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1.
Nat Commun ; 11(1): 4056, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792483

RESUMO

Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid ß-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia.


Assuntos
Autofagia/fisiologia , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia/metabolismo , Mitocôndrias/metabolismo , Animais , Autofagia/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Citometria de Fluxo , Humanos , Leucemia/genética , Leucemia Mieloide Aguda/patologia , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Lipogênese/genética , Lipogênese/fisiologia , Camundongos , Mitocôndrias/genética , Oxirredução , Fosforilação Oxidativa
2.
PLoS One ; 15(8): e0236249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804964

RESUMO

BACKGROUND: The insect predator Coccinella septempunctata can effectively control many types of pests, such as aphids, whiteflies, and small lepidopteran larvae. We previously found that C. septempunctata fed an artificial diet showed diminished biological properties(e.g. fecundity, egg hatching rate, survival rate, etc.) compared with those fed natural prey (Aphis craccivora), likely due to different nutritional characteristics of the diet. In this study, we used transcriptome sequencing analysis to identify nutrition- and metabolism-related genes of C. septempunctata that were differentially expressed depending on diet. METHODOLOGY/PRINCIPAL FINDINGS: The Illumina HiSeq2000 was used to sequence 691,942,058 total clean reads from artificial diet-fed and A. craccivora-fed C. septempunctata libraries, and the clean reads were assembled using Trinity de novo software (Tabel 2). Comparison of transcriptome sequences revealed that expression of 38,315 genes was affected by the artificial diet, and 1,182 of these genes showed a significant change in expression levels (FDR ≤ 0.05,|log2FC|≥1, "FC" stands for "fold change"). These differentially expressed genes (DEGs) were likely associated with the decreased egg laying capacity, hatching rate, longevity, and increased sex ratio (♀:♂) of adult C. septempunctata observed in the group fed the artificial diet. Furthermore, in the most DEGs metabolic pathways for C. septempunctata feeding on the artificial diet accumulated amino acid metabolic pathways, lipid metabolic pathways, and starch and glucose metabolism were down-regulated. CONCLUSIONS/SIGNIFICANCE: We found some differentially expressed genes and metabolic pathways are related to nutrition, from which a more informative feedback for diet formulation was obtained and the artificial diet could be more efficiently optimized.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal/genética , Afídeos , Besouros/fisiologia , Genes de Insetos , Comportamento Predatório/fisiologia , Aminoácidos/metabolismo , Animais , Regulação para Baixo , Fertilidade/fisiologia , Perfilação da Expressão Gênica , Glucose/metabolismo , Metabolismo dos Lipídeos/genética , Longevidade/fisiologia , Redes e Vias Metabólicas/genética , Controle Biológico de Vetores/métodos , Razão de Masculinidade , Amido/metabolismo , Sequenciamento Completo do Exoma
3.
PLoS Genet ; 16(8): e1008955, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776921

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by excess lipid accumulation in the liver without significant consumption of alcohol. The transmembrane 6 superfamily member 2 (TM6SF2) E167K missense variant strongly associates with NAFLD in humans. The E167K mutation destabilizes TM6SF2, resulting in hepatic lipid accumulation and low serum lipid levels. However, the molecular mechanism by which TM6SF2 regulates lipid metabolism remains unclear. By using tandem affinity purification in combination with mass spectrometry, we found that apolipoprotein B (APOB), ER lipid raft protein (ERLIN) 1 and 2 were TM6SF2-interacting proteins. ERLINs and TM6SF2 mutually bound and stabilized each other. TM6SF2 bound and stabilized APOB via two luminal loops. ERLINs did not interact with APOB directly but still increased APOB stability through stabilizing TM6SF2. This APOB stabilization was hampered by the E167K mutation that reduced the protein expression of TM6SF2. In mice, knockout of Tm6sf2 and knockdown of Tm6sf2 or Erlins decreased hepatic APOB protein level, causing lipid accumulation in the liver and lowering lipid levels in the serum. We conclude that defective APOB stabilization, as a result of ERLINs or TM6SF2 deficiency or E167K mutation, is a key factor contributing to NAFLD.


