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2.
PLoS Negl Trop Dis ; 14(8): e0008669, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866146

RESUMO

Exposure of adult mosquitoes to pyriproxyfen (PPF), an analog of insect juvenile hormone (JH), has shown promise to effectively sterilize female mosquitoes. However, the underlying mechanisms of the PPF-induced decrease in mosquito fecundity are largely unknown. We performed a comprehensive study to dissect the mode of PPF action in Aedes aegypti mosquitoes. Exposure to PPF prompted the overgrowth of primary follicles in sugar-fed Ae. aegypti females but blocked the development of primary follicles at Christopher's Stage III after blood feeding. Secondary follicles were precociously activated in PPF-treated mosquitoes. Moreover, PPF substantially altered the expression of many genes that are essential for mosquito physiology and oocyte development in the fat body and ovary. In particular, many metabolic genes were differentially expressed in response to PPF treatment, thereby affecting the mobilization and utilization of energy reserves. Furthermore, PPF treatment on the previtellogenic female adults considerably modified mosquito responses to JH and 20-hydroxyecdysone (20E), two major hormones that govern mosquito reproduction. Krüppel homolog 1, a JH-inducible transcriptional regulator, showed consistently elevated expression after PPF exposure. Conversely, PPF upregulated the expression of several key players of the 20E regulatory cascades, including HR3 and E75A, in the previtellogenic stage. After blood-feeding, the expression of these 20E response genes was significantly weaker in PPF-treated mosquitoes than the solvent-treated control groups. RNAi-mediated knockdown of the Methoprene-tolerant (Met) protein, the JH receptor, partially rescued the impaired follicular development after PPF exposure and substantially increased the hatching of the eggs produced by PPF-treated female mosquitoes. Thus, the results suggested that PPF relied on Met to exert its sterilizing effects on female mosquitoes. In summary, this study finds that PPF exposure disturbs normal hormonal responses and metabolism in Ae. aegypti, shedding light on the molecular targets and the downstream signaling pathways activated by PPF.


Assuntos
Aedes/efeitos dos fármacos , Culicidae/efeitos dos fármacos , Inseticidas/farmacologia , Metoprene/metabolismo , Esterilização , Animais , Ecdisterona/farmacologia , Corpo Adiposo/crescimento & desenvolvimento , Feminino , Glicogênio/metabolismo , Proteínas de Insetos/genética , Hormônios Juvenis/farmacologia , Ovário/crescimento & desenvolvimento , Piridinas , Interferência de RNA , Triglicerídeos/metabolismo
3.
Proc Natl Acad Sci U S A ; 117(37): 23131-23139, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32868427

RESUMO

Lipid droplets (LDs) are intracellular organelles found in a wide range of organisms and play important roles in stress tolerance. During nitrogen (N) starvation, Chlamydomonas reinhardtii stores large amounts of triacylglycerols (TAGs) inside LDs. When N is resupplied, the LDs disappear and the TAGs are degraded, presumably providing carbon and energy for regrowth. The mechanism by which cells degrade LDs is poorly understood. Here, we isolated a mutant (dth1-1, Delayed in TAG Hydrolysis 1) in which TAG degradation during recovery from N starvation was compromised. Consequently, the dth1-1 mutant grew poorly compared to its parental line during N recovery. Two additional independent loss-of-function mutants (dth1-2 and dth1-3) also exhibited delayed TAG remobilization. DTH1 transcript levels increased sevenfold upon N resupply, and DTH1 protein was localized to LDs. DTH1 contains a putative lipid-binding domain (DTH1LBD) with alpha helices predicted to be structurally similar to those in apolipoproteins E and A-I. Recombinant DTH1LBD bound specifically to phosphatidylethanolamine (PE), a major phospholipid coating the LD surface. Overexpression of DTH1LBD in Chlamydomonas phenocopied the dth1 mutant's defective TAG degradation, suggesting that the function of DTH1 depends on its ability to bind PE. Together, our results demonstrate that the lipid-binding DTH1 plays an essential role in LD degradation and provide insight into the molecular mechanism of protein anchorage to LDs at the LD surface in photosynthetic cells.


