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1.
Adv Exp Med Biol ; 1185: 289-293, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884626

RESUMO

The retinal pigment epithelium (RPE) is a monolayer of pigmented cells whose function is essential for the integrity of the retina and for visual function. Retinal diseases that eventually end in vision loss and blindness involve inflammation, oxidative stress (OS), and alterations in the RPE-photoreceptor cellular partnership. This chapter summarizes the role of lipid signaling pathways and lipidic molecules in RPE cells exposed to inflammatory and OS conditions. The modulation of these pathways in the RPE, through either enzyme inhibitors or receptor stimulation or blockage, could open new therapeutic strategies for retinal degenerative diseases.


Assuntos
Lipídeos/fisiologia , Estresse Oxidativo , Degeneração Retiniana/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais , Humanos , Epitélio Pigmentado da Retina/citologia
2.
Physiol Int ; 106(3): 213-224, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31578075

RESUMO

BACKGROUND AND AIMS: In this study, we aimed to investigate the effects of 10 weeks of high-intensity interval training (HIIT) and endurance training (END) on irisin, betatrophin, insulin, fasting blood glucose (FBG) concentrations, and lipid profiles in diabetic rats. METHODS: Twenty-four Wistar rats (weight: 200-250 g) were randomly assigned into four groups as follows: (1) control (Cnt), (2) diabetic (Dibt), (3) diabetic HIIT (Dibt-HIIT), and (4) diabetic END (Dibt-END). For inducing diabetes, after 12 h of food starvation, nicotinamide (120 mg/kg) and streptozotocin (STZ; 65 mg/kg) were intraperitoneally injected. The diabetic training groups received 10 weeks of HIIT or END training following the induction of diabetes. Twenty-four hours following the last training session, blood serum samples were collected for evaluating the concentration of irisin, betatrophin, and insulin hormones through enzyme-linked immunosorbent assay. RESULTS: FBG and lipid profiles were measured by biochemical kits. A significant increase in the serum concentration of irisin (p < 0.05), betatrophin (p < 0.05), and insulin (p < 0.001) and significant decrease in the FBG (P < 0.01) and lipid profiles (p < 0.01) were observed in the Dibt-HIIT group compared to the Dibt-END group. In addition, irisin revealed a significant positive association with betatrophin and insulin values in diabetic training groups (p < 0.01). CONCLUSIONS: It seems that HIIT leads to a more extensive improvement in diabetic conditions compared to the END training. Therefore, HIIT appears to be an important time-efficient approach for the treatment of type 2 diabetes.


Assuntos
Proteínas Semelhantes a Angiopoietina/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fibronectinas/metabolismo , Lipídeos/fisiologia , Animais , Peso Corporal/fisiologia , Treino Aeróbico/métodos , Jejum/metabolismo , Treinamento Intervalado de Alta Intensidade/métodos , Insulina/metabolismo , Masculino , Condicionamento Físico Animal/fisiologia , Ratos , Ratos Wistar
3.
PLoS Comput Biol ; 15(10): e1007400, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31581241

RESUMO

Given the association of disturbances in non-esterified fatty acid (NEFA) metabolism with the development of Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease, computational models of glucose-insulin dynamics have been extended to account for the interplay with NEFA. In this study, we use arteriovenous measurement across the subcutaneous adipose tissue during a mixed meal challenge test to evaluate the performance and underlying assumptions of three existing models of adipose tissue metabolism and construct a new, refined model of adipose tissue metabolism. Our model introduces new terms, explicitly accounting for the conversion of glucose to glyceraldehye-3-phosphate, the postprandial influx of glycerol into the adipose tissue, and several physiologically relevant delays in insulin signalling in order to better describe the measured adipose tissues fluxes. We then applied our refined model to human adipose tissue flux data collected before and after a diet intervention as part of the Yoyo study, to quantify the effects of caloric restriction on postprandial adipose tissue metabolism. Significant increases were observed in the model parameters describing the rate of uptake and release of both glycerol and NEFA. Additionally, decreases in the model's delay in insulin signalling parameters indicates there is an improvement in adipose tissue insulin sensitivity following caloric restriction.


