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2.
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
3.
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
4.
Medicine (Baltimore) ; 99(32): e21464, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769877

RESUMO

To investigate the effects of probiotics on liver function, glucose and lipids metabolism, and hepatic fatty deposition in patients with non-alcoholic fatty liver disease (NAFLD).Totally 140 NAFLD cases diagnosed in our hospital from March 2017 to March 2019 were randomly divided into the observation group and control group, 70 cases in each. The control group received the diet and exercise therapy, while the observation group received oral probiotics based on the control group, and the intervention in 2 groups lasted for 3 months. The indexes of liver function, glucose and lipids metabolism, NAFLD activity score (NAS), and conditions of fecal flora in 2 groups were compared before and after the treatment.Before the treatment, there were no significant differences on alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamine transferase (GGT), total bilirubin (TBIL), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), insulin resistance index (HOMA-IR), NAFLD activity score (NAS), and conditions of fecal flora in 2 groups (P > .05). After the treatment, ALT, AST, GGT, TC, TG, HOMA-IR, NAS, and conditions of fecal flora in the observation group were better than those in the control group, and the observation group was better after treatment than before. All these above differences were statistically significant (P < .05).Probiotics can improve some liver functions, glucose and lipids metabolism, hepatic fatty deposition in patients with NAFLD, which will enhance the therapeutic effects of NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica/terapia , Probióticos/uso terapêutico , Adulto , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Resultado do Tratamento
5.
Wiad Lek ; 73(7): 1373-1376, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32759423

RESUMO

OBJECTIVE: The aim: To assess carbohydrate and lipid metabolic profiles of tuberculosis patients with bilateral injuries of the lungs and mycobacteria excretion. PATIENTS AND METHODS: Materials and methods: Seventy two newly diagnosed pulmonary TB patients were examined. Group I - 17 newly diagnosed TB patients who had unilateral pulmonary lesions and had no mycobacteria excretion. Group II - 55 newly diagnosed TB patients who had bilateral pulmonary lesions and mycobacteria excretion. The control group included 20 healthy persons. Fasting insulin level, indices of lipidogram were measured, oral glucose tolerance test was performed. Statistical processing of the obtained results was carried out by analyzing the contingency tables using the StatisticaBasicAcademic 13 for Windows software package. RESULTS: Results: Tuberculosis patients develop insulin resistance - condition that is a precursor to developing type 2 diabetes and metabolic disorder of lipid exchange - dyslipidemia. Patients with bilateral pulmonary lesions and mycobacteria excretion have the most pronounced disorders of carbohydrate and lipid metabolism compared to patients with limited lesions of the lungs. CONCLUSION: Conclusions: We suppose that mycobacteria excretion and bilateral lesions of lungs may be the markers of the degree of carbohydrate and lipid metabolism disorders in patients with pulmonary tuberculosis.


Assuntos
Tuberculose , Carboidratos , Diabetes Mellitus Tipo 2 , Humanos , Metabolismo dos Lipídeos , Lipídeos , Metaboloma
6.
Medicine (Baltimore) ; 99(34): e21744, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846797

RESUMO

BACKGROUND: In recent years, clinical studies about Yangxin Decoction combined acupuncture (YXDA) for the treatment of Qi Deficiency and Blood Stasis type of Chest Bi-Syndrome (CBS-QDBS) has been increased, but the results are different. The aim of this study is to investigate the effect of YXDA on blood lipid metabolism (BLMB) in patients with CBS-QDBS. METHODS: We will collect any randomized controlled trials that assess the effect of YXDA on BLMB in CBS-QDBS from PUBMED, EMBASE, Cochrane Library, PsycINFO, CINAHL, Allied and Complementary Medicine Database, and China National Knowledge Infrastructure. All of these databases will be searched from their initial time to the present. All language limitation will be imposed. Literature selection, information collection, and risk of bias assessment will be performed independently by two authors, respectively. All data analysis will be undertaken using RevMan 5.3 Software. RESULTS: This study will summarize the systematic nature of the literature search and its methods for assessing study quality and analyzing all relevant outcome data. Considering the inconsistent results, this study will improve the existing evidence on the effect of YXDA on BLMB in CBS-QDBS. CONCLUSION: The findings of this study will present the latest evidence of YXDA on BLMB in patients with CBS-QDBS. STUDY REGISTRATION: INPLASY202070047.