Assuntos
Proteínas de Algas/metabolismo , Chlamydomonas reinhardtii/metabolismo , Gotículas Lipídicas/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Sequência de Aminoácidos , Metabolismo dos Lipídeos/fisiologia , Nitrogênio/metabolismo , Fosfolipídeos/metabolismo , Fotossíntese/fisiologia , Triglicerídeos/metabolismo
5.
Nat Commun ; 11(1): 3944, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769983

RESUMO

Triacylglycerols (TG) are synthesized at the endoplasmic reticulum (ER) bilayer and packaged into organelles called lipid droplets (LDs). LDs are covered by a single phospholipid monolayer contiguous with the ER bilayer. This connection is used by several monotopic integral membrane proteins, with hydrophobic membrane association domains (HDs), to diffuse between the organelles. However, how proteins partition between ER and LDs is not understood. Here, we employed synthetic model systems and found that HD-containing proteins strongly prefer monolayers and returning to the bilayer is unfavorable. This preference for monolayers is due to a higher affinity of HDs for TG over membrane phospholipids. Protein distribution is regulated by PC/PE ratio via alterations in monolayer packing and HD-TG interaction. Thus, HD-containing proteins appear to non-specifically accumulate to the LD surface. In cells, protein editing mechanisms at the ER membrane would be necessary to prevent unspecific relocation of HD-containing proteins to LDs.


Assuntos
Membrana Celular/metabolismo , Bicamadas Lipídicas/metabolismo , Gotículas Lipídicas/metabolismo , Proteínas de Membrana/metabolismo , Triglicerídeos/metabolismo , Dicroísmo Circular , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/química , Simulação de Dinâmica Molecular , Domínios Proteicos , Transporte Proteico , Triglicerídeos/química
6.
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
7.
Nat Commun ; 11(1): 4107, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796836

RESUMO

Foamy macrophages, which have prominent lipid droplets (LDs), are found in a variety of disease states. Toll-like receptor agonists drive triacylglycerol (TG)-rich LD development in macrophages. Here we explore the basis and significance of this process. Our findings indicate that LD development is the result of metabolic commitment to TG synthesis on a background of decreased fatty acid oxidation. TG synthesis is essential for optimal inflammatory macrophage activation as its inhibition, which prevents LD development, has marked effects on the production of inflammatory mediators, including IL-1ß, IL-6 and PGE2, and on phagocytic capacity. The failure of inflammatory macrophages to make PGE2 when TG-synthesis is inhibited is critical for this phenotype, as addition of exogenous PGE2 is able to reverse the anti-inflammatory effects of TG synthesis inhibition. These findings place LDs in a position of central importance in inflammatory macrophage activation.


Assuntos
Inflamação/metabolismo , Lipidômica/métodos , Triglicerídeos/metabolismo , Animais , Células Cultivadas , Citometria de Fluxo , Glucose/metabolismo , Glicerol/metabolismo , Células HEK293 , Humanos , Metabolismo dos Lipídeos/fisiologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microscopia Eletrônica , Palmitatos/metabolismo , Análise de Sequência de RNA
8.
Am J Physiol Regul Integr Comp Physiol ; 319(3): R376-R386, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32755464

