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1.
PLoS Genet ; 16(8): e1008941, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760060

RESUMO

Apolipoprotein B-containing lipoproteins (B-lps) are essential for the transport of hydrophobic dietary and endogenous lipids through the circulation in vertebrates. Zebrafish embryos produce large numbers of B-lps in the yolk syncytial layer (YSL) to move lipids from yolk to growing tissues. Disruptions in B-lp production perturb yolk morphology, readily allowing for visual identification of mutants with altered B-lp metabolism. Here we report the discovery of a missense mutation in microsomal triglyceride transfer protein (Mtp), a protein that is essential for B-lp production. This mutation of a conserved glycine residue to valine (zebrafish G863V, human G865V) reduces B-lp production and results in yolk opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. However, this phenotype is milder than that of the previously reported L475P stalactite (stl) mutation. MTP transfers lipids, including triglycerides and phospholipids, to apolipoprotein B in the ER for B-lp assembly. In vitro lipid transfer assays reveal that while both MTP mutations eliminate triglyceride transfer activity, the G863V mutant protein unexpectedly retains ~80% of phospholipid transfer activity. This residual phospholipid transfer activity of the G863V mttp mutant protein is sufficient to support the secretion of small B-lps, which prevents intestinal fat malabsorption and growth defects observed in the mttpstl/stl mutant zebrafish. Modeling based on the recent crystal structure of the heterodimeric human MTP complex suggests the G865V mutation may block triglyceride entry into the lipid-binding cavity. Together, these data argue that selective inhibition of MTP triglyceride transfer activity may be a feasible therapeutic approach to treat dyslipidemia and provide structural insight for drug design. These data also highlight the power of yolk transport studies to identify proteins critical for B-lp biology.


Assuntos
Proteínas de Transporte/genética , Lipídeos/genética , Lipoproteínas/genética , Triglicerídeos/genética , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Trato Gastrointestinal/metabolismo , Humanos , Imunoprecipitação , Gotículas Lipídicas/metabolismo , Lipoproteínas/metabolismo , Mutação de Sentido Incorreto/genética , Mutação Puntual/genética , Transporte Proteico/genética , Triglicerídeos/metabolismo , Peixe-Zebra/genética
2.
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
3.
Proc Natl Acad Sci U S A ; 117(27): 15650-15658, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571937

RESUMO

Liquid-liquid phase separation of multivalent intrinsically disordered protein-RNA complexes is ubiquitous in both natural and biomimetic systems. So far, isotropic liquid droplets are the most commonly observed topology of RNA-protein condensates in experiments and simulations. Here, by systematically studying the phase behavior of RNA-protein complexes across varied mixture compositions, we report a hollow vesicle-like condensate phase of nucleoprotein assemblies that is distinct from RNA-protein droplets. We show that these vesicular condensates are stable at specific mixture compositions and concentration regimes within the phase diagram and are formed through the phase separation of anisotropic protein-RNA complexes. Similar to membranes composed of amphiphilic lipids, these nucleoprotein-RNA vesicular membranes exhibit local ordering, size-dependent permeability, and selective encapsulation capacity without sacrificing their dynamic formation and dissolution in response to physicochemical stimuli. Our findings suggest that protein-RNA complexes can robustly create lipid-free vesicle-like enclosures by phase separation.


Assuntos
Proteínas Intrinsicamente Desordenadas/química , Lipídeos/química , Nucleoproteínas/química , RNA/química , Anisotropia , Proteínas Intrinsicamente Desordenadas/genética , Lipídeos/genética , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Nucleoproteínas/genética , Pinças Ópticas , Transição de Fase , RNA/genética
4.
Sheng Wu Gong Cheng Xue Bao ; 36(5): 899-907, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32567273