Assuntos
Apolipoproteína B-100/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Hepatopatia Gordurosa não Alcoólica/genética , Animais , Colesterol/genética , Colesterol/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Imunoprecipitação , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Lipídeos/genética , Camundongos , Camundongos Knockout , Complexos Multiproteicos/genética , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica/genética , Transfecção
4.
Georgian Med News ; (303): 161-167, 2020 Jun.
Artigo em Russo | MEDLINE | ID: mdl-32841199

RESUMO

The review summarizes the current knowledge about inborn errors of fatty acid metabolism (disorders of carnitine transport and mitochondrial fatty acid oxidation), characterized by high mortality, predominant damage of the central nervous system, heart, liver and skeletal muscles. The article presents the main clinical genetic features of diseases this group. After the introduction of newborn screening using the tandem mass-spectrometry (MS/MS), early identification of fatty acid metabolism defects became possible. Using of MS/MS method is promising for mass newborn screening. Early identification and accordingly timely initiated treatment prevents unfavorable outcome. Moreover, a specified medical-genetic diagnosis allows further prenatal diagnosis of pathology in subsequent pregnancies.


Assuntos
Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/genética , Erros Inatos do Metabolismo , Triagem Neonatal , Espectrometria de Massas em Tandem , Feminino , Humanos , Recém-Nascido , Mitocôndrias , Oxirredução , Gravidez
5.
J Toxicol Sci ; 45(8): 449-473, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741897

RESUMO

Although peroxisome proliferator-activated receptor α (PPARα) agonists are obviously hepatocarcinogenic in rodents, they have been widely used for dyslipidemia and proven to be safe for clinical use without respect to the species difference. It is established that PPARα acts as a part of the transcription factor complex, but its precise mechanism is still unknown. Using the data of Toxicogenomics Database, reliable genes responsive to PPARα agonists, clofibrate, fenofibrate and WY-14,643, in rat liver, were extracted from both in vivo and in vitro data, and sorted by their fold increase. It was found that there were many genes responding to fibrates exclusively in vivo. Most of the in vivo specific genes appear to be unrelated to lipid metabolism and are not upregulated in the kidney. Fifty-seven genes directly related to cell proliferation were extracted from in vivo data, but they were not induced in vitro at all. Analysis of PPAR-responsive elements could not explain the observed difference in induction. To evaluate possible interaction between neighboring genes in gene expression, the correlation of the fold changes of neighboring genes for 22 drugs with various PPARα agonistic potencies were calculated for the genes showing more than 2.5 fold induction by 3 fibrates in vivo, and their genomic location was compared with that of the human orthologue. In the present study, many candidates of genes other than lipid metabolism were selected, and these could be good starting points to elucidate the mechanism of PPARα agonist-induced rodent-specific toxicity.


Assuntos
Bases de Dados Genéticas , Fenofibrato/toxicidade , Loci Gênicos/genética , Armazenamento e Recuperação da Informação/métodos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , PPAR alfa/agonistas , Pirimidinas/toxicidade , Animais , Epistasia Genética , Expressão Gênica , Estudos de Associação Genética , Masculino , Ratos Sprague-Dawley , Especificidade da Espécie
6.
Nat Commun ; 11(1): 4150, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811819

RESUMO

The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.


Assuntos
Adipócitos/metabolismo , Envelhecimento/fisiologia , Autofagia/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Doenças Metabólicas/metabolismo , Adipócitos/patologia , Adipogenia/genética , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Adiposidade/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/fisiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Técnicas de Inativação de Genes , Glucose/genética , Glucose/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Coativador 1 de Receptor Nuclear/metabolismo , Coativador 2 de Receptor Nuclear/metabolismo , PPAR gama/metabolismo
7.
Chemosphere ; 258: 127360, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32554016