RESUMO

The present study was conducted to understand key biochemical, physiological, and molecular changes associated with ovarian growth and with lipid transfer and/or accumulation into the ovary during oogenesis in captive beluga sturgeon. Plasma levels of triacylglycerides, cholesterol, phospholipid, and sex steroid hormones were determined and all were found to increase notably throughout development from the perinucleolar to the tertiary yolk stage. Using fast protein liquid chromatography, we recognized three major lipoprotein peaks in chromatograms from all samples. These peaks were characterized as containing very low-density lipoprotein (Vldl), low-density lipoprotein/high-density lipoprotein (Ldl/Hdl), and plasma proteins. While Ldl/Hdl represented the most abundant lipoprotein fraction, the relative abundance of different lipoprotein classes did not change with the stage of oogenesis. Eluted lipoproteins were separated using sodium dodecyl-sulfate polyacrylamide gel electrophoresis and sequenced. The peptide sequence spectra for 66-kDa, 205-kDa, 29-kDa, and 70-kDa bands matched with albumin, vitellogenin (Vtg) AB2b, immunoglobulin light-chain precursor, and immunoglobulin heavy-chain, respectively. The large amount of albumin in the plasma protein peak and the confined presence of Vtg AB2b to within Ldl/Hdl reinforce the lipoprotein classification. Lastly, transcript levels of genes encoding ovarian lipoprotein lipase (lpl), apolipoprotein E (apoe), very low-density lipoprotein receptors (vldlr), and low-density lipoprotein receptor-related protein 8-like (lrp8) were estimated using quantitative RT-PCR. The high mRNA levels of lpl, apoe, and lipoprotein receptors vldlr and lrp8 in previtellogenic females suggest that sturgeon oocytes need to be prepared to accept and traffic Vtg and lipids internally, before the start of vitellogenesis.


Assuntos
Lipase Lipoproteica/metabolismo , Lipoproteínas VLDL/sangue , Ovário/crescimento & desenvolvimento , Triglicerídeos/metabolismo , Animais , Apolipoproteínas E/metabolismo , Colesterol/sangue , Feminino , Lipoproteínas LDL/metabolismo , Ovário/metabolismo
9.
Food Chem ; 332: 127405, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603919

RESUMO

The two-phase technology for olive oil extraction generates large amounts of patè olive cake (POC), a by-product that is rich in bioactive health-promoting compounds. Here, response surface methodology (RSM) was used to maximize supercritical-CO2 oil extraction from POC, while minimizing operative temperature, pressure and time. Under the optimal parameters (40.2 °C, 43.8 MPa and time 30 min), the oil yield was 14.5 g·100 g-1 dw (~65% of the total oil content of the freeze-dried POC matrix), as predicted by RSM. Compared with freeze-dried POC, the oil contained more phytosterols (13-fold), tocopherols (6-fold) and squalene (8-fold) and was a good source of pentacyclic triterpenes. When the biological effects of POC oil intake (20-40 µL·die-1) were evaluated in the livers of BALB/c mice, no significant influence on redox homeostasis was observed. Notably, a decline in liver triglycerides alongside increased activities of NAD(P)H:Quinone Oxidoreductase 1, Carnitine Palmitoyl-CoA Transferase and mitochondrial respiratory complexes suggested a potential beneficial effect on liver fatty acid oxidation.


Assuntos
Cromatografia com Fluido Supercrítico/métodos , Azeite de Oliva/química , Animais , Dióxido de Carbono/química , Peroxidação de Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Olea/metabolismo , Azeite de Oliva/isolamento & purificação , Azeite de Oliva/farmacologia , Fitosteróis/química , Fitosteróis/isolamento & purificação , Propriedades de Superfície , Temperatura , Tocoferóis/química , Tocoferóis/isolamento & purificação , Triglicerídeos/metabolismo
10.
Life Sci ; 257: 118028, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32615185