Assuntos
Tecido Adiposo/metabolismo , Biologia Computacional/métodos , Metabolismo dos Lipídeos/fisiologia , Anastomose Arteriovenosa/metabolismo , Glicemia/metabolismo , Simulação por Computador , Ácidos Graxos/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Isótopos , Lipídeos/fisiologia , Modelos Biológicos , Período Pós-Prandial/fisiologia
4.
Adv Exp Med Biol ; 1161: 1-2, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562616

RESUMO

In addition to this introduction, this book contains 18 outstanding chapters based on comprehensive and detailed reviews of timely topics presented at the 15th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases held in Puerto Vallarta, Mexico on October 22-25, 2017.


Assuntos
Inflamação , Lipídeos , Neoplasias , Congressos como Assunto , Humanos , Lipídeos/fisiologia , México , Neoplasias/fisiopatologia
5.
Adv Exp Med Biol ; 1161: 193-217, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562631

RESUMO

Headache is a common complaint after mild traumatic brain injury (mTBI). Changes in the CNS lipidome were previously associated with acrolein-induced headache in rodents. mTBI caused similar headache-like symptoms in rats; therefore, we tested the hypothesis that mTBI might likewise alter the lipidome. Using a stereotaxic impactor, rats were given either a single mTBI or a series of 4 mTBIs 48 h apart. 72 h later for single mTBI and 7 days later for repeated mTBI, the trigeminal ganglia (TG), trigeminal nucleus (TNC), and cerebellum (CER) were isolated. Using HPLC/MS/MS, ~80 lipids were measured in each tissue and compared to sham controls. mTBI drove widespread alterations in lipid levels. Single mTBI increased arachidonic acid and repeated mTBI increased prostaglandins in all 3 tissue types. mTBI affected multiple TRPV agonists, including N-arachidonoyl ethanolamine (AEA), which increased in the TNC and CER after single mTBI. After repeated mTBI, AEA increased in the TG, but decreased in the TNC. Common to all tissue types in single and repeated mTBI was an increase the AEA metabolite, N-arachidonoyl glycine, a potent activator of microglial migration. Changes in the CNS lipidome associated with mTBI likely play a role in headache and in long-term neurodegenerative effects of repeated mTBI.


Assuntos
Lesões Encefálicas Traumáticas , Sistema Nervoso Central , Cefaleia , Inflamação , Lipídeos , Neoplasias , Animais , Lesões Encefálicas Traumáticas/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Cefaleia/fisiopatologia , Inflamação/fisiopatologia , Lipídeos/química , Lipídeos/genética , Lipídeos/fisiologia , Neoplasias/fisiopatologia , Ratos
6.
Oxid Med Cell Longev ; 2019: 7524878, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31485298

RESUMO

Objective: The aim of the study was to estimate the impact of whole-body cryotherapy (WBC) and subsequent kinesiotherapy on oxidative stress and lipid profile when performed in a closed cryochamber on healthy subjects. Material and Methods: The effect of ten WBC procedures lasting 3 minutes a day followed by a 60-minute session kinesiotherapy on oxidative stress and lipid profile in healthy subjects (WBC group, n = 16) was investigated. The WBC group was compared to the kinesiotherapy only (KT; n = 16) group. The routine parameters of oxidative stress (antioxidant enzymatic and nonenzymatic antioxidant status, lipid peroxidation products, total oxidative status (TOS), and oxidative stress index (OSI)) and lipid profile were estimated one day before the beginning and one day after the completion of the research program. Results: After treatment, in the WBC group, a significant decrease of oxidative stress markers (TOS and OSI) and a significant increase of total antioxidant capacity were observed. The activity of plasma SOD-Mn and erythrocyte total SOD increased significantly in the WBC group. In the KT group, the erythrocyte activity of total SOD, CAT, and GR decreased significantly after the treatment. The levels of T-Chol and LDL-Chol decreased significantly after treatment in both groups, but the observed decrease of these lipid parameters in the WBC group was higher in comparison to the KT group. The level of TG decreased significantly after treatment in the WBC group only. Conclusion: WBC performed in a closed cryochamber followed by kinesiotherapy improves lipid profile and decreases oxidative stress in healthy subjects.