RESUMO

Environmental pollutants are thought to be a risk factor for the prevalence of hepatic steatosis. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous, and human exposure is inevitable. In the present study, phenanthrene (Phe) was used as a representative PAH to investigate the effects of in utero exposure to PAH on hepatic lipid metabolism and the toxicological mechanism involved. Pregnant mice (C57BL/6J) were orally administered Phe (0, 60, 600 and 6000 µg kg-1 body weight) once every 3 days with 6 doses in total. F1 female mice aged 125 days showed significantly elevated hepatic lipid levels in the liver. The protein expression of hepatic peroxisome proliferator-activated receptors (PPARß and PPARγ) and retinoid X receptors (RXRs) was upregulated; the transcription of genes related to lipogenesis, such as srebp1 (encoding sterol regulatory element binding proteins), acca (acetyl-CoA carboxylase), fasn (fatty acid synthase) and pcsk9 (proprotein convertase subtilisin/kexin type 9), showed an upregulation, while the mRNA levels of the lipolysis gene lcat (encoding lecithin cholesterol acyl transferase) were downregulated. These results could be responsible for lipid accumulation. The promoter methylation levels of pparγ were reduced and were the lowest in the 600 µg kg-1 group, and the promoter methylation levels of lcat were significantly increased in all the Phe treatments. These changes were matched with the alterations in their mRNA levels, suggesting that prenatal Phe exposure could induce abnormal lipid metabolism in later life via epigenetic modification.


Assuntos
Poluentes Ambientais/toxicidade , Epigênese Genética/efeitos dos fármacos , Fígado Gorduroso/virologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fenantrenos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/virologia , Idoso de 80 Anos ou mais , Animais , Fígado Gorduroso/embriologia , Fígado Gorduroso/metabolismo , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Lipólise/efeitos dos fármacos , Lipólise/genética , Fígado/efeitos dos fármacos , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Transcrição Genética/genética
8.
PLoS One ; 15(6): e0234328, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32579617

RESUMO

FABP4 is a candidate gene for carcass and meat quality traits in livestock and poultry. However, the effects of FABP4 have not been examined in the Yanbian yellow cattle, an economically important local cattle breed in China. In this study, we characterized single nucleotide polymorphisms (SNPs) in FABP4 in this cattle breed and their associations with meat quality traits. Six SNPs (referred to as SNP1-6) were identified in FABP4 by direct sequencing and polymerase chain reaction-restriction fragment length polymorphism. The six SNPs were significantly correlated with meat quality traits. In particular, the GG and GA genotypes of SNP1 were significantly associated with water and fat contents and GG and AA genotypes of SNP1 were significantly associated with protein contents (P < 0.05). The fat content and marbling in heterozygous individuals at SNP2-6 were significantly higher than those in wild-type or mutant individuals (P < 0.05), while protein content was significantly higher in wild-type and mutant individuals than in heterozygous individuals (P < 0.05). A gene expression analysis indicated that the lipid metabolism-related genes FABP4, PPARγ, ANGPTL4, and LPL show similar expression patterns with respect to FABP4 genotypes, with the highest levels in wild-type individuals and the lowest levels in mutants. In conclusion, FABP4 SNPs can be used for marker-assisted selection in Yanbian yellow cattle breeding.


Assuntos
Bovinos/genética , Proteínas de Ligação a Ácido Graxo/genética , Metabolismo dos Lipídeos/genética , Animais , China , Feminino , Qualidade dos Alimentos , Expressão Gênica/genética , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Genótipo , Masculino , Mutação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Carne Vermelha/análise , Análise de Sequência de DNA/métodos
9.
Life Sci ; 256: 117997, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32585242

