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

RESUMO

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


Assuntos
Autofagia/fisiologia , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia/metabolismo , Mitocôndrias/metabolismo , Animais , Autofagia/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Citometria de Fluxo , Humanos , Leucemia/genética , Leucemia Mieloide Aguda/patologia , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Lipogênese/genética , Lipogênese/fisiologia , Camundongos , Mitocôndrias/genética , Oxirredução , Fosforilação Oxidativa
2.
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
3.
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
4.
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
5.
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
6.
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
7.
PLoS One ; 15(6): e0234439, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530967

RESUMO

Disturbance of circadian rhythms underlies various metabolic diseases. Constant light exposure (LL) is known to disrupt both central and peripheral circadian rhythms. Here, we attempted to determine whether the effects of LL are different between various peripheral tissues and whether time-restricted feeding restores the circadian rhythms especially in white adipose tissue (WAT). Six-week-old mice were subjected to three feeding regimes: ad libitum feeding under light/dark phase (LD), ad libitum feeding under LL cycle, and restricted feeding at night-time under LL cycle with a normal chow. After 3 weeks, we compared body weight, food intake, plasma levels of lipids and glucose, and the expression patterns of the clock genes and the genes involved in lipid metabolism in the liver and WAT. The mice kept under LL with or without time-restricted feeding were 5.2% heavier (p<0.001, n = 16) than the mice kept under LD even though the food intakes of the two groups were the same. Food intake occurred mostly in the dark phase. LL disrupted this pattern, causing disruptions in circadian rhythms of plasma levels of triglycerides (TG) and glucose. Time-restricted feeding partially restored the rhythms. LL eliminated the circadian rhythms of the expression of the clock genes as well as most of the genes involved in lipid metabolism in both liver and WAT. More notably, LL markedly decreased not only the amplitude but also the average levels of the expression of the genes in the liver, but not in the WAT, suggesting that transcription in the liver is sensitive to constant light exposure. Time-restricted feeding restored the circadian rhythms of most of the genes to various degrees in both liver and WAT. In conclusion, LL disrupted the peripheral circadian rhythms more severely in liver than in WAT. Time-restricted feeding restored the circadian rhythms in both tissues.


Assuntos
Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Jejum/fisiologia , Luz/efeitos adversos , Metabolismo dos Lipídeos/fisiologia , Tecido Adiposo Branco/metabolismo , Animais , Ritmo Circadiano/efeitos da radiação , Regulação da Expressão Gênica/efeitos da radiação , Metabolismo dos Lipídeos/efeitos da radiação , Fígado/metabolismo , Masculino , Camundongos , Modelos Animais , Fotoperíodo
8.
Nat Commun ; 11(1): 2980, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532986

RESUMO

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


Assuntos
Angiopoietina-2/metabolismo , Ácidos Graxos/metabolismo , Resistência à Insulina/fisiologia , Integrina alfa5beta1/metabolismo , Metabolismo dos Lipídeos/fisiologia , Gordura Subcutânea/metabolismo , Adulto , Angiopoietina-2/genética , Animais , Células Cultivadas , Feminino , Perfilação da Expressão Gênica/métodos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Resistência à Insulina/genética , Integrina alfa5beta1/genética , Metabolismo dos Lipídeos/genética , Lipídeos/análise , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Transdução de Sinais/genética
9.
Am J Med Sci ; 360(3): 222-228, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32591091