RESUMO

Stearoyl-CoAdesaturase-1 (SCD-1) is a key regulator of monounsaturated fatty acid synthesis. It plays a vital role in lipid synthesis and metabolism. Ca²âº is an important cation in the body and plays an important role in the organism. The aims of this study were to investigate the correlation of SCD-1 gene overexpression with lipid indexes and calcium ion level. The pcDNA3.1 (+) + SCD-1 +Flag eukaryotic expression vector and cultured duck uterine epithelial cells were co-transfected. The overexpression of SCD-1 gene was measured using the Flag Label Detection Kit. Ca ions and lipid contents were detected through Fluo-3/AM Calcium Ion Fluorescence Labeling method and Lipid Measuring Kit, respectively. SCD-1 gene overexpression was negatively correlated with triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C), and positively correlated with Ca ion, total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C) and low density lipoprotein cholesterol (LDL-C) levels. Meanwhile, Ca ion was positively correlated with TG, LDL-C and HDL-C contents, and negatively correlated with TC and VLDL-C levels. Overexpression of SCD-1 gene could regulate Ca ion secretion, as well as lipid synthesis and transport in duck uterine epithelial cells.


Assuntos
Cálcio , Coenzima A Ligases , Células Epiteliais , Expressão Gênica , Lipídeos , Animais , Cálcio/metabolismo , Coenzima A Ligases/genética , Patos , Células Epiteliais/química , Células Epiteliais/enzimologia , Íons , Lipídeos/genética , Triglicerídeos/metabolismo
5.
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
6.
Gene ; 753: 144806, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32461018

RESUMO

BACKGROUND: The aim of the present study was to detect potential gender-specific associations between some common CD36 single nucleotide polymorphisms (SNPs) and the lipid profile, as well as the susceptibility to premature multi-vessel coronary artery heart disease (CHD) in the Han population of Northern China. METHODS: A systematic three-step study process was employed to detect associations between CD36 gene variants and blood lipid profiles, as well as premature multi-vessel CHD in a gender-specific manner. RESULTS: The current study documented the following novel findings: (I) the full population-based association study in 329 Northern Han Chinese showed that four common CD36 polymorphisms were significantly related to extreme lipid profiles, with statistically significant effects based on gender interactions (rs1049673: P = 0.001; rs7755: P = 0.008; rs3211956: P = 0.034; and rs3173798: P = 0.004); (ii) these statistically significant effects could be decomposed into statistically significant atherogenic effects in males, but non-significant non-atherogenic effects in females; (iii) the results of logistic regression analysis indicated that current smoking status, low density lipoprotein cholesterol (LDL-C) levels, and type-2 diabetes were independent risk factors for premature multi-vessel CHD phenotype (P < 0.0001). CONCLUSIONS: Four common CD36 polymorphisms (rs1049673, rs7755, rs3211956, and rs3173798) were identified to be significantly associated with extreme lipid profiles and had statistically opposite gender-specific clinical lipid profile effects. Thus, the 3'-untranslated regions (3'-UTR) CD36 SNPs could be a novel target for metabolic abnormalities in males of the Han nationality from Northern China.


Assuntos
Antígenos CD36/genética , Doença da Artéria Coronariana/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Estudos de Casos e Controles , China/epidemiologia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Grupos Étnicos/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Lipídeos/sangue , Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Caracteres Sexuais
7.
PLoS Genet ; 16(3): e1008684, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226016

RESUMO

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.


Assuntos
Grupos de Populações Continentais/genética , Lipídeos/sangue , Lipídeos/genética , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Lipídeos/análise , Masculino , Metagenômica/métodos , Grupos Minoritários , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
8.
Proc Natl Acad Sci U S A ; 117(14): 7792-7798, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32209662