Assuntos
Terapia por Acupuntura/métodos , Dor no Peito/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Qi , Terapia Combinada , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
7.
Toxicol Lett ; 332: 42-55, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32629074

RESUMO

Obesity is associated with several female reproductive complications, such as polycystic ovary syndrome (PCOS). The exact mechanism of this relationship remains unclear. Few previous studies using diet containing refined carbohydrate (HCD) leading to obesity have been performed and it is unclear if HCD is linked with reproductive dysfunctions. In this investigation, we assessed whether subchronic HCD exposure results in reproductive and other irregularities. Female rats were fed with HCD for 15 days and metabolic outcomes and reproductive tract morphophysiology were assessed. We further assessed reproductive tract inflammation, oxidative stress (OS) and fibrosis. HCD rats displayed metabolic impairments, such as an increase in body weight/adiposity, adipocyte hypertrophic, abnormal lipid profile, glucose tolerance and insulin resistance (IR) and hyperleptinemia. Improper functioning of the HCD reproductive tract was observed. Specifically, irregular estrous cyclicity, high LH levels and abnormal ovarian morphology coupled with reduction in primordial and primary follicle numbers was observed, suggesting ovarian reserve depletion. Improper follicular development and a reduction in antral follicles, corpora lutea and granulosa layer area together with an increase in cystic follicles were apparent. Uterine atrophy and reduction in endometrial gland (GE) number was observed in HCD rats. Reproductive tract inflammation, OS and fibrosis were seen in HCD rats. Further, strong positive correlations were observed between body weight/adiposity and IR with estrous cycle length, cystic follicles, ovarian reserve, GE and other abnormalities. Thus, these data suggest that the subchronic HCD exposure led to PCOS-like features, impaired ovarian reserve, GE number, and other reproductive abnormalities in female rats.


Assuntos
Carboidratos da Dieta/toxicidade , Reserva Ovariana/efeitos dos fármacos , Ovário/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Adiposidade/efeitos dos fármacos , Animais , Peso Corporal , Dieta , Ciclo Estral/efeitos dos fármacos , Feminino , Fibrose , Intolerância à Glucose/sangue , Intolerância à Glucose/induzido quimicamente , Resistência à Insulina , Leptina/sangue , Metabolismo dos Lipídeos , Folículo Ovariano/efeitos dos fármacos , Ovário/patologia , Estresse Oxidativo , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Ratos , Ratos Wistar
8.
Proc Natl Acad Sci U S A ; 117(29): 17381-17388, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632018

RESUMO

Adiponectin (Acrp30) is an adipokine associated with protection from cardiovascular disease, insulin resistance, and inflammation. Although its effects are conventionally attributed to binding Adipor1/2 and T-cadherin, its abundance in circulation, role in ceramide metabolism, and homology to C1q suggest an overlooked role as a lipid-binding protein, possibly generalizable to other C1q/TNF-related proteins (CTRPs) and C1q family members. To investigate this, adiponectin, representative family members, and variants were expressed in Expi293 cells and tested for binding to lipids in liposomes using density centrifugation. Binding to physiological lipids were also analyzed using gradient ultracentrifugation, liquid chromatography-mass spectrometry, and shotgun lipidomics. Interestingly, adiponectin selectively bound several anionic phospholipids and sphingolipids, including phosphatidylserine, ceramide-1-phosphate, glucosylceramide, and sulfatide, via the C1q domain in an oligomerization-dependent fashion. Binding to lipids was observed in liposomes, low-density lipoproteins, cell membranes, and plasma. Other CTRPs and C1q family members (Cbln1, CTRP1, CTRP5, and CTRP13) also bound similar lipids. These findings suggest that adiponectin and CTRPs function not only as hormones, but also as lipid opsonins, as may other C1q family proteins.