RESUMO

The present review aimed to present the research highlights on C1q/TNF-related protein 1 (CTRP1), a member of the recently discovered family of highly conserved adiponectin paralog proteins, C1q tumor necrosis factor-related proteins. CTRP1 plays an important role in regulating body energy homeostasis and sensitivity to insulin. Studies on animal models have shown that it lowers the concentration of glucose. Elevated concentrations of CTRP1 reduce weight gain and diet-induced insulin resistance. CTRP1 limits the extent of ischemia-reperfusion injury in acute myocardial infarction. It inhibits platelet aggregation by blocking von Willebrand factor binding to collagen. In patients with chronic kidney disease, an increase in CTRP1 levels is associated with a lesser degree of disease progression. CTRP1 stimulates aldosterone synthesis in the adrenal cortex by affecting aldosterone synthase expression. In dehydration, an increase in CTRP1 concentration helps to maintain normotension. It participates in processes related to the proliferation and maturation of chondrocytes. It also promotes atherosclerosis, and a surge in its concentration is correlated with a higher cardiovascular risk in patients with coronary atherosclerosis. In vascular smooth muscle cells, it induces the expression of proinflammatory cytokines. An increase in CTRP1 levels is correlated with the progression of the neoplastic process in patients with glioblastoma.


Assuntos
Adipocinas/fisiologia , Proteínas/fisiologia , Animais , Doenças Cardiovasculares , Condrogênese/fisiologia , Metabolismo Energético , Glucose/metabolismo , Homeostase/fisiologia , Humanos , Inflamação , Resistência à Insulina/fisiologia , Nefropatias , Metabolismo dos Lipídeos/fisiologia , MEDLINE , Neoplasias , PubMed
10.
Am J Physiol Gastrointest Liver Physiol ; 319(1): G87-G96, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32475129

RESUMO

Hydroxysteroid sulfotransferase 2B1b (SULT2B1b) plays a critical role in hepatic energy homeostasis. Liver X receptors (LXRs) are implicated in multiple physiological functions, including the inhibition of hepatocyte proliferation and regulation of fatty acid and cholesterol metabolism. We have previously reported that SULT2B1b promotes hepatocyte proliferation by inactivating LXR signaling in vivo and in vitro, leading to our hypothesis that SULT2B1b promotes fatty liver regeneration. In the present study, female C57BL/6 and S129 mice were fed a high-fat diet for 8 wk to establish a nonalcoholic fatty liver disease (NAFLD) mouse model. 70% partial hepatectomy (PH) was performed to induce liver regeneration. Our experiments revealed that the SULT2B1b overexpression significantly promotes the regeneration of hepatocytes in NAFLD C57BL/6 mice after PH, increasing liver regrowth by 11% within 1 day, and then by 21%, 33%, and 24% by 2, 3, and 5 days post-PH, respectively. Compared with the wild-type NAFLD S129 mice, SULT2B1 deletion NAFLD S129 mice presented reduced hepatocyte regeneration at postoperative day 2, as verified by decreased liver regrowth (37.4% vs. 46.1%, P < 0.05) and the results of immunohistochemical staining, quantitative real-time polymerase chain reaction, and Western blot analysis. Moreover, LXRα signaling and SULT2B1b expression are highly correlated in the regeneration of NAFLD mouse liver; SULT2B1b overexpression suppresses LXRα signaling, while the LXRα-signaling agonist T0901317 blocks SULT2B1b-induced hepatocyte regeneration in NAFLD mouse liver. Thus, the upregulation of SULT2B1b may promote hepatocyte regeneration via the suppression of LXRα activation in NAFLD mice, providing a potential strategy for improving hepatic-steatosis-related liver regeneration disorders.NEW & NOTEWORTHY This study demonstrates for the first time that hydroxysteroid sulfotransferase 2B1b (SULT2B1b) overexpression promotes the regeneration of fatty liver after partial hepatectomy in mice with nonalcoholic fatty liver disease, while reducing triglyceride accumulation in the regenerative fatty liver. Liver X receptor signaling may be crucial in the SULT2B1b-mediated regeneration of fatty liver. Thus, SULT2B1b may be a potential target for treating hepatic steatosis-related liver regeneration disorders.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Regeneração Hepática/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Hepatectomia/métodos , Hidrocarbonetos Fluorados/farmacologia , Metabolismo dos Lipídeos/fisiologia , Receptores X do Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Sulfonamidas/farmacologia
11.
Life Sci ; 257: 117889, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32502541