RESUMO

A significant fraction of the glycerophospholipids in the human body is composed of plasmalogens, particularly in the brain, cardiac, and immune cell membranes. A decline in these lipids has been observed in such diseases as Alzheimer's and chronic obstructive pulmonary disease. Plasmalogens contain a characteristic 1-O-alk-1'-enyl ether (vinyl ether) double bond that confers special biophysical, biochemical, and chemical properties to these lipids. However, the genetics of their biosynthesis is not fully understood, since no gene has been identified that encodes plasmanylethanolamine desaturase (E.C. 1.14.99.19), the enzyme introducing the crucial alk-1'-enyl ether double bond. The present work identifies this gene as transmembrane protein 189 (TMEM189). Inactivation of the TMEM189 gene in human HAP1 cells led to a total loss of plasmanylethanolamine desaturase activity, strongly decreased plasmalogen levels, and accumulation of plasmanylethanolamine substrates and resulted in an inability of these cells to form labeled plasmalogens from labeled alkylglycerols. Transient expression of TMEM189 protein, but not of other selected desaturases, recovered this deficit. TMEM189 proteins contain a conserved protein motif (pfam10520) with eight conserved histidines that is shared by an alternative type of plant desaturase but not by other mammalian proteins. Each of these histidines is essential for plasmanylethanolamine desaturase activity. Mice homozygous for an inactivated Tmem189 gene lacked plasmanylethanolamine desaturase activity and had dramatically lowered plasmalogen levels in their tissues. These results assign the TMEM189 gene to plasmanylethanolamine desaturase and suggest that the previously characterized phenotype of Tmem189-deficient mice may be caused by a lack of plasmalogens.


Assuntos
Lipídeos/genética , Oxirredutases/genética , Plasmalogênios/genética , Enzimas de Conjugação de Ubiquitina/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Linhagem Celular , Humanos , Camundongos , Oxirredução , Oxirredutases/metabolismo , Fenótipo , Plasmalogênios/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Compostos de Vinila/metabolismo
9.
Proc Natl Acad Sci U S A ; 117(14): 7803-7813, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32213593

RESUMO

Protein-lipid interactions are a key element of the function of many integral membrane proteins. These potential interactions should be considered alongside the complexity and diversity of membrane lipid composition. Inward rectifier potassium channel (Kir) Kir2.2 has multiple interactions with plasma membrane lipids: Phosphatidylinositol (4, 5)-bisphosphate (PIP2) activates the channel; a secondary anionic lipid site has been identified, which augments the activation by PIP2; and cholesterol inhibits the channel. Molecular dynamics simulations are used to characterize in molecular detail the protein-lipid interactions of Kir2.2 in a model of the complex plasma membrane. Kir2.2 has been simulated with multiple, functionally important lipid species. From our simulations we show that PIP2 interacts most tightly at the crystallographic interaction sites, outcompeting other lipid species at this site. Phosphatidylserine (PS) interacts at the previously identified secondary anionic lipid interaction site, in a PIP2 concentration-dependent manner. There is interplay between these anionic lipids: PS interactions are diminished when PIP2 is not present in the membrane, underlining the need to consider multiple lipid species when investigating protein-lipid interactions.


Assuntos
Metabolismo dos Lipídeos/genética , Lipídeos/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Animais , Ânions/metabolismo , Membrana Celular/genética , Membrana Celular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Simulação de Dinâmica Molecular , Fosfatidilinositol 4,5-Difosfato/metabolismo , Potássio/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo
10.
J Biotechnol ; 310: 21-31, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32004579

RESUMO

Some Rhodotorula spp. have been characterized as oleaginous yeasts. Under certain culture conditions they can accumulate neutral lipids, which are mainly triglycerides (TAG). Microbial TAG that can be used as raw material for biodiesel synthesis are attractive for the biofuel industry. In this study, the ability to synthesize lipids of Rhodotorula glutinis R4, isolated in Antarctica, was compared with eight strains belonging to the genera Rhodotorula and Yarrowia with the aim of proposing a novel source of oils for biodiesel synthesis. All strains were cultured under nitrogen (N) limiting conditions and an excess of carbon (C) in the culture medium. We found that yeasts accumulated between 9-48.9 % (w/w) of lipids. Among them, R. glutinis R4 showed the highest growth (14 g L-1, µmax 0,092 h-1) and lipid production (7 g L-1; 47 % w/w). Microbial oils produced by R. glutinis R4 are similar to vegetable oils, with 61 % of oleic acid, indicating that it is adequate for biodiesel synthesis. Our results demonstrate that biodiesel derived from R. glutinis R4 complies with international fuel standards ASTM D6751 and EN 14214. Therefore, this work demonstrates that Rhodotorula glutinis R4 is a novel and valuable source of microbial oils for biodiesel synthesis.