RESUMO

AIMS: Sertoli cells (SCs) play an important role in the process of spermatogenesis. SCs provide energy for germ cells (GCs) and themselves through glycolysis and fatty acid oxidation (FAO) respectively. High fat diet (HFD) impairs spermatogenesis by damaging function of SCs, however whether HFD disrupts energy metabolism in SCs remains unclear. MAIN METHODS: To explore this hypothesis, we built male Wistar rat model fed on HFD and cultured rats' primary SCs with palmitic acid (PA). Rats' fertility and sperm quality were evaluated in vivo. Glycolysis, lactate production and mitochondrial respiration were assessed by using extracellular flux analyzer, and the expression of enzymes involved in glucose and FAO was analyzed by Real-Time PCR or Western Blotting. KEY FINDINGS: The showed that the sperm concentration and pups per litter significantly decreased in rats fed on HFD compared to those rats fed on normal diet. There was an elevation of lactate levels in testicular tissue of rats fed on HFD and primary SCs exposed to PA. In vitro, PA increased glycolytic flux, and lactate production, and the levels of carnitine palmitoyltransferase I (CPT1) and long chain acyl-CoA dehydrogenase (LCAD) which were two key enzymes for fatty acid ß oxidation. Further analysis showed that mitochondrial respiration was impaired by PA, followed by the decrease in ATP turnover, maximal respiration and the increase in proton leak. SIGNIFICANCE: Taken together, the elevated lactate level, lipid metabolism disorder and mitochondrial dysfunction caused by HFD lead to SCs dysfunction, which ultimately leads to decreased sperm quality.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Células de Sertoli/metabolismo , Espermatogênese/fisiologia , Animais , Metabolismo Energético , Ácidos Graxos/metabolismo , Glucose/metabolismo , Glicólise , Insulina/metabolismo , Metabolismo dos Lipídeos/fisiologia , Masculino , Oxirredução , Ácido Palmítico , Ratos , Ratos Wistar , Triglicerídeos/metabolismo
11.
PLoS Pathog ; 16(6): e1008554, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32542055

RESUMO

Lipid droplets are essential cellular organelles for storage of fatty acids and triglycerides. The hepatitis C virus (HCV) translocates several of its proteins onto their surface and uses them for production of infectious progeny. We recently reported that the lipid droplet-associated α/ß hydrolase domain-containing protein 5 (ABHD5/CGI-58) participates in HCV assembly by mobilizing lipid droplet-associated lipids. However, ABHD5 itself has no lipase activity and it remained unclear how ABHD5 mediates lipolysis critical for HCV assembly. Here, we identify adipose triglyceride lipase (ATGL) as ABHD5 effector and new host factor involved in the hepatic lipid droplet degradation as well as in HCV and lipoprotein morphogenesis. Modulation of ATGL protein expression and lipase activity controlled lipid droplet lipolysis and virus production. ABHD4 is a paralog of ABHD5 unable to activate ATGL or support HCV assembly and lipid droplet lipolysis. Grafting ABHD5 residues critical for activation of ATGL onto ABHD4 restored the interaction between lipase and co-lipase and bestowed the pro-viral and lipolytic functions onto the engineered protein. Congruently, mutation of the predicted ABHD5 protein interface to ATGL ablated ABHD5 functions in lipid droplet lipolysis and HCV assembly. Interestingly, minor alleles of ABHD5 and ATGL associated with neutral lipid storage diseases in human, are also impaired in lipid droplet lipolysis and their pro-viral functions. Collectively, these results show that ABHD5 cooperates with ATGL to mobilize triglycerides for HCV infectious virus production. Moreover, viral manipulation of lipid droplet homeostasis via the ABHD5-ATGL axis, akin to natural genetic variation in these proteins, emerges as a possible mechanism by which chronic HCV infection causes liver steatosis.


Assuntos
1-Acilglicerol-3-Fosfato O-Aciltransferase/metabolismo , Hepacivirus/fisiologia , Lipase/metabolismo , Gotículas Lipídicas/metabolismo , Lipólise , Montagem de Vírus/fisiologia , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , Linhagem Celular Tumoral , Ativação Enzimática , Células HEK293 , Humanos , Lipase/genética , Gotículas Lipídicas/virologia , Triglicerídeos/genética , Triglicerídeos/metabolismo
12.
Am J Clin Nutr ; 112(2): 373-380, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32511694