RESUMO

PURPOSE: Gestational diabetes mellitus (GDM) has many adverse effects on offspring, such as abnormal glycolipid metabolism, obesity, insulin resistance, mental retardation, schizophrenia and so on. METHODS: We established a GDM rat model by injecting 1% streptozotocin associated with a high-fat diet one week before pregnancy, and offspring rats were sacrificed at 8 weeks of age to obtain liver tissue for study. We used hematoxylin-eosin (HE) staining to observe liver morphological changes, Tunel staining for hepatocyte apoptosis, transmission electron microscope for liver ultrastructure, and western blot for protein expression in liver tissue. RESULTS: Compared with normal offspring rats, hepatocytes of GDM offspring rats showed obvious edema, liver organ index increased, and hepatocyte apoptosis and autophagosome in the liver were significantly increased; Bax, cleaved-caspase3/caspase3, LCII, Beclin 1, P-IKBα/IKBα and P-p65/p6 protein expression in the liver were significantly increased; Bcl2, p62 and PPARγ protein expression in the liver were significantly decreased. Tau prevented the GDM-related effects in the offspring: Tau decreased hepatocyte edema (or even disappears), liver organ index, hepatocyte apoptosis and the number of autophagosomes in the liver. In addition, Tau also decreased Bax, cleaved-caspase3/caspase3, LCII, Beclin 1, P-IKBα/IKBα and P-p65/p6 protein expression, and increased Bcl2, p62 and PPARγ protein expression in the liver of GDM offspring rats. CONCLUSION: Taurine should be considered as a potential gestational nutritional supplement to prevent liver damage in GDM offspring.


Assuntos
Diabetes Gestacional/tratamento farmacológico , Taurina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Diabetes Mellitus Experimental , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/fisiologia , Fígado/efeitos dos fármacos , Masculino , Obesidade/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley , Taurina/metabolismo
12.
Nat Commun ; 11(1): 2123, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358558

RESUMO

Mammals differ in their regeneration potential after traumatic injury, which might be caused by species-specific regeneration programs. Here, we compared murine and human Schwann cell (SC) response to injury and developed an ex vivo injury model employing surgery-derived human sural nerves. Transcriptomic and lipid metabolism analysis of murine SCs following injury of sural nerves revealed down-regulation of lipogenic genes and regulator of lipid metabolism, including Pparg (peroxisome proliferator-activated receptor gamma) and S1P (sphingosine-1-phosphate). Human SCs failed to induce similar adaptations following ex vivo nerve injury. Pharmacological PPARg and S1P stimulation in mice resulted in up-regulation of lipid gene expression, suggesting a role in SCs switching towards a myelinating state. Altogether, our results suggest that murine SC switching towards a repair state is accompanied by transcriptome and lipidome adaptations, which are reduced in humans.


Assuntos
Metabolismo dos Lipídeos/fisiologia , Células de Schwann/citologia , Células de Schwann/metabolismo , Animais , Feminino , Humanos , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Bainha de Mielina/metabolismo , Regeneração Nervosa/genética , Regeneração Nervosa/fisiologia , Sistema Nervoso/citologia , Sistema Nervoso/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , PPAR gama/metabolismo , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo
13.
Am J Physiol Gastrointest Liver Physiol ; 319(1): G11-G22, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32463334