RESUMO

AIMS: Non-alcoholic fatty liver disease (NAFLD) characterized by excessive hepatic fat deposition is an increasing public health issue worldwide. Insulin resistance is a pivotal factor in NAFLD progression. Studies have found that IGFBP5 was related to insulin sensitivity. Nevertheless, the role of IGFBP5 in NAFLD remains unclear. MATERIALS AND METHODS: NAFLD models were established in vitro and in vivo by treating HepG2 cells with free fatty acids (FFA) and feeding mice with high-fat diet (HFD), respectively. IGFBP5 expression was then analyzed in these models. The effects and mechanism of IGFBP5 on lipid lipogenesis, fatty acid ß-oxidation, and insulin resistance were investigated following IGFBP5 overexpression. Additionally, AMPK inhibitor compound C was used to treat HepG2 cells to confirm whether IGFBP5 functioned via activating AMPK pathway. KEY FINDINGS: IGFBP5 expression was decreased in both NAFLD models. IGFBP5 overexpression reduced levels of lipogenesis-associated proteins (SREBP-1c, FAS and ACC1), elevated expression of fatty acid ß-oxidation-related genes (PPARα, CPT1A and ACOX1), decreased intracellular lipid droplets, promoted glucose uptake and glycogenesis, and activated IRS1/Akt and AMPK pathways. Administration of IGFBP5 vectors also decreased body weight and relieved liver damage in HFD-treated mice. In contrast, compound C abrogated the influences of IGFBP5 overexpression on cell models. SIGNIFICANCE: IGFBP5 dampened hepatic lipid accumulation and insulin resistance in NAFLD development via activating AMPK pathway. This study indicates that IGFBP5 may be a novel therapeutic agent for NAFLD.


Assuntos
Resistência à Insulina/genética , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Metabolismo dos Lipídeos/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proteínas de Transporte/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/administração & dosagem , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Lipogênese/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética
10.
Chemosphere ; 258: 127255, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32554004

RESUMO

Trifluoromethanesulfonic acid (TFMS) is the shortest chain perfluorinated compound. Recently, it has been identified as a persistent and mobile organic chemical with a maximum concentration of 1 µg/L in the environment. However, its toxicological mechanism remains unclear. In this study, to evaluate the liver and intestinal toxicity of TFMS in mammals, male mice were orally exposed to 0, 1, 10 and 100 µg/kg for 12 weeks. Our results showed that TFMS exposure reduced the epididymal fat weight in mice, caused the decrease of serum and liver triglyceride (TG) level and the increase of serum low density lipoprotein (LDL) level. Also, we observed the inflammatory cell infiltration in the liver of mice exposed to 10 µg/kg and 100 µg/kg TFMS, which was coupled with the increased mRNA expression levels of inflammatory factors such as COX2, TNF-α, IL-1ß in the liver. In addition, the mRNA expression levels of lipid metabolism-related genes (PPAR-α, ACOX, SCD1, PPAR-γ, etc.) were significantly decreased in the liver of mice after exposure to both doses of TFMS. We also found TFMS exposure caused the imbalance of cecal gut microbiota and change of cecal microbiota diversity. KEGG pathway predictions showed that the exposure of 100 µg/kg TFMS changed the synthesis and degradation of ketone bodies, benzoate degradation and several other metabolic pathways. Our findings indicated that TFMS exposure disturbed the liver lipid metabolism possibly via altering the gut microbiota.


Assuntos
Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Mesilatos/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Ceco/efeitos dos fármacos , Ceco/microbiologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Disbiose , Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Triglicerídeos/sangue
11.
Nat Commun ; 11(1): 2850, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503972

RESUMO

Integrating association evidence across multiple traits can improve the power of gene discovery and reveal pleiotropy. Most multi-trait analysis methods focus on individual common variants in genome-wide association studies. Here, we introduce multi-trait analysis of rare-variant associations (MTAR), a framework for joint analysis of association summary statistics between multiple rare variants and different traits. MTAR achieves substantial power gain by leveraging the genome-wide genetic correlation measure to inform the degree of gene-level effect heterogeneity across traits. We apply MTAR to rare-variant summary statistics for three lipid traits in the Global Lipids Genetics Consortium. 99 genome-wide significant genes were identified in the single-trait-based tests, and MTAR increases this to 139. Among the 11 novel lipid-associated genes discovered by MTAR, 7 are replicated in an independent UK Biobank GWAS analysis. Our study demonstrates that MTAR is substantially more powerful than single-trait-based tests and highlights the value of MTAR for novel gene discovery.