Assuntos
Adiponectina/metabolismo , Complemento C1q/metabolismo , Fosfolipídeos/metabolismo , Esfingolipídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adipocinas/metabolismo , Adiponectina/genética , Animais , Ânions , Membrana Celular , LDL-Colesterol , Humanos , Metabolismo dos Lipídeos , Lipidômica , Lipoproteínas/metabolismo , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Opsonizantes/metabolismo , Plasma
9.
Toxicol Lett ; 332: 65-73, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32649966

RESUMO

Exposure to multi-walled carbon nanotubes (MWCNTs) might induce lipid droplet (LD) biogenesis, but the roles of physicochemical properties of MWCNTs, as well as the mechanisms, remain poorly understood. In this study, we investigated lipid laden foam formation in THP-1 macrophages exposed to MWCNTs of different diameters, and attempted transcriptomic analysis to study the possible mechanisms. We observed diameter-dependent cytotoxicity, lipid accumulation and intracellular reactive oxygen species production that were more pronounced for MWCNTs with smaller diameters compared with those with larger diameters. However, more MWCNTs with larger diameters were retained in macrophages after 24 h exposure. One possible explanation for the inverse relationship between MWCNT bio-effects and internalization is that macrophages altered the expression of exocytotic genes to export toxic MWCNTs. Transcriptomic data showed that MWCNTs with smaller diameters more effectively altered the expression of genes related with cytotoxicity and lipid metabolism, and KEGG pathway analysis suggested that MWCNTs with smaller diameters activated peroxisome proliferator-activated receptor (PPAR) signalling pathway (map03320), leading to over-expression of perilipin 2, the surface proteins of LDs. Western blot confirmed that MWCNTs effectively promoted CD36, PPARγ and perilipin 2, key components in map03320. Moreover, inhibition of PPARγ by chemicals or siRNA significantly inhibited lipid accumulation induced by MWCNTs with smaller diameters, and perilipin 2 proteins in MWCNT-exposed macrophages could be decreased by PPARγ siRNA. In conclusion, the results of this study revealed the induction of LDs by MWCNTs in a diameter-dependent manner through the activation of PPAR signalling pathway.


Assuntos
Gotículas Lipídicas/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Tamanho da Partícula , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos
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.
Eur J Endocrinol ; 183(4): 439-452, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698159

RESUMO

Objective: Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. Design: Randomized, double-blind, crossover pilot trial with washout was conducted at Pennington Biomedical Research Center. Eight postmenopausal women (age 50-60 years, BMI 30-40 kg/m2) were randomized to 8 weeks CE/BZA or placebo. Primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp). Secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); serum inflammatory markers; and serum metabolome (LC/MS). Results: CE/BZA treatment produced no detectable effect on insulin sensitivity, body composition, ectopic fat, fat cell size, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: P = 0.06; high-dose clamp: P = 0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein (HDL)-cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs) and decreased long-chain acylcarnitines, possibly reflecting increased hepatic de novo FA synthesis and esterification into TAGs for export into very low-density lipoproteins, as well as decreased FA oxidation, respectively (P < 0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in serum lipoproteins (P < 0.05). Conclusions: A short treatment of obese postmenopausal women with CE/BZA does not alter insulin action or ectopic fat but increases serum markers of hepatic de novo lipogenesis and TAG production.


Assuntos
Metabolismo dos Carboidratos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Estrogênios Conjugados (USP)/farmacologia , Glucose/metabolismo , Indóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Estrogênios Conjugados (USP)/uso terapêutico , Feminino , Humanos , Indóis/uso terapêutico , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Projetos Piloto , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/metabolismo
12.
PLoS One ; 15(7): e0235338, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609782