RESUMO

Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer death in the world. Although most cases occur in stiff, cirrhotic livers, and stiffness is a significant risk factor, HCC can also arise in noncirrhotic livers in the setting of nonalcoholic fatty liver disease (NAFLD). We hypothesized that lipid droplets in NAFLD might apply mechanical forces to the nucleus, functioning as mechanical stressors akin to stiffness. We investigated the effect of lipid droplets on cellular mechanosensing and found that primary human hepatocytes loaded with the fatty acids oleate and linoleate exhibited decreased stiffness-induced cell spreading and disrupted focal adhesions and stress fibers. The presence of large lipid droplets in hepatocytes resulted in increased nuclear localization of the mechano-sensor Yes-associated protein (YAP). In cirrhotic livers from patients with NAFLD, hepatocytes filled with large lipid droplets showed significantly higher nuclear localization of YAP as compared with cells with small lipid droplets. This work suggests that lipid droplets induce a mechanical signal that disrupts the ability of the hepatocyte to sense its underlying matrix stiffness and that the presence of lipid droplets can induce intracellular mechanical stresses.NEW & NOTEWORTHY This work examines the impact of lipid loading on mechanosensing by human hepatocytes. In cirrhotic livers, the presence of large (although not small) lipid droplets increased nuclear localization of the mechanotransducer YAP. In primary hepatocytes in culture, lipid droplets led to decreased stiffness-induced cell spreading and disrupted focal adhesions and stress fibers; the presence of large lipid droplets resulted in increased YAP nuclear localization. Collectively, the data suggest that lipid droplets induce intracellular mechanical stress.


Assuntos
Carcinoma Hepatocelular/metabolismo , Hepatócitos/metabolismo , Gotículas Lipídicas/metabolismo , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/patologia , Núcleo Celular/metabolismo , Humanos , Metabolismo dos Lipídeos/fisiologia , Lipídeos , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
14.
Med Sci (Paris) ; 36(5): 497-503, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32452372

RESUMO

In healthy subjects, the balance between glucose production and its usage is precisely controlled. When circulating glucose reaches a critical threshold, pancreatic ß-cells secrete insulin, which has two major actions: lowering circulating glucose concentrations by facilitating its uptake mainly in skeletal muscles and the liver, and inhibiting glucose production. Triglycerides are the main source of fatty acids to meet the energy needs of oxidative tissues and any excess is stored in adipocytes. Thus, adipose tissue acts as a trap for excess fatty acids released from plasma triglycerides. When the buffering action of adipose tissue to store fatty acids is impaired, they accumulate in other tissues where they are metabolized in several lipid species, including sphingolipid derivatives such as ceramides. Numerous studies have shown that ceramides are among the most active lipid second messengers to inhibit insulin signalling. This review describes the major role played by ceramides in the development of insulin resistance in peripheral tissues.


Assuntos
Ceramidas/fisiologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Tecido Adiposo/metabolismo , Animais , Humanos , Metabolismo dos Lipídeos/fisiologia , Transdução de Sinais/fisiologia
15.
Life Sci ; 252: 117633, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32289432

RESUMO

AIMS: High-fat intake induces obesity and non-alcoholic fatty liver disease (NAFLD). However, high-altitude chronic hypoxia might alleviate NAFLD progression through improved mitochondrial function and AMP-activated protein kinase (AMPK) signaling. We hypothesized that high-altitude chronic hypoxia would have protective effects against NAFLD development. MAIN METHODS: C57BL/6J mice were randomly divided into control (normal diet and altitude 50 m), CHH (normal diet and altitude 4300 m), HFD (high-fat diet and altitude 50 m), and HFD-CHH (high-fat diet and altitude 4300 m) groups. After being maintained for 8 weeks under the appropriate conditions, mice were evaluated. KEY FINDINGS: The degree of liver lipid accumulation and expression of the lipid synthesis-related genes acetyl-CoA carboxylase1 (ACC1), fatty acid synthesis (FAS), and sterol regulatory element binding protein-1c (SREBP-1c) were reduced in the HFD-CHH group; however, expression of the lipolysis-related gene carnitine palmitoyl transferase 1 (CPT1) was increased. Furthermore, in addition to increased expression of mitochondrial biogenesis-related genes, mitochondrial respiratory function and mitochondrial DNA content were elevated in the HFD-CHH group compared to those in the HFD group. The HFD-CHH group also exhibited significantly increased antioxidation activity and decreased reactive oxygen species production (P < 0.05). Finally, AMPK signaling in the liver was activated and the expression of phosphorylated-AMPK (P-AMPK) was significantly increased in the HFD-CHH group. SIGNIFICANCE: Collectively, our findings suggest that high altitude-induced hypoxia might improve impaired mitochondrial function and activate AMPK signaling in obesity-induced NAFLD. High-altitude chronic hypoxia could be a new treatment strategy for obesity-induced NAFLD.