Assuntos
Crioterapia/efeitos adversos , Cinesiologia Aplicada/métodos , Lipídeos/fisiologia , Estresse Oxidativo/fisiologia , Crioterapia/métodos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade
7.
J Physiol Pharmacol ; 70(3)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31539884

RESUMO

Conjugated dienes of linoleic acid (CLA) are constitutional and geometric isomers of linoleic acid that are commonly used as dietary supplements during body mass reduction. Their role in the reduction of lipid deposits in liver tissue is not unequivocal. CLA contain an equimolar mixture of two isomers of linoleic acid: trans-10,cis-12 CLA and cis-9,trans-11. Only one isomer - trans-10,cis-12 CLA exhibits fat-reducing properties, cis-9,trans-11 CLA does not. The main goal of this study was to determine if CLA isomers affect the activation of forkhead box O1 (FoxO1) in liver cells and tissue. FoxO1 is a protein that plays a crucial role in regulation of lipid and carbohydrates metabolism. In vitro and in vivo models of our study were HepG2 cells and C57BL/6J mice. Methods used in the study were qPCR - quantification of FoxO1 gene expression, Western blot - posttranslational phosphorylation of FoxO1, Oil Red O (ORO) - lipid staining and ELISA - quantification of apoB100. In both models trans-10,cis-12 CLA diminished FoxO1 gene expression: decrease by 44.1 ± 20.9% SD in the cells and 65.4 ± 29.8% SD in mice. The lowest accumulation of lipids (drop of 37.2 ± 1.7% SD) and the highest increase of apoB100 protein (74 ± 12.8% SD) were detected in the medium of cells cultured with trans-10,cis-12 CLA. Both isomers of linoleic acid have different effects on lipid metabolism. Isomer c9,t11 CLA accelerates lipogenesis, whereas isomer t10,c12 CLA activates secretion of lipids in HepG2 cells. In contrast to the in vitro study, unfortunately this pro-health property of t10,c12 CLA was not confirmed in the in vivo model. This casts a shadow on CLA dietary supplements that are commonly used among people with type 2 diabetes, NAFLD (non-alcoholic liver disease) or a metabolic syndrome in order to lose weight.


Assuntos
Proteína Forkhead Box O1/antagonistas & inibidores , Ácidos Linoleicos Conjugados/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Suplementos Nutricionais , Feminino , Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Lipídeos/fisiologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
8.
PLoS Biol ; 17(8): e3000412, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31369546

RESUMO

Lipid species patterns are conserved within cells to maintain physicochemical properties of membranes and cellular functions. We present the lipidome, including sterols, glycerolipids (GLs), glycerophospholipids (GPLs), and sphingolipids (SLs), of primary ex vivo differentiated (I) white, (II) brite, and (III) brown adipocytes derived from primary preadipocytes isolated from (I) epididymal white, (II) inguinal white, and (III) intrascapular brown adipose tissue. Quantitative lipidomics revealed significantly decreased fractions of phosphatidylcholine (PC) and phosphatidylethanolamine (PE), with longer (C > 36) and more polyunsaturated species, as well as lower levels of cardiolipin (CL) in white than in brite and brown adipocytes. Together, the brite and brown lipidome was comparable and indicates differences in membrane lipid packing density compared with white adipocytes. Changes in ceramide species profile could be related to the degree of browning. Beta-adrenergic stimulation of brown adipocytes led to generation of saturated lyso-PC (LPC) increasing uncoupling protein (UCP) 1-mediated leak respiration. Application of stable isotope labeling showed that LPC formation was balanced by an increased de novo synthesis of PC.