Assuntos
Biologia Computacional/métodos , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Herança Multifatorial , Conjuntos de Dados como Assunto , Genoma Humano , Humanos , Metabolismo dos Lipídeos/genética
12.
Nat Commun ; 11(1): 2835, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503983

RESUMO

Inherited peripheral neuropathies (IPNs) represent a broad group of disorders including Charcot-Marie-Tooth (CMT) neuropathies characterized by defects primarily arising in myelin, axons, or both. The molecular mechanisms by which mutations in nearly 100 identified IPN/CMT genes lead to neuropathies are poorly understood. Here we show that the Ras-related GTPase Rab35 controls myelin growth via complex formation with the myotubularin-related phosphatidylinositol (PI) 3-phosphatases MTMR13 and MTMR2, encoded by genes responsible for CMT-types 4B2 and B1 in humans, and found that it downregulates lipid-mediated mTORC1 activation, a pathway known to crucially regulate myelin biogenesis. Targeted disruption of Rab35 leads to hyperactivation of mTORC1 signaling caused by elevated levels of PI 3-phosphates and to focal hypermyelination in vivo. Pharmacological inhibition of phosphatidylinositol 3,5-bisphosphate synthesis or mTORC1 signaling ameliorates this phenotype. These findings reveal a crucial role for Rab35-regulated lipid turnover by myotubularins to repress mTORC1 activity and to control myelin growth.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Bainha de Mielina/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Astrócitos , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Regulação para Baixo , Técnicas de Introdução de Genes , Células HEK293 , Células HeLa , Humanos , Metabolismo dos Lipídeos/genética , Camundongos Transgênicos , Mutação , Bainha de Mielina/patologia , Cultura Primária de Células , Proteínas Tirosina Fosfatases não Receptoras/antagonistas & inibidores , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas rab de Ligação ao GTP/genética
13.
Nat Commun ; 11(1): 2980, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532986

RESUMO

Proper storage of excessive dietary fat into subcutaneous adipose tissue (SAT) prevents ectopic lipid deposition-induced insulin resistance, yet the underlying mechanism remains unclear. Here, we identify angiopoietin-2 (Angpt2)-integrin α5ß1 signaling as an inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of Angpt2 markedly reduced fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic insulin resistance. Mechanistically, Angpt2 activated integrin α5ß1 signaling in the endothelium and triggered fatty acid transport via CD36 and FATP3 into SAT. Genetic or pharmacological inhibition of the endothelial integrin α5ß1 recapitulated adipocyte-specific Angpt2 knockout phenotypes. Our findings demonstrate the critical roles of Angpt2-integrin α5ß1 signaling in SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte-endothelial crosstalk as a potential target for prevention of ectopic lipid deposition-induced lipotoxicity and insulin resistance.


Assuntos
Angiopoietina-2/metabolismo , Ácidos Graxos/metabolismo , Resistência à Insulina/fisiologia , Integrina alfa5beta1/metabolismo , Metabolismo dos Lipídeos/fisiologia , Gordura Subcutânea/metabolismo , Adulto , Angiopoietina-2/genética , Animais , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Resistência à Insulina/genética , Integrina alfa5beta1/genética , Metabolismo dos Lipídeos/genética , Lipídeos/análise , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Transdução de Sinais/genética
14.
PLoS One ; 15(5): e0233087, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407372