Assuntos
Altitude , Hipóxia/metabolismo , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/complicações , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , DNA Mitocondrial/metabolismo , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Transdução de Sinais/fisiologia
16.
Life Sci ; 252: 117661, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32305523

RESUMO

AIMS: Hydrogen sulfide (H2S) as a novel gasotransmitter can be endogenously produced in liver by cystathionine gamma-lyase (CSE). The dysfunctions of CSE/H2S system have been linked to various liver diseases. Acetyl-CoA is the key intermediate from the metabolism of lipid. This study examined the roles of H2S in hepatic acetyl-CoA and lipid metabolism. MATERIALS AND METHODS: Both in vitro cell model and in vivo animal model of lipid accumulation were used in this study. Western blotting and real-time PCR were used for analysis of protein and mRNA expression. Acetyl-CoA was analyzed by a coupled enzyme assay, and lipid accumulation was observed with Oil Red O staining. KEY FINDINGS: Incubation of human liver carcinoma (HepG2) cells with a mixture of free fatty acids (FFAs) or high glucose reduced CSE expression and H2S production, promoted intracellular accumulation of acetyl-CoA and lipid. Supply of exogenous NaHS or cysteine reduced acetyl-CoA contents and lipid accumulation, while blockage of CSE activity promoted intracellular lipid accumulation. Furthermore, H2S blocked FFAs-induced transcriptions of de novo lipogenesis, inflammation, and fibrosis-related genes. In vivo, knockout of CSE gene stimulated more hepatic acetyl-CoA and lipid accumulation in mice induced by high-fat choline-deficient diet. The expressions of lipogenesis, inflammation, and fibrosis-related genes were significantly higher in liver tissues from CSE knockout mice when compared with wild-type mice. SIGNIFICANCE: CSE/H2S system is indispensable for maintaining the homeostasis of acetyl-CoA and lipid accumulation and protecting from the development of inflammation and fibrosis in liver under excessive caloric ingestion.


Assuntos
Acetilcoenzima A/metabolismo , Cistationina gama-Liase/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Sulfeto de Hidrogênio/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Animais , Cistationina gama-Liase/genética , Modelos Animais de Doenças , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
17.
Chem Biol Interact ; 324: 109090, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32283070

RESUMO

Epidermal growth factor receptor (EGFR) is conventionally known to play a crucial role in hepatocyte proliferation, liver regeneration and is also associated with hepatocellular carcinogenesis. In addition to these proliferative roles, EGFR has also implicated in apoptotic cell death signaling in various hepatic cells, mitochondrial dysfunction and acute liver necrosis in a clinically relevant murine model of acetaminophen overdose, warranting further comprehensive exploration of this paradoxical role of EGFR in hepatotoxicity. Apart from ligand dependent activation, EGFR can also be activated in ligand-independent manner, which is mainly associated to liver injury. Recent evidence has also emerged demonstrating important role of EGFR in lipid and fatty acid metabolism in quiescent and regenerating liver. Based on these findings, EGFR has also been shown to play an important role in steatosis in clinically relevant murine NAFLD models via regulating master transcription factors governing fatty acid synthesis and lipolysis. Moreover, several lines of evidences indicate that EGFR is also involved in hepatocellular injury, oxidative stress, inflammation, direct stellate cell activation and fibrosis in chronic liver injury models, including repeated CCl4 exposure, high-fat diet and fast-food diet models. In addition to briefly summarizing role of EGFR in liver regeneration, this review comprehensively discusses all these non-conventional emerging roles of EGFR. Considering evidences of multi-facet role of EGFR at various levels in these pathophysiological process, EGFR can be a promising therapeutic target for various liver diseases, including acute liver failure and NAFLD, requiring further exploration. These roles of EGFR are relevant for alcoholic liver diseases (ALD) as well, thus providing a valid rationale for future investigations exploring a role of EGFR in ALD.