RESUMO

The goal of this study was to use liquid chromatography mass spectrometry to assess metabolic changes of two different diets in three distinct rat strains. Sprague-Dawley, Fischer 344, and Brown-Norway male rats were maintained on a high-fat, or regular diet for 24 weeks. Liver tissue was collected at 4, 12, and 24 weeks to assess global small molecule metabolite changes using high resolution accurate mass spectrometry coupled to ultra-high-performance liquid chromatography. The results of the global metabolomics analysis revealed significant changes based on both age and diet within all three strains. Principal component analysis revealed that the influence of diet caused a greater variation in significantly changing metabolites than that of age for the Brown Norway and Fisher 344 strains, whereas diet had the greatest influence in the Sprague Dawley strain only at the 4-week time point. As expected, metabolites involved in lipid metabolism were changed in the animals maintained on a high fat diet compared to the regular diet. There were also significant changes observed in the concentration of Tri carboxylic acid cycle intermediates that were extracted from the liver of all three strains based on diet. The results of this study showed that a high fat diet caused significant liver and metabolic changes compared to a regular diet in multiple rat strains. The inbred Fisher 344 and Brown Norway rats were more metabolically sensitive to the diet changes than outbred Sprague Dawley strain. The study also showed that age, as was the case for Sprague Dawley, is an important variable to consider when assessing metabolic changes.


Assuntos
Fatores Etários , Dieta Hiperlipídica/efeitos adversos , Fígado/metabolismo , Metaboloma , Metabolômica/métodos , Animais , Cromatografia Líquida de Alta Pressão , Ciclo do Ácido Cítrico , Metabolismo dos Lipídeos , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos
13.
N Z Med J ; 133(1518): 54-63, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32683432

RESUMO

AIM: To describe patterns of community lipid testing and subsequent therapeutic alteration in a cohort of patients taking statins. METHOD: We conducted a population-based cohort study. Our cohort comprised all people enrolled with a general practice in the Pegasus Health primary care network in Canterbury, New Zealand between 1 January 2016 and 31 December 2017 who were dispensed a statin between 1 January 2016 and 30 June 2016. We defined two six-month study periods: a baseline period (1 January to 30 June 2016) and a follow-up period (1 July to 31 December 2017). We identified statin dispensings for all people in our cohort in both study periods, and identified instances of lipid testing in the 12 months following each person's most recent baseline period dispensing. We examined the effect of gender, ethnicity and socioeconomic deprivation on the likelihood of lipid testing; and compared frequency of alteration of statin dose or type among tested and non-tested people. RESULTS: Data were available for analysis for 32,943 individuals who were dispensed a statin in the baseline period. Lipid testing was performed in 16,199 (49.2%) of individuals. Women were less likely to have been tested than men (OR 0.87, 95% CI 0.83-0.91). Compared to those with European ethnicity, testing was more likely for Maori (OR 1.20, 95% CI 1.07-1.34), Pacific (OR 1.22, 95% CI 1.03-1.44) and Asian (OR 1.41, 95% CI 1.25-1.59) individuals. Socioeconomic deprivation was associated with reduced testing (OR 0.80, 95% CI 0.74-0.87). Dose or type of statin dispensed was altered between baseline and follow-up study periods in 3,762 (23.2%) of those who were tested, and in 3,122 (18.6%) of those who were not tested (OR 1.32, 95% CI 1.25-1.39). CONCLUSION: Almost half (49.1%) of patients had a lipid test within 12 months of baseline period statin dispensing. Lipid testing was more likely for Maori, Pacific and Asian patients than for European patients. Testing was less likely for women and for those with greater socioeconomic deprivation. Subsequent statin therapy alteration was slightly more likely for those who had been tested than for those who had not.


Assuntos
Doenças Cardiovasculares/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metabolismo dos Lipídeos/fisiologia , Monitorização Fisiológica/métodos , Atenção Primária à Saúde/estatística & dados numéricos , Fatores Etários , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Morbidade/tendências , Nova Zelândia/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida/tendências
14.
Nat Commun ; 11(1): 3298, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620747