RESUMO

BACKGROUND: Evidence suggests low-grade inflammation as the cause of metabolic syndrome and suggests diet as a promoter of chronic inflammation. OBJECTIVE: We evaluated the association between inflammatory diets and the development of metabolic syndrome in Mexican adults. METHODS: A total of 399 participants of the Health Workers Cohort Study were included in this study. The follow-up period was 13 y. Metabolic syndrome definition was the presence of ≥3 of the following components: waist circumference ≥102 cm for males or ≥88 cm for females, blood pressure ≥130 mmHg for systolic or ≥85 mmHg for diastolic, HDL cholesterol <40 mg/dL for males and <50 mg/dL for females; triglycerides ≥150 mg/dL, and glucose ≥100 mg/dL. To evaluate the inflammatory potential of the diet we used the Dietary Inflammatory Index (DII), which was divided into quartiles. To assess the risk of metabolic syndrome we estimated HRs and 95% CIs using Cox proportional hazards models. RESULTS: After adjustment for potential confounders, we found a positive association between participants in the highest quartile (Q) of DII and the incidence of metabolic syndrome (HRQ4vsQ1 = 1.99; 95% CI: 1.03, 3.85; P-trend = 0.04) over a period of 13 y. When we divided the metabolic syndrome by its components, we found that participants in the highest quartile of DII were associated with hypertriglyceridemia (HRQ4vsQ1 = 2.28; 95% CI: 1.13, 4.57; P-trend = 0.01), hypertension (HRQ4vsQ1 = 2.22; 95% CI: 1.03, 4.77; P-trend = 0.032), and abdominal obesity (HRQ4vsQ1 = 2.68; 95% CI: 1.06, 6.79; P-trend = 0.02). CONCLUSIONS: A highly inflammatory diet is associated with metabolic syndrome, hypertension, abdominal obesity, and hypertriglyceridemia. Further studies are needed to corroborate the role of inflammation and diet in the development of metabolic syndrome; yet, a reduction in dietary components that have been linked to inflammation is desirable.


Assuntos
Dieta/efeitos adversos , Síndrome Metabólica/etnologia , Síndrome Metabólica/imunologia , Adulto , Glicemia/metabolismo , Pressão Sanguínea , HDL-Colesterol/metabolismo , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/fisiopatologia , Americanos Mexicanos , Pessoa de Meia-Idade , Triglicerídeos/metabolismo
13.
Clin Sci (Lond) ; 134(12): 1537-1553, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32556103

RESUMO

Hyperuricaemia (HUA) significantly increases the risk of metabolic syndrome and is strongly associated with the increased prevalence of high serum free fatty acids (FFAs) and insulin resistance. However, the underlying mechanisms are not well established, especially the effect of uric acid (UA) on adipose tissue, a vital organ in regulating whole-body energy and FFA homeostasis. In the present study, we noticed that adipocytes from the white adipose tissue of patients with HUA were hypertrophied and had decreased UCP1 expression. To test the effects of UA on adipose tissue, we built both in vitro and in vivo HUA models and elucidated that a high level of UA could induce hypertrophy of adipocytes, inhibit their hyperplasia and reduce their beige-like characteristics. According to mRNA-sequencing analysis, UA significantly decreased the expression of leptin in adipocytes, which was closely related to fatty acid metabolism and the AMPK signalling pathway, as indicated by KEGG pathway analysis. Moreover, lowering UA using benzbromarone (a uricosuric agent) or metformin-induced activation of AMPK expression significantly attenuated UA-induced FFA metabolism impairment and adipose beiging suppression, which subsequently alleviated serum FFA elevation and insulin resistance in HUA mice. Taken together, these observations confirm that UA is involved in the aetiology of metabolic abnormalities in adipose tissue by regulating leptin-AMPK pathway, and metformin could lessen HUA-induced serum FFA elevation and insulin resistance by improving adipose tissue function via AMPK activation. Therefore, metformin could represent a novel treatment strategy for HUA-related metabolic disorders.