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a pathological condition caused by excess triglyceride deposition in the liver. The SMXA-5 severe fatty liver mouse model has been established from the SM/J and A/J strains. To explore the genetic factors involved in fatty liver development in SMXA-5 mice, we had previously performed quantitative trait locus (QTL) analysis, using (SM/J×SMXA-5)F2 intercross mice, and identified Fl1sa on chromosome 12 (centromere-53.06 Mb) as a significant QTL for fatty liver. Furthermore, isoamyl acetate-hydrolyzing esterase 1 homolog (Iah1) was selected as the most likely candidate gene for Fl1sa. Iah1 gene expression in fatty liver-resistant A/J-12SM mice was significantly higher than in fatty liver-susceptible A/J mice. These data indicated that the Iah1 gene might be associated with fatty liver development. However, the function of murine Iah1 remains unknown. Therefore, in this study, we created Iah1 knockout (KO) mice with two different backgrounds [C57BL/6N (B6) and A/J-12SM (A12)] to investigate the relationship between Iah1 and liver lipid accumulation. Liver triglyceride accumulation in Iah1-KO mice of B6 or A12 background did not differ from their respective Iah1-wild type mice under a high-fat diet. These results indicated that loss of Iah1 did not contribute to fatty liver. On the other hands, adipose tissue dysfunction causes lipid accumulation in ectopic tissues (liver, skeletal muscle, and pancreas). To investigate the effect of Iah1 deficiency on white adipose tissue, we performed DNA microarray analysis of epididymal fat in Iah1-KO mice of A12 background. This result showed that Iah1 deficiency might decrease adipokines Sfrp4 and Metrnl gene expression in epididymal fat. This study demonstrated that Iah1 deficiency did not cause liver lipid accumulation and that Iah1 was not a suitable candidate gene for Fl1sa.


Assuntos
Hidrolases de Éster Carboxílico/genética , Deleção de Genes , Metabolismo dos Lipídeos , Hepatopatia Gordurosa não Alcoólica/genética , Adiposidade , Animais , Peso Corporal , Hidrolases de Éster Carboxílico/metabolismo , Colesterol/sangue , Dieta Hiperlipídica , Epididimo/metabolismo , Regulação Enzimológica da Expressão Gênica , Metabolismo dos Lipídeos/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triglicerídeos/sangue
15.
BMC Med Genet ; 21(1): 94, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375665

RESUMO

BACKGROUND: Niemann-Pick disease (NPD) is a rare autosomal recessive hereditary disease characterized by deficient activity of acid sphingomyelinase. CASE PRESENTATION: We present a case of NPD type B with a unique compound heterozygosity for SMPD1 (NM_000543.4:c.[84delC];[96G > A]) in which both mutations that induce an early stop codon are located before the second in-frame initiation codon. The clinical presentation of the patient is compatible with NPD type B. She was initially diagnosed of Gaucher Disease, but her altered lipid profile led to a clinical suspicion of NPD. Combined high doses of atorvastatin and ezetimibe were given to treat the severe hypercholesterolemia. CONCLUSIONS: The pharmacological management of the lipid profile in these patients is important. A unique compound mutation in SMPD1 gene is described.


Assuntos
Lipídeos/genética , Doença de Niemann-Pick Tipo B/genética , Esfingomielina Fosfodiesterase/genética , Atorvastatina/administração & dosagem , Códon de Terminação/genética , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Mutação/genética , Doença de Niemann-Pick Tipo B/tratamento farmacológico , Doença de Niemann-Pick Tipo B/metabolismo , Doença de Niemann-Pick Tipo B/patologia
16.
PLoS One ; 15(5): e0227720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407314

RESUMO

Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erbα) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erbα expression induces muscular atrophy, high adiposity, and metabolic syndrome in mice. Here we show that, unlike knockout mice, Nr1d1 heterozygous mice are not susceptible to muscular atrophy and in fact paradoxically possess larger myofiber diameters and improved neuromuscular function, compared to wildtype mice. Heterozygous mice lacked dyslipidemia, a characteristic of Nr1d1 knockout mice and displayed increased whole-body fatty-acid oxidation during periods of inactivity (light cycle). Heterozygous mice also exhibited higher rates of glucose uptake when fasted, and had elevated basal rates of gluconeogenesis compared to wildtype and knockout littermates. Rev-erbα ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erbα loss, curiously stimulated these processes. Our investigations revealed that Rev-erbα dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.