RESUMO

Communication between organelles is essential for their cellular homeostasis. Neurodegeneration reflects the declining ability of neurons to maintain cellular homeostasis over a lifetime, where the endolysosomal pathway plays a prominent role by regulating protein and lipid sorting and degradation. Here we report that TMEM16K, an endoplasmic reticulum lipid scramblase causative for spinocerebellar ataxia (SCAR10), is an interorganelle regulator of the endolysosomal pathway. We identify endosomal transport as a major functional cluster of TMEM16K in proximity biotinylation proteomics analyses. TMEM16K forms contact sites with endosomes, reconstituting split-GFP with the small GTPase RAB7. Our study further implicates TMEM16K lipid scrambling activity in endosomal sorting at these sites. Loss of TMEM16K function led to impaired endosomal retrograde transport and neuromuscular function, one of the symptoms of SCAR10. Thus, TMEM16K-containing ER-endosome contact sites represent clinically relevant platforms for regulating endosomal sorting.


Assuntos
Anoctaminas/metabolismo , Retículo Endoplasmático/metabolismo , Endossomos/metabolismo , Lisossomos/metabolismo , Animais , Anoctaminas/genética , Transporte Biológico , Células COS , Linhagem Celular Tumoral , Células Cultivadas , Chlorocebus aethiops , Retículo Endoplasmático/ultraestrutura , Endossomos/ultraestrutura , Células HEK293 , Humanos , Metabolismo dos Lipídeos , Lisossomos/ultraestrutura , Camundongos Knockout , Microscopia Eletrônica , Mutação , Transporte Proteico , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo
15.
Anticancer Res ; 40(7): 3697-3705, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620608

RESUMO

BACKGROUND/AIM: Time restricted feeding (TRF) mitigates the high-fat diet-enhanced mammary tumorigenesis in a MMTV-PyMT breast cancer model. MATERIALS AND METHODS: We performed untargeted metabolomic and targeted transcriptomic analyses on mammary tumors from MMTV-PyMT mice fed a standard AIN93G diet, a high-fat diet (HFD), or HFD with TRF (12 h, dark phase) and mammary glands from wild-type mice fed the AIN93G diet. RESULTS: The metabolic profile of mammary tumors differed from that of mammary glands; there was no impact of TRF upon tumor metabolome. TRF did reduce elevated expression of Hmgcr, Srebp1, Fads2, and Ppard in mammary tumors, indicating a down-regulation of lipid metabolism. CONCLUSION: The null effect of TRF on the metabolomic profile does not rule out changes in more refined intracellular signaling pathways. It suggests that the protection of TRF against mammary tumorigenesis may rely upon its action on the host rather than a direct effect on tumor metabolism.


Assuntos
Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Metaboloma/fisiologia , Obesidade/metabolismo , Animais , Carcinogênese/metabolismo , Dieta Hiperlipídica/métodos , Modelos Animais de Doenças , Regulação para Baixo/fisiologia , Feminino , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos
16.
Medicine (Baltimore) ; 99(29): e20735, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702819

RESUMO

BACKGROUND: Type 2 diabetes mellitus is one of the most common chronic diseases, which endangers peoples health and life qualities. Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been widely recognized since their clinical application in blood glucose control. While, dyslipidemia caused by SGLT2 inhibitors has been identified that affected the prognosis of this disease. METHODS: We will retrieve 8 databases including English and Chinese. After multiple screening, all randomized controlled trials (RCTs) related to SGLT2 inhibitors will be included by the 2 authors and data will be extracted. After completion of the risk of bias assessment, we will use these effect values including risk ratio (RR), weighted mean difference (WMD) and 95% confidence interval (CI) to conduct data analysis. Chi-Squared test and I test will be used to assess heterogeneity between studies. The robustness of meta-analysis results will be determined by sensitivity analysis. It will be assessed that evidence quality of the outcomes on the GRADE. RESULTS: The results of our research will be published in a peer-reviewed journal. CONCLUSION: The purpose of this systematic review and meta-analysis is to evaluate the association and degree of association between different doses of SGLT2 inhibitors and changes on blood lipid levels in patients with type 2 diabetes mellitus, in order to provide a reliable basis for clinical medication. INPLASY REGISTRATION NUMBER: INPLASY202040201.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Glicemia/efeitos dos fármacos , Estudos de Casos e Controles , Protocolos Clínicos/normas , Feminino , Humanos , Masculino , Placebos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
17.
Analyst ; 145(17): 5725-5732, 2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32696763