Assuntos
Adipócitos/patologia , Tecido Adiposo Bege/patologia , Tecido Adiposo Branco/patologia , Ácidos Graxos não Esterificados/sangue , Hiperuricemia/sangue , Hiperuricemia/tratamento farmacológico , Resistência à Insulina , Metformina/uso terapêutico , Células 3T3-L1 , Adenilato Quinase/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Adulto , Animais , Ativação Enzimática , Feminino , Humanos , Hipertrofia , Leptina/metabolismo , Lipogênese , Lipólise , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transdução de Sinais , Triglicerídeos/metabolismo , Ácido Úrico/sangue
14.
Nat Med ; 26(6): 964-973, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32528151

RESUMO

Metabolic responses to food influence risk of cardiometabolic disease, but large-scale high-resolution studies are lacking. We recruited n = 1,002 twins and unrelated healthy adults in the United Kingdom to the PREDICT 1 study and assessed postprandial metabolic responses in a clinical setting and at home. We observed large inter-individual variability (as measured by the population coefficient of variation (s.d./mean, %)) in postprandial responses of blood triglyceride (103%), glucose (68%) and insulin (59%) following identical meals. Person-specific factors, such as gut microbiome, had a greater influence (7.1% of variance) than did meal macronutrients (3.6%) for postprandial lipemia, but not for postprandial glycemia (6.0% and 15.4%, respectively); genetic variants had a modest impact on predictions (9.5% for glucose, 0.8% for triglyceride, 0.2% for C-peptide). Findings were independently validated in a US cohort (n = 100 people). We developed a machine-learning model that predicted both triglyceride (r = 0.47) and glycemic (r = 0.77) responses to food intake. These findings may be informative for developing personalized diet strategies. The ClinicalTrials.gov registration identifier is NCT03479866.


Assuntos
Glicemia/metabolismo , Microbioma Gastrointestinal , Insulina/metabolismo , Nutrientes , Período Pós-Prandial , Triglicerídeos/metabolismo , Adolescente , Adulto , Idoso , Peptídeo C/metabolismo , Carboidratos da Dieta , Gorduras na Dieta , Fibras na Dieta , Proteínas na Dieta , Feminino , Variação Genética , Teste de Tolerância a Glucose , Voluntários Saudáveis , Humanos , Individualidade , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medicina de Precisão , Adulto Jovem
15.
Arterioscler Thromb Vasc Biol ; 40(8): 1935-1941, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32580631

RESUMO

OBJECTIVE: Genetic determinants of severe hypertriglyceridemia include both common variants with small effects (assessed using polygenic risk scores) plus heterozygous and homozygous rare variants in canonical genes directly affecting triglyceride metabolism. Here, we broadened our scope to detect associations with rare loss-of-function variants in genes affecting noncanonical pathways, including those known to affect triglyceride metabolism indirectly. Approach and Results: From targeted next-generation sequencing of 69 metabolism-related genes in 265 patients of European descent with severe hypertriglyceridemia (≥10 mmol/L or ≥885 mg/dL) and 477 normolipidemic controls, we focused on the association of rare heterozygous loss-of-function variants in individual genes. We observed that compared with controls, severe hypertriglyceridemia patients were 20.2× (95% CI, 1.11-366.1; P=0.03) more likely than controls to carry a rare loss-of-function variant in CREB3L3, which encodes a transcription factor that regulates several target genes with roles in triglyceride metabolism. CONCLUSIONS: Our findings indicate that rare variants in a noncanonical gene for triglyceride metabolism, namely CREB3L3, contribute significantly to severe hypertriglyceridemia. Secondary genes and pathways should be considered when evaluating the genetic architecture of this complex trait.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Hipertrigliceridemia/genética , Adulto , Idoso , Apolipoproteína A-V/genética , Feminino , Heterozigoto , Humanos , Lipase Lipoproteica/genética , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Triglicerídeos/metabolismo
16.
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
17.
Science ; 368(6498): 1495-1499, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32587022

RESUMO

Although sled dogs are one of the most specialized groups of dogs, their origin and evolution has received much less attention than many other dog groups. We applied a genomic approach to investigate their spatiotemporal emergence by sequencing the genomes of 10 modern Greenland sled dogs, an ~9500-year-old Siberian dog associated with archaeological evidence for sled technology, and an ~33,000-year-old Siberian wolf. We found noteworthy genetic similarity between the ancient dog and modern sled dogs. We detected gene flow from Pleistocene Siberian wolves, but not modern American wolves, to present-day sled dogs. The results indicate that the major ancestry of modern sled dogs traces back to Siberia, where sled dog-specific haplotypes of genes that potentially relate to Arctic adaptation were established by 9500 years ago.