Assuntos
Biocombustíveis , Lipídeos/biossíntese , Rhodotorula/metabolismo , Lipídeos/genética , Rhodotorula/genética , Especificidade da Espécie
11.
Cell ; 180(5): 956-967.e17, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32084332

RESUMO

Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying essential physiological functions such as touch and pain sensing, hearing, and proprioception. Although the mechanisms for some of these functions have been identified, the molecules essential to the sense of pain have remained elusive. Here we report identification of TACAN (Tmem120A), an ion channel involved in sensing mechanical pain. TACAN is expressed in a subset of nociceptors, and its heterologous expression increases mechanically evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel. Finally, a nociceptor-specific inducible knockout of TACAN decreases the mechanosensitivity of nociceptors and reduces behavioral responses to painful mechanical stimuli but not to thermal or touch stimuli. We propose that TACAN is an ion channel that contributes to sensing mechanical pain.


Assuntos
Mecanotransdução Celular/genética , Nociceptores/metabolismo , Dor/genética , Tato/genética , Animais , Regulação da Expressão Gênica/genética , Humanos , Lipídeos/genética , Camundongos , Camundongos Knockout , Dor/fisiopatologia , Técnicas de Patch-Clamp , Estresse Mecânico , Tato/fisiologia
12.
Molecules ; 25(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936538

RESUMO

Microalgae are freshwater and marine unicellular photosynthetic organisms that utilize sunlight to produce biomass. Due to fast microalgal growth rate and their unique biochemical profiles and potential applications in food and renewable energy industries, the interest in microalgal research is rapidly increasing. Biochemical and genetic engineering have been considered to improve microalgal biomass production but these manipulations also limited microalgal growth. The aim of the study was the biochemical characterization of recently identified microalgal strain Planktochlorella nurekis with elevated cell size and DNA levels compared to wild type strain that was achieved by a safe non-vector approach, namely co-treatment with colchicine and cytochalasin B (CC). A slight increase in growth rate was observed in twelve clones of CC-treated cells. For biochemical profiling, several parameters were considered, namely the content of proteins, amino acids, lipids, fatty acids, ß-glucans, chlorophylls, carotenoids, B vitamins and ash. CC-treated cells were characterized by elevated levels of lipids compared to unmodified cells. Moreover, the ratio of carotenoids to chlorophyll a and total antioxidant capacity were slightly increased in CC-treated cells. We suggest that Planktochlorella nurekis with modified DNA levels and improved lipid content can be considered to be used as a dietary supplement and biofuel feedstock.


Assuntos
Biomassa , DNA/química , Lipídeos/genética , Microalgas/genética , Biocombustíveis , Clorofila A/biossíntese , Clorofila A/química , DNA/genética , Lipídeos/biossíntese , Lipídeos/química , Microalgas/química , Microalgas/metabolismo , Fotossíntese/genética
13.
PLoS One ; 15(1): e0221915, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945064

RESUMO

The crystal structure of a C-terminal deletion of apolipoprotein A-I (apoA1) shows a large helical bundle structure in the amino half of the protein, from residues 8 to 115. Using site directed mutagenesis, guanidine or thermal denaturation, cell free liposome clearance, and cellular ABCA1-mediated cholesterol efflux assays, we demonstrate that apoA1 lipidation can occur when the thermodynamic barrier to this bundle unfolding is lowered. The absence of the C-terminus renders the bundle harder to unfold resulting in loss of apoA1 lipidation that can be reversed by point mutations, such as Trp8Ala, and by truncations as short as 8 residues in the amino terminus, both of which facilitate helical bundle unfolding. Locking the bundle via a disulfide bond leads to loss of apoA1 lipidation. We propose a model in which the C-terminus acts on the N-terminus to destabilize this helical bundle. Upon lipid binding to the C-terminus, Trp8 is displaced from its interaction with Phe57, Arg61, Leu64, Val67, Phe71, and Trp72 to destabilize the bundle. However, when the C-terminus is deleted, Trp8 cannot be displaced, the bundle cannot unfold, and apoA1 cannot be lipidated.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Apolipoproteína A-I/genética , Metabolismo dos Lipídeos/genética , Lipídeos/química , Transportador 1 de Cassete de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Apolipoproteína A-I/química , Transporte Biológico/genética , Dicroísmo Circular , Cristalografia por Raios X , Humanos , Cinética , Lipídeos/genética , Camundongos , Mutagênese Sítio-Dirigida , Ligação Proteica , Estrutura Secundária de Proteína , Desdobramento de Proteína , Células RAW 264.7 , Deleção de Sequência/genética
14.
Artigo em Inglês | MEDLINE | ID: mdl-31928669