RESUMO

The SARS-CoV-2 virus is known as the causal agent for the current COVID-19 global pandemic. The majority of COVID-19 patients develop acute respiratory distress syndrome (ARDS), while some experience a cytokine storm effect, which is considered as one of the leading causes of patient mortality. Lipids are known to be involved in the various stages of the lifecycle of a virus functioning as receptors or co-receptors that controls viral propagation inside the host cell. Therefore, lipid-related metabolomics aims to provide insight into the immune response of the novel coronavirus. Our study has focused on determination of the potential metabolomic biomarkers utilizing a Teslin® Substrate in paper spray mass spectrometry (PS-MS) for the development of a rapid detection test within 60 seconds of analysis time. In this study, results were correlated with PCR tests to reflect that the systemic responses of the cells were affected by the COVID-19 virus.


Assuntos
Infecções por Coronavirus/patologia , Metabolismo dos Lipídeos/fisiologia , Espectrometria de Massas/métodos , Pneumonia Viral/patologia , Betacoronavirus/isolamento & purificação , Biomarcadores/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Análise Discriminante , Humanos , Lipídeos/análise , Nasofaringe/virologia , Pandemias , Papel , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia
18.
Life Sci ; 257: 118036, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622949

RESUMO

AIMS: Anti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice. MAIN METHODS: Male C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR. KEY FINDINGS: We found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid ß-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. SIGNIFICANCE: Therefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Leptina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 23-26, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476369

RESUMO

OBJECTIVE: To investigate the effects of aerobic exercise on Cdc2-like kinase (CLK2) protein expression and the fat content in liver of mice fed with high fat diet. METHODS: C57BL/6 mice were distributed in normal diet, high fat diet (fed with highfat diet during 16 weeks) and trained high fat diet group (fed with high-fat diet during 16 weeks and exercised during 8 weeks),10 mice in each group. The expression of CLK2 protein in liver of each group was detected by Western blot. The fat content of liver in each group was detected by oil red O staining, and the relative genes of fat metabolism in each group were evaluated by real-time quantitative PCR. RESULTS: The mice fed with high fat diet showed insulin resistance, the hepatic CLK2 content and fat content were increased compared to the normal diet group. Otherwise, the chronic physical exercise improved insulin resistance state, prevented the increasing of CLK2 in the liver and attenuated hepatic fat accumulation. CONCLUSION: Aerobic exercise could reduce the expression of CLK2 protein in the liver of mice fed with high fat diet.


Assuntos
Dieta Hiperlipídica , Resistência à Insulina , Fígado/enzimologia , Condicionamento Físico Animal , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos C57BL
20.
Cell ; 182(1): 59-72.e15, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32492406

RESUMO

Early detection and effective treatment of severe COVID-19 patients remain major challenges. Here, we performed proteomic and metabolomic profiling of sera from 46 COVID-19 and 53 control individuals. We then trained a machine learning model using proteomic and metabolomic measurements from a training cohort of 18 non-severe and 13 severe patients. The model was validated using 10 independent patients, 7 of which were correctly classified. Targeted proteomics and metabolomics assays were employed to further validate this molecular classifier in a second test cohort of 19 COVID-19 patients, leading to 16 correct assignments. We identified molecular changes in the sera of COVID-19 patients compared to other groups implicating dysregulation of macrophage, platelet degranulation, complement system pathways, and massive metabolic suppression. This study revealed characteristic protein and metabolite changes in the sera of severe COVID-19 patients, which might be used in selection of potential blood biomarkers for severity evaluation.


Assuntos
Infecções por Coronavirus/sangue , Metabolômica , Pneumonia Viral/sangue , Proteômica , Adulto , Aminoácidos/metabolismo , Biomarcadores/sangue , Análise por Conglomerados , Infecções por Coronavirus/fisiopatologia , Feminino , Humanos , Metabolismo dos Lipídeos , Aprendizado de Máquina , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , Índice de Gravidade de Doença
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