Assuntos
Adaptação Fisiológica/genética , Cães/genética , Animais , Apolipoproteínas/genética , Regiões Árticas , Ácidos Graxos/metabolismo , Genoma , Groenlândia , Haplótipos , Proteínas de Transporte da Membrana Mitocondrial/genética , Seleção Artificial , Análise de Sequência de DNA , Sibéria , Triglicerídeos/metabolismo , Lobos/genética
18.
J Food Sci ; 85(6): 1907-1914, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32421231

RESUMO

Different chain lengths diacylglycerols (DAG) (long- and medium-chain) were synthesized from peanut and coconut oils. The effects of DAG with different chain lengths on body fat, blood lipids, and lipid metabolism-related enzymes in the liver and adipose tissue of C57BL/6J mice were investigated. Compared to peanut and coconut oils containing triacylglycerol (TAG), DAG-rich oils can significantly reduce the body weight, kidney weight, serum triglyceride (TG) content, hepatic fatty acid synthase (FAS), and Acetyl-CoA carboxylase (ACC) enzyme levels (p < 0.05) in C57BL/6J mice. Therefore, the effect of coconut oil DAG on improving body fat metabolism was probably due to the impact of DAG. Meanwhile, the body weight and serum TG content in coconut oil DAG group were lower than those in peanut oil DAG group. In addition, the spleen weight, hepatic ACC, and lipoprotein lipase (LPL) enzymes in coconut oil DAG group (0.07 ± 0.01 g, 2.08 ± 0.42 ng/mg pro, and 18.44 ± 5.23 ng/mg pro, respectively) were significantly lower than those in peanut oil DAG group. Although coconut oil DAG and peanut oil DAG have different fatty acid compositions, their effects on lipid metabolism showed no significant changes. Coconut oil DAG (peanut oil DAG) showed the improved lipid metabolism than that of coconut oil (peanut oil), which was probably due to the effect of DAG. PRACTICAL APPLICATION: Peanut and coconut oils are common edible oils. The oil containing DAG synthesized decreased the body weight and lipid accumulation in mice. Coconut oil is rich in medium-chain fatty acids, while peanut oil mainly consists of long-chain fatty acids. Due to the different contents of fatty acids, the synthesized structural lipids have different effects on lipid metabolism. Medium-chain triglycerides were considered as agents to alleviate obesity.


Assuntos
Óleo de Coco/metabolismo , Diglicerídeos/metabolismo , Obesidade/dietoterapia , Óleo de Amendoim/metabolismo , Triglicerídeos/metabolismo , Tecido Adiposo/metabolismo , Animais , Óleo de Coco/química , Ácido Graxo Sintases/metabolismo , Ácidos Graxos/metabolismo , Humanos , Metabolismo dos Lipídeos , Lipase Lipoproteica/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/fisiopatologia , Óleo de Amendoim/química
19.
Am J Physiol Endocrinol Metab ; 319(1): E146-E162, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32421370