Assuntos
Dislipidemias/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Tecido Adiposo Branco/metabolismo , Adiposidade/genética , Animais , Comportamento Animal/fisiologia , Relógios Circadianos/genética , Dislipidemias/metabolismo , Dislipidemias/patologia , Ácidos Graxos/metabolismo , Gluconeogênese/genética , Glucose/metabolismo , Heterozigoto , Humanos , Metabolismo dos Lipídeos/genética , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Camundongos Knockout , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Miofibrilas/genética , Miofibrilas/metabolismo , Miofibrilas/patologia , Fotoperíodo
17.
Mol Genet Genomics ; 295(4): 1039-1053, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32253496

RESUMO

Premature ovarian insufficiency (POI) is a clinically and etiologically heterogeneous disorder characterized by menstrual irregularities and elevated levels of FSH before age of 40 years. Genetic anomalies are among the recognized causes of POI. Here, we aimed to identify the genetic cause of POI in an inbred pedigree with nine POI and two ichthyosis-affected members. Inheritance of POI and ichthyosis were, respectively, dominant and recessive. Reproduction-related information and measurements of relevant hormones were obtained. Genetic studies included homozygosity mapping, linkage analysis, exome sequencing, and screening of candidate variants. A mutation within ALOX12B, which is a known ichthyosis causing gene, was identified as cause of ichthyosis. ALOX12B encodes a protein involved in steroidogenesis and lipid metabolism. Considering the importance of steroidogenesis in reproduction functions, the possibility that the ALOX12B mutation is also cause of POI was considered. Screenings showed that the mutation segregated with POI status. Linkage analysis with respect to POI identified a single strongly linked locus (LOD > 3) that includes ALOX12B. Exome sequencing on POI-affected females identified the mutation in ALOX12B and also a sequence variation in SPNS2 within the linked locus. A possible contribution of the SPNS2 variation to POI was not strictly ruled out, but various data presented in the text including reported association of variations in related gene ALOX12 with menopause-age and role of ALOX12B in atretic bovine follicle formation argue in favor of ALOX12B. It is, therefore, concluded that the mutation in ALOX12B is the likely cause of POI in the pedigree.


Assuntos
Proteínas de Transporte de Ânions/genética , Araquidonato 12-Lipoxigenase/genética , Ictiose/genética , Insuficiência Ovariana Primária/genética , Adulto , Consanguinidade , Feminino , Ligação Genética/genética , Predisposição Genética para Doença , Homozigoto , Humanos , Ictiose/complicações , Ictiose/patologia , Irã (Geográfico)/epidemiologia , Metabolismo dos Lipídeos/genética , Menopausa Precoce/genética , Mutação/genética , Linhagem , Insuficiência Ovariana Primária/complicações , Insuficiência Ovariana Primária/patologia , Sequenciamento Completo do Exoma
18.
Anim Sci J ; 91(1): e13371, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32285539

RESUMO

Protein proteolytic enzymes (Proprotein Convertase, PC) is a Ca2+ -dependent serine protease family, whose main function is to cleave precursors of biologically inactive proteins or peptide chains into active functional molecules. Proprotein convertase subtilisin/kexin type 1 (PCSK1) gene is mainly expressed in nerve and endocrine tissues. In this study, PCSK1 was selected as an important candidate gene for abdominal fat content in broilers. We cloned the exon region of chicken PCSK1 gene and found six single-nucleotide polymorphisms (SNPs). Association analysis was carried out and we found that the polymorphisms of these six SNPs were significantly associated with abdominal fat content in G19 and G20 populations. Five of these SNPs were significantly associated with abdominal fat content in G19 and G20 combined population. The polymorphism of these five SNPs was significantly correlated with the abdominal fat content of AA broilers. Together, our study demonstrated that c.927T>C, c.1880C>T, c.*900G>A, and c.*1164C>T were significantly associated with abdominal fat content in populations used in this study, which means that these SNPs in PCSK1 gene could be used as candidate markers to select lean broiler lines.


