty acid synthesis could decrease hepatic glucose production. METHODS: Low-passage HepG2 cells derived from human liver tissue were cultured in medium supplemented with FFA to induce IR, the influences of sterol regulatory element binding protein-1c (SREBP-1c) silencing on glucose production of HepG2 cells were investigated, and genes responsible for fatty acid and glucose metabolism were detected by real-time PCR. RESULTS: Compared with HepG2 cells cultured in normal growth medium, glucose production of HepG2 cells treated by FFA was significantly increased {[(0.28 ± 0.01) vs (0.83 ± 0.02)] umol.ug- 1 protein, n = 6 wells, P < 0.01}; the mRNA expression of phosphoenolpyruvate carboxylase kinase (PEPCK) and glucose-6-phosphatase (G6PC) in HepG2 cells increased by more than 5-fold and 3-fold, respectively; the mRNA expression of fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1) increased by approximately 4-fold and 1.1-fold, respectively; the mRNA expression of carnitine palmitoyltransferase-1 (CPT-1) changed slightly. Compared with the scrambled siRNA control, glucose production of HepG2 cells treated by FFA significantly increased after SREBP-1c silencing {[(0.018 ± 0.001) vs (0.028 ± 0.002)] umol.ug- 1 protein, n = 6 wells, P < 0.01}; the mRNA expression of PEPCK and G6PC increased by approximately 1.5-fold and 5-fold, respectively, but the mRNA expression of FAS, SCD1 and CPT-1 changed slightly. CONCLUSIONS: SREBP-1c silencing further augmented glucose production of HepG2 cells treated by FFA significantly, genes responsible for fatty acid synthesis and gluconeogenesis played an important role in this process. SREBP-1c functions not only as a lipid regulator but also plays an important role in regulation of glucose metabolism.


Assuntos
Meios de Cultura/farmacologia , Ácidos Graxos não Esterificados/farmacologia , Glucose/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Carnitina O-Palmitoiltransferase/genética , Ácido Graxo Sintases/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Resistência à Insulina/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Triglicerídeos/metabolismo
7.
J Exp Clin Cancer Res ; 38(1): 116, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845964

RESUMO

BACKGROUND: Angiotensin II (ANGII) and its receptor (AGTR1) have been proposed as significant contributors to metastasis in multiple cancers. Further, high AGTR1 levels are associated with poor epithelial ovarian cancer (EOC) outcomes. However, the mechanistic basis for these effects is unknown. Recent studies have suggested that ovarian cancer metastasis is highly dependent on the formation of multicellular spheroids (MCS). To understand the associations between the ANGII/AGTR1 pathway and cancer outcomes, we evaluated the effects of ANGII on MCS formation by ovarian cancer cells and used a proteomic approach to analyze the mechanistic basis. METHODS: We used the data from the GENT database and immunohistochemistry staining to assess the AGTR1 expression in epithelial ovarian cancer (EOC) patients and to assess its role in cancer progression. Colony formation assay, 3D culture assay, and transwell assays were used to analyze the effect of ANGII on the MCS formation and cell migration. The signaling pathways of AGTR1 and transactivation of epidermal growth factor receptor (EGFR) transactivation were investigated by the western blotting analysis. Xenograft models were used to determine the role of AGTR1 in ovarian cancer metastasis. ANGII release from ovarian cancer cells and ANGII levels in the EOC ascites fluid were measured by immunoassay. A shotgun proteomic approach was used to explore the detail molecular mechanism. Modulation of lipid desaturation and endoplasmic reticulum stress were verified by the in vitro and in vivo functional assays. RESULTS: AGTR1 expression was negatively correlated with EOC prognosis. AGTR1activation significantly enhanced the MCS formation and cell migration. ANGII triggered both of the classical AGTR1 pathway and the EGFR transactivation. ANGII administration increased peritoneal metastasis. In addition, ovarian cancer cells secreted ANGII and enhanced cancer metastasis in a positive feedback manner. Based on the proteomic data, lipid desaturation was activated by induction of stearoyl-CoA desaturase-1 (SCD1), which suggests that inhibition of SCD1 may significantly reduce MCS formation by increasing endoplasmic reticulum stress. CONCLUSIONS: ANGII promotes MCS formation and peritoneal metastasis of EOC cells. AGTR1 activation increases the lipid desaturation via SCD1 upregulation, which ultimately reduces endoplasmic reticulum stress in MCS. This mechanism explained the association between high levels of AGTR1 and poor clinical outcomes in EOC patients.