Assuntos
Receptores ErbB/fisiologia , Metabolismo dos Lipídeos/fisiologia , Hepatopatias/fisiopatologia , Animais , Morte Celular/fisiologia , Células Estreladas do Fígado/fisiologia , Humanos , Regeneração Hepática/fisiologia
18.
Am J Pathol ; 190(7): 1513-1529, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32305353

RESUMO

Atrophy and fat accumulation are debilitating aspects of muscle diseases and are rarely prevented. Using a vertical approach combining anatomic techniques with omics methodology in a tenotomy-induced sheep model of rotator cuff disease, we tested whether mitochondrial dysfunction is implicated in muscle wasting and perturbed lipid metabolism, speculating that both can be prevented by the stimulation of ß-oxidation with l-carnitine. The infraspinatus muscle lost 22% of its volume over the first 6 weeks after tenotomy before the area-percentage of lipid increased from 8% to 18% at week 16. Atrophy was associated with the down-regulation of mitochondrial transcripts and protein and a slow-to-fast shift in muscle composition. Correspondingly, amino acid levels were increased 2 weeks after tendon release, when the levels of high-energy phosphates and glycerophospholipids were lowered. l-Carnitine administration (0.9 g/kg per day) prevented atrophy over the first 2 weeks, and mitigated alterations of glutamate, glycerophospholipids, and carnitine levels in released muscle, but did not prevent the level decrease in high-energy phosphates or protein constituents of mitochondrial respiration, promoting the accumulation of longer lipids with an increasing saturation. We conclude that the early phase of infraspinatus muscle degeneration after tendon release involves the elimination of oxidative characteristics associated with an aberrant accumulation of lipid species but is largely unrelated to the prevention of atrophy with oral l-carnitine administration.


Assuntos
Metabolismo dos Lipídeos/fisiologia , Mitocôndrias/metabolismo , Atrofia Muscular/metabolismo , Lesões do Manguito Rotador/metabolismo , Lesões do Manguito Rotador/patologia , Animais , Regulação para Baixo , Feminino , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Manguito Rotador/metabolismo , Manguito Rotador/patologia , Lesões do Manguito Rotador/complicações , Ovinos , Tenotomia
20.
Invest Ophthalmol Vis Sci ; 61(3): 1, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32150252

RESUMO

Purpose: We recently discovered that a hypoxic environment is beneficial for meibomian gland (MG) function. The mechanisms underlying this effect are unknown, but we hypothesize that it is due to an increase in the levels of hypoxia-inducible factor 1α (HIF1α). In other tissues, HIF1α is the primary regulator of cellular responses to hypoxia, and HIF1α expression can be induced by multiple stimuli, including hypoxia and hypoxia-mimetic agents. The objective of this study was to test our hypothesis. Methods: Human eyelid tissues were stained for HIF1α. Immortalized human MG epithelial cells (IHMGECs) were cultured for varying time periods under normoxic (21% O2) or hypoxic (1% O2) conditions, in the presence or absence of the hypoxia-mimetic agent roxadustat (Roxa). IHMGECs were then processed for the analysis of cell number, HIF1α expression, lipid-containing vesicles, neutral and polar lipid content, DNase II activity, and intracellular pH. Results: Our results show that HIF1α protein is present in human MG acinar epithelial cells in vivo. Our findings also demonstrate that exposure to 1% O2 or to Roxa increases the expression of HIF1α, the number of lipid-containing vesicles, the content of neutral lipids, and the activity of DNase II and decreases the pH in IHMGECs in vitro. Conclusions: Our data support our hypothesis that the beneficial effect of hypoxia on the MG is mediated through an increased expression of HIF1α.


Assuntos
Células Epiteliais/citologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Glândulas Tarsais/citologia , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isoquinolinas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Masculino , Glândulas Tarsais/efeitos dos fármacos , Glândulas Tarsais/metabolismo
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