RESUMO

Both suberin and its associated waxes contribute to the formation of apoplastic barriers that protect plants from the environment. Some transcription factors have emerged as regulators of the suberization process. The potato StNAC103 gene was reported as a repressor of suberin polyester and suberin-associated waxes deposition because its RNAi-mediated downregulation (StNAC103-RNAi) over-accumulated suberin and associated waxes in the tuber phellem concomitantly with the induction of representative biosynthetic genes. Here, to explore if other genes of the large NAC gene family participate to this repressive function, we extended the silencing to other NAC members by targeting the conserved NAC domain of StNAC103 (StNAC103-RNAi-c). Transcript profile of the StNAC103-RNAi-c phellem indicated that StNAC101 gene was an additional potential target. In comparison with StNAC103-RNAi, the silencing with StNAC103-RNAi-c construct resulted in a similar effect in suberin but yielded an increased load of associated waxes in tuber phellem, mainly alkanes and feruloyl esters. Globally, the chemical effects in both silenced lines are supported by the transcript accumulation profile of genes involved in the biosynthesis, transport and regulation of apoplastic lipids. In contrast, the genes of polyamine biosynthesis were downregulated. Altogether these results point out to StNAC101 as a candidate to repress the suberin-associated waxes.


Assuntos
Inativação Gênica , Lipídeos/genética , Proteínas de Plantas/genética , Solanum tuberosum/genética , Proteínas de Plantas/metabolismo , Solanum tuberosum/metabolismo
15.
Sci Adv ; 6(1): eaaz1441, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31911951

RESUMO

Longevity is dictated by a combination of environmental and genetic factors. One of the key mechanisms to regulate life-span extension is the induction of protein chaperones for protein homeostasis. Ectopic activation of the unfolded protein response of the endoplasmic reticulum (UPRER) specifically in neurons is sufficient to enhance organismal stress resistance and extend life span. Here, we find that this activation not only promotes chaperones but also facilitates ER restructuring and ER function. This restructuring is concomitant with lipid depletion through lipophagy. Activation of lipophagy is distinct from chaperone induction and is required for the life-span extension found in this paradigm. Last, we find that overexpression of the lipophagy component, ehbp-1, is sufficient to deplete lipids, remodel ER, and promote life span. Therefore, UPR induction in neurons triggers two distinct programs in the periphery: the proteostasis arm through protein chaperones and metabolic changes through lipid depletion mediated by EH domain binding protein 1 (EHBP-1).


Assuntos
Autofagia/genética , Proteínas de Caenorhabditis elegans/genética , Longevidade/genética , Resposta a Proteínas não Dobradas/genética , Proteínas de Transporte Vesicular/genética , Animais , Caenorhabditis elegans , Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/genética , Humanos , Lipídeos/genética , Chaperonas Moleculares/genética , Neurônios/metabolismo , Transdução de Sinais/genética
16.
Life Sci ; 241: 117118, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790686