RESUMO

Secreted hormones facilitate tissue cross talk to maintain energy balance. We previously described C1q/TNF-related protein 12 (CTRP12) as a novel metabolic hormone. Gain-of-function and partial-deficiency mouse models have highlighted important roles for this fat-derived adipokine in modulating systemic metabolism. Whether CTRP12 is essential and required for metabolic homeostasis is unknown. We show here that homozygous deletion of Ctrp12 gene results in sexually dimorphic phenotypes. Under basal conditions, complete loss of CTRP12 had little impact on male mice, whereas it decreased body weight (driven by reduced lean mass and liver weight) and improved insulin sensitivity in female mice. When challenged with a high-fat diet, Ctrp12 knockout (KO) male mice had decreased energy expenditure, increased weight gain and adiposity, elevated serum TNFα level, and reduced insulin sensitivity. In contrast, female KO mice had reduced weight gain and liver weight. The expression of lipid synthesis and catabolism genes, as well as profibrotic, endoplasmic reticulum stress, and oxidative stress genes were largely unaffected in the adipose tissue of Ctrp12 KO male mice. Despite greater adiposity and insulin resistance, Ctrp12 KO male mice fed an obesogenic diet had lower circulating triglyceride and free fatty acid levels. In contrast, lipid profiles of the leaner female KO mice were not different from those of WT controls. These data suggest that CTRP12 contributes to whole body energy metabolism in genotype-, diet-, and sex-dependent manners, underscoring complex gene-environment interactions influencing metabolic outcomes.


Assuntos
Adipocinas/genética , Peso Corporal/genética , Dieta Hiperlipídica , Metabolismo Energético/genética , Resistência à Insulina/genética , Tecido Adiposo/metabolismo , Adiposidade/genética , Animais , Estresse do Retículo Endoplasmático/genética , Ácidos Graxos não Esterificados/metabolismo , Feminino , Fibrose/genética , Expressão Gênica , Interação Gene-Ambiente , Metabolismo dos Lipídeos/genética , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Tamanho do Órgão , Estresse Oxidativo/genética , Fatores Sexuais , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ganho de Peso/genética
20.
Cardiovasc Diabetol ; 19(1): 70, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471503

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that collectively cause an increased risk of type 2 diabetes mellitus (T2DM) and nonatherosclerotic cardiovascular disease. This study aimed to evaluate the role of myocardial steatosis in T2DM patients with or without MetS, as well as the relationship between subclinical left ventricular (LV) myocardial dysfunction and myocardial steatosis. METHODS AND MATERIALS: We recruited 53 T2DM patients and 20 healthy controls underwent cardiac magnetic resonance examination. All T2DM patients were subdivide into two group: MetS group and non-MetS. LV deformation, perfusion parameters and myocardial triglyceride (TG) content were measured and compared among these three groups. Pearson's and Spearman analysis were performed to investigate the correlation between LV cardiac parameters and myocardial steatosis. The receiver operating characteristic curve (ROC) was performed to illustrate the relationship between myocardial steatosis and LV subclinical myocardial dysfunction. RESULTS: An increase in myocardial TG content was found in the MetS group compared with that in the other groups (MetS vs. non-MetS: 1.54 ± 0.63% vs. 1.16 ± 0.45%; MetS vs. normal: 1.54 ± 0.63% vs. 0.61 ± 0.22%; all p < 0.001). Furthermore, reduced LV deformation [reduced longitudinal and radial peak strain (PS); all p < 0.017] and microvascular dysfunction [increased time to maximum signal intensity (TTM) and reduced Upslope; all p < 0.017)] was found in the MetS group. Myocardial TG content was positively associated with MetS (r = 0.314, p < 0.001), and it was independently associated with TTM (ß = 0.441, p < 0.001) and LV longitudinal PS (ß = 0.323, p = 0.021). ROC analysis exhibited that myocardial TG content might predict the risk of decreased LV longitudinal myocardial deformation (AUC = 0.74) and perfusion function (AUC = 0.71). CONCLUSION: Myocardial TG content increased in T2DM patients with concurrent MetS. Myocardial steatosis was positively associated with decreased myocardial deformation and perfusion dysfunction, which may be an indicator for predicting diabetic cardiomyopathy.


Assuntos
Cardiomiopatias/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Síndrome Metabólica/metabolismo , Miocárdio/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Triglicerídeos/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Adulto , Idoso , Doenças Assintomáticas , Biomarcadores/metabolismo , Cardiomiopatias/diagnóstico , Cardiomiopatias/fisiopatologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Miocárdio/patologia , Variações Dependentes do Observador , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/fisiopatologia
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