Assuntos
Carcinoma Epitelial do Ovário/genética , Neoplasias Peritoneais/genética , Receptor Tipo 1 de Angiotensina/genética , Estearoil-CoA Dessaturase/genética , Angiotensina II/genética , Angiotensina II/metabolismo , Animais , Carcinoma Epitelial do Ovário/patologia , Movimento Celular/genética , Estresse do Retículo Endoplasmático/genética , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Camundongos , Metástase Neoplásica , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Prognóstico , Proteômica , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Lipids Health Dis ; 18(1): 69, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885208

RESUMO

OBJECTIVE: To generate novel rabbit models with a large-fragment deletion of either LDL receptor (LDLR) and/or apolipoprotein (apoE) genes for the study of hyperlipidemic and atherosclerosis. METHODS: CRISPR/Cas9 system directed by a multiple sgRNAs system was used in rabbit embryos to edit their LDLR and apoE genes. The LDLR and apoE genes of founder rabbits were sequenced, and their plasma lipids and lipoprotein profiles on a normal chow diet were analyzed, western blotting was also performed to evaluate the expression of apolipoprotein. Sudan IV and HE staining of aortic were performed to confirm the formation of atherosclerosis. RESULTS: Six knockout (KO) rabbits by injection of both LDLR and apoE sgRNAs were obtained, including four LDLR KO rabbits and two LDLR/apoE double- KO rabbits. Sequence analysis of these KO rabbits revealed that they contained multiple mutations including indels, deletions, and substitutions, as well as two rabbit lines containing biallelic large fragment deletion in the LDLR region. Analysis of their plasma lipids and lipoprotein profiles of these rabbits fed on a normal chow diet revealed that all of these KO rabbits exhibited remarkable hyperlipidemia with total cholesterol levels increased by up to 10-fold over those of wild-type rabbits. Pathological examinations of two founder rabbits showed that KO rabbits developed prominent aortic and coronary atherosclerosis. CONCLUSION: Large fragment deletions can be achieved in rabbits using Cas9 mRNA and multiple sgRNAs. LDLR KO along with LDLR/apoE double KO rabbits should provide a novel means for translational investigations of human hyperlipidemia and atherosclerosis.


Assuntos
Sistemas CRISPR-Cas , Modelos Animais de Doenças , Edição de Genes/métodos , Hiperlipidemias/genética , Animais , Animais Geneticamente Modificados , Apolipoproteínas E/genética , Aterosclerose/etiologia , Aterosclerose/genética , Feminino , Técnicas de Inativação de Genes , Lipídeos/sangue , Lipídeos/genética , Lipoproteínas/sangue , Lipoproteínas/genética , Gravidez , RNA Guia , Coelhos , Receptores de LDL/genética
9.
Nat Genet ; 51(4): 636-648, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926973

RESUMO

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.


Assuntos
Lipídeos/sangue , Lipídeos/genética , Fumar/sangue , Fumar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Estilo de Vida , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Nat Genet ; 51(3): 414-430, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30820047

RESUMO

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aß processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Imunidade/genética , Lipídeos/genética , Proteínas tau/genética , Idoso , Estudos de Casos e Controles , Feminino , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Humanos , Metabolismo dos Lipídeos/genética , Masculino
11.
Nature ; 567(7747): 187-193, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30814737

RESUMO

Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity.


Assuntos
Metabolismo dos Lipídeos/genética , Lipídeos/análise , Lipídeos/genética , Proteômica , Animais , Células HEK293 , Humanos , Metabolismo dos Lipídeos/fisiologia , Lipídeos/sangue , Lipídeos/classificação , Fígado/química , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Obesidade/genética , Obesidade/metabolismo , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo
12.
J Hum Genet ; 64(6): 573-587, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30911093