RESUMO

AIMS: Acute pancreatitis (AP) is usually complicated with multiple organ insufficiency, including renal injury. Hyperlipidemia is regarded as a risk factor to induce AP. High-fat diet-induced hyperlipidemic pancreatitis (HP) increased nowadays and showed more severe symptoms and complications than other AP. However, detailed mechanisms or mediators involved in HP complicated with acute renal injury were less studied. Here, we aimed to study how miR-214 expresses in the HP and whether miR-214 has functions to regulate pathological kidney damages induced by HP. MAIN METHODS: Sprague-Dawley rats were adopted to establish HP model complicated with acute renal injury through long-term high-fat diet and sodium taurocholic injection. Models were injected with LV-rno-miR-214-3p or LV-anti-rno-miR-214-3p to exogenously regulate miR-214-3p to study its impacts on HP via a series of molecular and histological experiments. KEY FINDINGS: MiR-214-3p was found to be up-regulated in the kidney, pancreas and serum of HP rats and also could intensify the pathological alterations, kidney and pancreas damages and fibrosis induced by HP. Inflammatory response in HP was enhanced when miR-214-3p was overexpressed. Besides, miR-214-3p up-regulation was showed to inhibit PTEN expression but increased P-Akt levels in the HP kidney, which might be a possible mechanism to induce severe symptoms of pancreatitis. Knockdown of miR-214-3p showed opposite effects. SIGNIFICANCE: MiR-214-3p is indicated to exacerbate the tissue damages and inflammatory response caused by HP complicated with acute renal injury, which may provide a novel therapeutic perspective targeting miR-214-3p to treat HP with acute renal injury.


Assuntos
Lesão Renal Aguda/genética , Hiperlipidemias/complicações , MicroRNAs/genética , Pancreatite/complicações , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Amilases/sangue , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hiperlipidemias/genética , Rim/patologia , Lipídeos/sangue , Lipídeos/genética , Masculino , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Pancreatite/genética , Pancreatite/patologia , Ratos Sprague-Dawley
17.
Mol Cell Biochem ; 463(1-2): 13-31, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31541353

RESUMO

Insulin stimulates de novo lipid synthesis in the liver and in cultured hepatocytes via its ability to activate sterol regulatory element-binding protein 1c (SREBP-1c). Although PI3K-AKT-mTORC1-p70S6K-signaling kinases are known to drive feed-forward expression of SREBP-1c, the identity of the phosphorylated amino acid residue(s) putatively involved in insulin-stimulated de novo lipogenesis remains elusive. We obtained in silico and mass spectrometry evidence, that was combined with siRNA strategies, to discover that insulin-induced phosphorylation of serine 418, serine 419, and serine 422 in rat SREBP-1c was most likely mediated by p70S6 kinase. Here, for the first time, we show that insulin-induced phosphorylation of these 3 serine residues mainly impinged on the mechanisms of proteostasis of both full-length and mature SREBP-1c in the McArdle-RH7777 hepatoma cells. Consistent with this conclusion, nascent SREBP-1c, substituted with phosphomimetic aspartic acid residues at these 3 sites, was resistant to proteasomal degradation. As a consequence, endoplasmic reticulum to Golgi migration and proteolytic maturation of pSREBP-1c was significantly enhanced which led to increased accumulation of mature nSREBP-1c, even in the absence of insulin. Remarkably, aspartic acid substitutions at S418, S419 and S422 also protected the nascent SREBP-1c from ubiquitin-mediated proteasome degradation thus increasing its steady-state levels and transactivation potential in the nucleus. These complementary effects of p70S6K-mediated phosphorylation on proteostasis of pSREBP-1c were necessary and sufficient to account for insulin's ability to enhance transcription of genes controlling de novo lipogenesis in hepatocytes.


Assuntos
Hepatócitos/metabolismo , Lipídeos/biossíntese , Lipogênese , Proteostase , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral , Hepatócitos/citologia , Humanos , Lipídeos/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Serina-Treonina Quinases TOR/genética , Transcrição Genética
18.
Biochim Biophys Acta Gen Subj ; 1864(1): 129422, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31491457