Assuntos
Galinhas/genética , Metabolismo dos Lipídeos/genética , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 1/genética , Gordura Abdominal/metabolismo , Animais , Estudos de Associação Genética , Polimorfismo Genético
19.
PLoS One ; 15(4): e0231650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315370

RESUMO

Exposure to ionizing radiation contributing to negative health outcomes is a widespread concern. However, the impact of low dose and sub-lethal dose radiation (SLDR) exposures remain contentious, particularly in pregnant women who represent a vulnerable group. The fetal programming hypothesis states that an adverse in utero environment or stress during development of an embryo or fetus can result in permanent physiologic changes often resulting in progressive metabolic dysfunction with age. To assess changes in gene expression profiles of glucose/insulin signaling and lipid metabolism caused by radiation exposure in utero, pregnant C57Bl/6J mice were irradiated using a dose response ranging from low dose to SLDR and compared to a Sham-irradiated group. mRNA expression analysis in 16 week old offspring (n = 84) revealed that genes involved in metabolic function including glucose metabolism, insulin signaling and lipid metabolism were unaffected by prenatal radiation exposures up to 300 mGy. However, female offspring of dams exposed to 1000 mGy had upregulated expression of genes contributing to insulin resistance and gluconeogenesis. In a second cohort of mice, the effects of SLDR on fetal programming of hepatic SOCS3 and PEPCK protein expression were assessed. 4 month old female offspring of dams irradiated at 1000 mGy had: 1) increased liver weights, 2) increased hepatic expression of proteins involved in glucose metabolism and 3) increased 18F-fluorodeoxyglucose (FDG) uptake in interscapular brown adipose tissue (IBAT) measured by positron emission tomography (PET) (n = 25). The results of this study indicate that prenatal radiation exposure does not affect metabolic function up to 300 mGy and 1000 mGy may be a threshold dose for sex-specific alterations in glucose uptake and hepatic gene and protein expression of SOCS3, PEPCK, PPARGC1A and PPARGC1B. These findings suggest that SLDR doses alter glucose uptake in IBAT and hepatic gene and protein expression of offspring and these changes may progress with age.


Assuntos
Tecido Adiposo Marrom/crescimento & desenvolvimento , Desenvolvimento Fetal/genética , Resistência à Insulina/genética , Fígado/metabolismo , Tecido Adiposo Marrom/efeitos da radiação , Animais , Glicemia/metabolismo , Metabolismo dos Carboidratos/genética , Modelos Animais de Doenças , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Feminino , Desenvolvimento Fetal/efeitos da radiação , Feto , Glucose/metabolismo , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/efeitos da radiação , Fígado/patologia , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Radiação
20.
Ecotoxicol Environ Saf ; 197: 110650, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315788

RESUMO

Octylphenol (OP) is a widely distributed endocrine disrupting chemical (EDC), and can be commonly found in various and diverse environmental media. Previous studies have reported that OP exposure could cause many adverse effects on aquatic animals. However, knowledge concerning the impact of OP on lipid metabolism in amphibians was still limited. In our study, Rana chensinensis tadpoles were exposed to different OP concentrations (0, 10-8, 10-7 and 10-6 mol/L) from the Gosner stage (Gs) 25-38. The RNA-seq analysis of tadpole intestines was explored by RNA-seq, and six differentially expressed genes (DEGs) related to the fat digestion and absorption were validated by RT-qPCR. Moreover, we used 16s amplicon sequencing to evaluate effects of OP on intestinal microbiome in tadpoles, further determining the variations of lipid metabolism. Our results revealed that OP exposure influenced gene expression levels related to fat digestion and absorption and led to alteration of structure and composition of intestinal microbiome. At the phylum level, the Firmicutes/Bacteroidetes ratio was gradually decreased in OP exposure groups, which disrupted lipid metabolism. According to the results of intestinal microbial functional prediction, OP exposure interfered with metabolic function and increased risk of disease. These data provide us with powerful resources to assess the effects of OP on lipid metabolism by integrating RNAseq and 16s amplicon sequencing analysis of intestinal tract and intestinal microbiome.


Assuntos
Disruptores Endócrinos/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Larva/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fenóis/toxicidade , Animais , Classificação , Microbioma Gastrointestinal/genética , Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Intestinos/microbiologia , Larva/metabolismo , Metabolismo dos Lipídeos/genética , Anotação de Sequência Molecular , RNA/genética , Ranidae
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