RESUMO

Lipids foster energy production and their altered levels have been coupled with metabolic ailments. Indians feature high prevalence of metabolic diseases, yet uncharacterized for genes regulating lipid homeostasis. We performed first GWAS for quantitative lipids (total cholesterol, LDL, HDL, and triglycerides) exclusively in 5271 Indians. Further to corroborate our genetic findings, we investigated DNA methylation marks in peripheral blood in Indians at the identified loci (N = 233) and retrieved gene regulatory features from public domains. Recurrent GWAS loci-CELSR2, CETP, LPL, ZNF259, and BUD13 cropped up as lead signals in Indians, reflecting their universal applicability. Besides established variants, we found certain unreported variants at sub-genome-wide level-QKI, REEP3, TMCC2, FAM129C, FAM241B, and LOC100506207. These variants though failed to attain GWAS significance in Indians, but largely turned out to be active CpG sites in human subcutaneous adipose tissue and showed robust association to two or more lipid traits. Of which, QKI variants showed significant association to all four lipid traits and their designated region was observed to be a key gene regulatory segment denoting active transcription particularly in human subcutaneous adipose tissue. Both established and novel loci were observed to be significantly associated with altered DNA methylation in Indians for specific CpGs that resided in key regulatory elements. Further, gene-based association analysis pinpointed novel GWAS loci-LINC01340 and IQCJ-SCHIP1 for TC; IFT27, IFT88, and LINC02141 for HDL; and TEX26 for TG. Present study ascertains universality of selected known genes and also identifies certain novel loci for lipids in Indians by integrating data from various levels of gene regulation.


Assuntos
Colesterol/genética , Metilação de DNA/genética , Estudo de Associação Genômica Ampla , Metabolismo dos Lipídeos/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Colesterol/sangue , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Feminino , Humanos , Índia/epidemiologia , Lipídeos/sangue , Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Gordura Subcutânea/crescimento & desenvolvimento , Gordura Subcutânea/patologia , Triglicerídeos/sangue , Triglicerídeos/genética
13.
PLoS One ; 14(2): e0212464, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794634

RESUMO

Bone mineral density (BMD) and lipid levels are two of the most extensively studied risk factors for common diseases of aging, such as cardiovascular disease (CVD) and osteoporosis (OP). These two risk factors are also correlated with each other, but little is known about the molecular mechanisms behind this correlation. Recent studies revealed that circulating levels of several metabolites involved in the biosynthesis of androsterone correlate significantly with BMD and have the capacity to affect cholesterol and lipids levels. A main aim of the present study was to investigate the hypothesis that androsterone-related metabolites could provide a link between CVD and OP, as a common cause of lipid levels and BMD. The present study employed data from the NIHR BRC TwinsUK BioResource, comprising 1909 and 1994 monozygotic and dizygotic twin pairs, respectively, to address the causal relationships among BMD and lipids, and their associated metabolites, using reciprocal causation twin modelling, as well as Mendelian randomization (MR) using large publicly-available GWAS datasets on lipids and BMD, in conjunction with TwinsUK metabolite data. While results involving the twin modelling and MR analyses with metabolites were unable to establish a causal link between metabolite levels and either lipids or BMD, MR analyses of BMD and lipids suggest that lipid levels have a causal impact on BMD, which is consistent with findings from clinical trials of lipid-lowering drugs, which have also increased BMD.


Assuntos
Densidade Óssea/fisiologia , Lipídeos/sangue , Androsterona/metabolismo , Densidade Óssea/genética , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Causalidade , Estudo de Associação Genômica Ampla , Humanos , Lipídeos/genética , Osteoporose/etiologia , Osteoporose/genética , Osteoporose/metabolismo , Fenótipo , Fatores de Risco , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Reino Unido
14.
Nat Genet ; 51(3): 452-469, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778226

RESUMO

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Homeostase/genética , Lipídeos/genética , Proteínas/genética , Animais , Distribuição da Gordura Corporal/métodos , Índice de Massa Corporal , Estudos de Casos e Controles , Drosophila/genética , Exoma/genética , Feminino , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Fatores de Risco , Relação Cintura-Quadril/métodos
15.
Proc Natl Acad Sci U S A ; 116(9): 3919-3928, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808769

RESUMO

Ebola virus disease (EVD) often leads to severe and fatal outcomes in humans with early supportive care increasing the chances of survival. Profiling the human plasma lipidome provides insight into critical illness as well as diseased states, as lipids have essential roles as membrane structural components, signaling molecules, and energy sources. Here we show that the plasma lipidomes of EVD survivors and fatalities from Sierra Leone, infected during the 2014-2016 Ebola virus outbreak, were profoundly altered. Focusing on how lipids are associated in human plasma, while factoring in the state of critical illness, we found that lipidome changes were related to EVD outcome and could identify states of disease and recovery. Specific changes in the lipidome suggested contributions from extracellular vesicles, viremia, liver dysfunction, apoptosis, autophagy, and general critical illness, and we identified possible targets for therapies enhancing EVD survival.