RESUMO

BACKGROUND: Previous studies suggested that fibrillar human IAPP (hIAPP) is more likely to deposit in ß-cells, resulting in ß-cell injury. However, the changes in the conformation of hIAPP in lipid environment and the mechanism involved in ß-cell damage are unclear. METHODS: Synthetic hIAPP was incubated with five types of free fatty acids and phospholipids 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS), which constitute the cell membrane. Thioflavin-T fluorescence assay was conducted to analyze the degree of hIAPP fibrosis, and circular dichroism spectroscopy was performed to detect the ß-fold formation of hIAPP. Furthermore, INS-1 cells were infected with human IAPP delivered by a GV230-EGFP plasmid. The effects of endogenous hIAPP overexpression induced by sodium palmitate on the survival, endoplasmic reticulum (ER) stress, and apoptosis of INS-1 cells were evaluated. RESULTS: The five types of free fatty acids can accelerate the fibrosis of hIAPP. Sodium palmitate also maintained the stability of fibrillar hIAPP. POPS, not POPC, accelerated hIAPP fibrosis. Treatment of INS-1 cells with sodium palmitate increased the expression of hIAPP, activated ER stress and ER stress-dependent apoptosis signaling pathways, and increased the apoptotic rate. CONCLUSION: Free fatty acids and anionic phospholipid can promote ß-fold formation and fibrosis in hIAPP. High lipid induced the overexpression of hIAPP and aggravated ER stress and apoptosis in INS-1 cells, which caused ß-cell death in high lipid environment. GENERAL SIGNIFICANCE: Our study reveals free fatty acids and hIAPP synergistically implicated in endoplasmic reticulum stress and apoptosis of islet ß-cells.


Assuntos
Apoptose/genética , Fibrose/genética , Células Secretoras de Insulina/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Amiloide/genética , Amiloide/metabolismo , Membrana Celular/genética , Membrana Celular/metabolismo , Estresse do Retículo Endoplasmático/genética , Ácidos Graxos não Esterificados/genética , Ácidos Graxos não Esterificados/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Regulação da Expressão Gênica/genética , Humanos , Células Secretoras de Insulina/patologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/ultraestrutura , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Ácido Palmítico/metabolismo , Fosfatidilcolinas/genética , Fosfatidilcolinas/metabolismo , Fosfatidilserinas/genética , Fosfatidilserinas/metabolismo , Conformação Proteica em Folha beta , Dobramento de Proteína
19.
Clin Appl Thromb Hemost ; 25: 1076029619892088, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31833377

RESUMO

The apolipoprotein (Apo) B gene (APOB) is a susceptible gene for dyslipidemia. The purpose of this investigation was to explore the relationship between the APOB rs1042034 single-nucleotide polymorphism (SNP) and serum lipid levels in the Maonan and Han populations. A total of 598 Maonan participants and 609 Han participants were genotyped by polymerase chain reaction and restriction fragment length polymorphism, and the genotypes were also verified by sequencing. There were no differences in genotype and allele frequencies between the 2 ethnic groups or between males and females. The levels of triglyceride (TG) in Maonans were higher and high-density lipoprotein cholesterol was lower in the A allele carriers than the A allele noncarriers; the A allele carriers in Hans had higher TG levels and lower ApoA1/ApoB ratio than the A allele noncarriers (P < .05 for all). Subgroup analysis showed that the A allele carriers in Maonan females had higher TG levels and the A allele carriers in Han females had higher TG levels and lower ApoA1/ApoB ratio than the A allele noncarriers (P < .05 for all). In our study populations, there may be ethnicity- and/or sex-specific associations between the APOB rs1042034 SNP and serum lipid levels.


Assuntos
Apolipoproteínas B/genética , Lipídeos/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Grupos Étnicos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Genes (Basel) ; 10(12)2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816972

RESUMO

Lipid species are critical components of eukaryotic membranes. They play key roles in many biological processes such as signal transduction, cell homeostasis, and energy storage. Investigations of lipid-environment interactions, in addition to the lipid and environment main effects, have important implications in understanding the lipid metabolism and related changes in phenotype. In this study, we developed a novel penalized variable selection method to identify important lipid-environment interactions in a longitudinal lipidomics study. An efficient Newton-Raphson based algorithm was proposed within the generalized estimating equation (GEE) framework. We conducted extensive simulation studies to demonstrate the superior performance of our method over alternatives, in terms of both identification accuracy and prediction performance. As weight control via dietary calorie restriction and exercise has been demonstrated to prevent cancer in a variety of studies, analysis of the high-dimensional lipid datasets collected using 60 mice from the skin cancer prevention study identified meaningful markers that provide fresh insight into the underlying mechanism of cancer preventive effects.


Assuntos
Algoritmos , Biomarcadores Tumorais , Interação Gene-Ambiente , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Modelos Biológicos , Neoplasias Cutâneas , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Lipidômica , Camundongos , Transdução de Sinais/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
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