Assuntos
Estado Terminal/epidemiologia , Doença pelo Vírus Ebola/genética , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Adolescente , Adulto , Criança , Surtos de Doenças , Ebolavirus/genética , Ebolavirus/patogenicidade , Feminino , Regulação da Expressão Gênica/genética , Doença pelo Vírus Ebola/sangue , Doença pelo Vírus Ebola/patologia , Doença pelo Vírus Ebola/virologia , Humanos , Lipídeos/sangue , Masculino , Serra Leoa/epidemiologia , Adulto Jovem
16.
BMC Genomics ; 20(1): 129, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755157

RESUMO

BACKGROUND: A previous laboratory study involving wild type, mutant and devR/dosR complemented strains of Mycobacterium tuberculosis reported the attenuation phenotype of complemented strain, Comp1. This phenotype was intriguing since the parental strain H37Rv, devR mutant (Mut1) and additional complemented strains, Comp9 and Comp11, were virulent in the guinea pig model. RESULTS: Towards deciphering the mechanism underlying the attenuation of Comp1, a whole genome sequencing approach was undertaken. Eight Single Nucleotide Polymorphisms (SNPs) unique to the Comp1 strain were identified. Of these, 5 SNPs were non-synonymous and included a G➞A mutation resulting in a W1591Stop mutation in ppsD gene of the phthiocerol dimycocerosate (PDIM) biosynthetic cluster. Targeted sequence analysis confirmed this mutation in only Comp1 strain and not in wild type (H37Rv), devR knockout (Mut1) or other complemented (Comp9 and Comp11) bacteria. Differential expression of the PDIM locus in Comp1 bacteria was observed which was associated with a partial deficiency of PDIM, an increased sensitivity to detergent and a compromised ability to infect human THP-1 cells. CONCLUSIONS: It is proposed that a spontaneous mutation in the ppsD gene of Comp1 underlies down-modulation of the PDIM locus which is associated with defects in permeability and infectivity as well as virulence attenuation in guinea pigs. Our study demonstrates the value of whole genome sequencing for resolving unexplainable bacterial phenotypes and recommends the assessment of PDIM status while assessing virulence properties of laboratory-manipulated strains of M. tuberculosis.


Assuntos
Códon sem Sentido , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , Policetídeo Sintases/genética , Tuberculose/microbiologia , Animais , Proteínas de Bactérias/genética , Parede Celular/química , Modelos Animais de Doenças , Regulação Bacteriana da Expressão Gênica , Cobaias , Humanos , Lipídeos/biossíntese , Lipídeos/genética , Mycobacterium tuberculosis/classificação , Polimorfismo de Nucleotídeo Único , Células THP-1 , Virulência/genética , Sequenciamento Completo do Genoma
17.
Gene ; 692: 156-169, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30658068

RESUMO

A number of genome-wide association studies (GWASs) have identified several genetic determinants of plasma lipids in European populations, in which analytical approaches have often been based on the linear regression models and the association test between a SNP and each lipid component individually in cross-sectional designs. Since lipid variations are correlated, the consideration of pleiotropy is necessary and using methods that can perform simultaneous association test of multiple longitudinal traits provides more information about the recognition of the pleiotropic variants. To identify new pleiotropic variants and to determine whether loci identified in previous GWASs can also exert the same effect on lipid concentrations in Iranian population, longitudinal measurements of lipid variations were used in a sample of Iranian population (16,353 individuals within 3100 families) that followed up every 3 years and using a two-step model, the associations of 20,036 available SNPs on chromosome 16 were assessed. Twenty variants within the AC009035.1, SLC12A3, CETP, NLRC5, ESRP2 and, C16orf95 genes showed strong evidence for association with HDL-C, cholesterol, and triglycerides with p-values ranging from 1.7 × 10-102 to 6.6 × 10-5. Since many genetic variants associated with lipids still remain to be determined, the results of the present study may provide valuable information on identifying the associations of new genetic loci with lipid variations in other populations.


Assuntos
Lipídeos/sangue , Lipídeos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Proteínas de Transferência de Ésteres de Colesterol/genética , HDL-Colesterol/sangue , HDL-Colesterol/genética , Cromossomos Humanos Par 16 , Feminino , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Irã (Geográfico) , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Linhagem , Proteínas de Ligação a RNA/genética , Membro 3 da Família 12 de Carreador de Soluto/genética , Triglicerídeos/sangue , Triglicerídeos/genética
18.
Nat Commun ; 10(1): 376, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670697

RESUMO

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.


Assuntos
Exercício , Loci Gênicos/genética , Lipídeos/sangue , Lipídeos/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Brasil , Proteínas de Ligação ao Cálcio/genética , Colesterol/sangue , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hispano-Americanos/genética , Humanos , Proteínas com Homeodomínio LIM/genética , Metabolismo dos Lipídeos/genética , Masculino , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Triglicerídeos/sangue , Triglicerídeos/genética , Adulto Jovem
19.
Hum Genomics ; 13(1): 5, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30678728

RESUMO

BACKGROUND: The association of platelet endothelial cell adhesion molecule 1 (PECAM1), hypoxia-inducible factor 1 subunit alpha (HIF1A), and KIAA1462 in myocardial infarction (MI) was investigated. The study included 401 Han Chinese MI patients and 409 controls. Three tag single-nucleotide polymorphisms (SNPs)-PECAM1 rs1867624, HIF1A rs2057482, and KIAA1462 rs3739998-were selected. SNP genotyping was performed by an improved multiplex ligation detection reaction assay. A systematic review and meta-analysis of studies including 3314 cases and 2687 controls on the association of 5 HIF1A SNPs and the overall risk of MI or coronary artery disease (CAD) was performed. RESULTS: The rs1867624 variants were associated with high TG concentrations (p = 0.040) and the rs2057482 variants were associated with decreased HDL-C in MI patients compared with the control group (p = 0.003). Rs2057482 SNP interacted with age to influence TC levels. The SNP of rs3739998 interacted with sex and hypertension to modulate CRE and TG levels, respectively (p < 3.04E-5-0.002). No association between the three SNPs and susceptibility to MI was found (p > 0.05 for all). In the meta-analysis of HIF1A, the rs11549465 C > T and rs10873142 T > C polymorphisms, but not rs2057482, rs11549467, and rs41508050, were correlated with overall MI or CAD risk. CONCLUSIONS: Taken together, this study provides additional evidence that genetic variation of the PECAM1 rs1867624 and HIF1A rs2057482 can mediate lipid levels in MI patients.


Assuntos
Moléculas de Adesão Celular/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Infarto do Miocárdio/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Polimorfismo de Nucleotídeo Único , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Células Endoteliais/fisiologia , Feminino , Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Humanos , Lipídeos/sangue , Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Miócitos de Músculo Liso/fisiologia , Fumar/genética
20.
Lipids Health Dis ; 18(1): 26, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683111

RESUMO

Brain is a vital organ of the human body which performs very important functions such as analysis, processing, coordination, and execution of electrical signals. For this purpose, it depends on a complex network of nerves which are ensheathed in lipids tailored myelin; an abundant source of lipids in the body. The nervous system is enriched with important classes of lipids; sphingolipids and cholesterol which compose the major portion of the brain particularly in the form of myelin. Both cholesterol and sphingolipids are embedded in the microdomains of membrane rafts and are functional units of the neuronal cell membrane. These molecules serve as the signaling molecules; hold important roles in the neuronal differentiation, synaptogenesis, and many others. Thus, their adequate provision and active metabolism are of crucial importance in the maintenance of physiological functions of brain and body of an individual. In the present review, we have highlighted the physiological roles of cholesterol and sphingolipids in the development of the nervous system as well as the association of their altered metabolism to neurological and neurodegenerative diseases.


Assuntos
Encéfalo/crescimento & desenvolvimento , Colesterol/metabolismo , Doenças do Sistema Nervoso/genética , Esfingolipídeos/metabolismo , Animais , Encéfalo/metabolismo , Membrana Celular/genética , Colesterol/genética , Humanos , Lipídeos/genética , Microdomínios da Membrana/genética , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/fisiopatologia , Neurônios/metabolismo , Neurônios/patologia , Esfingolipídeos/genética
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