Assuntos
Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Adrenérgicos , Animais , Diferenciação Celular , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
9.
Can J Microbiol ; 65(12): 870-879, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31398296

RESUMO

In this study, we examined the lipid composition of two strains of the tropical basidiomycete Favolaschia manipularis (Berk.) Teng, which differ in their adaptive potential to high (35 °C) and low (5 °C) temperatures. The results suggest that adaptation to extreme temperatures involves a change in the molecular composition of sterols, in addition to other well-known mechanisms of regulating membrane thickness and fluidity, such as changes in the lipid unsaturation and in the proportion of bilayer- and non-bilayer-forming lipids. It was demonstrated for the first time that adaptation to high temperature stress in fungi is accompanied by the accumulation of 9(11)-dehydroergosterol and ergosterol peroxide. Furthermore, increased thermal plasticity correlates with high storage lipid (triglycerides) content, accumulation of phosphatidic acid in the membrane, and an equal proportion of bilayer and non-bilayer lipids in the membrane.


Assuntos
Agaricales/química , Agaricales/fisiologia , Lipídeos/fisiologia , Temperatura , Adaptação Fisiológica , Ergosterol/análogos & derivados , Ergosterol/metabolismo , Metabolismo dos Lipídeos , Lipídeos/química , Esteróis/química
10.
Med Sci Monit ; 25: 5327-5335, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31317882

RESUMO

BACKGROUND Previous studies of human and animal models indicate that inflammation alters lipid metabolism. The pro-protein convertase subtilisin kexin type 9 (PCSK9) plays an important role in lipid metabolism. MATERIAL AND METHODS We examined the effect of inflammation on PCSK9 expression and lipid deposition in the kidneys of mice with Adriamycin-induced nephropathy. RESULTS The results indicated an increased expression of inflammatory cytokines and lipid deposition over 12 weeks. During this time, the expression of PCSK9 and its transcriptional activator (hepatocyte nuclear factor 1alpha, HNF1alpha) decreased, and the expression of the low-density lipoprotein receptor (LDLR) and its transcriptional activator (sterol regulatory element binding protein-2, SREBP-2) increased. Exogenous inflammation appeared to further aggravate this process. CONCLUSIONS Our mouse model of nephropathy suggests that a key step in the inflammation-induced deposition of lipids in the kidneys is the downregulation renal PCSK9 expression.


Assuntos
Doxorrubicina/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Síndrome Nefrótica/induzido quimicamente , Síndrome Nefrótica/metabolismo , Pró-Proteína Convertase 9/metabolismo , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/farmacologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Inflamação/metabolismo , Rim/metabolismo , Nefropatias , Lipídeos/fisiologia , Lipoproteínas LDL/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nefrite/induzido quimicamente , Nefrite/metabolismo , Pró-Proteína Convertase 9/biossíntese , Pró-Proteína Convertases/metabolismo , Pró-Proteína Convertases/farmacologia , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
12.
Metabolism ; 99: 90-101, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31351995

RESUMO

Moderate or low level hydrogen peroxides has been shown to play an important role in vascular smooth muscle cell (VSMC) function, in which the polymerase DNA-directed interacting protein 2 (Poldip2), functioned as a key regulator of NOX4 activity. In current study, we unexpectedly found that type 2 diabetes mellitus (T2DM) substantially suppresses the hepatic Poldip2 expression, and that the hepatic deficiency of Poldip2 may be correlated with dysregulation of hepatic cholesterol and plasma triglycerides. In cultured hepatocytes, we found that both insulin and leptin may inhibit hepatic expression of Poldip2 under high glucose concentration, but these suppressions were totally abolished under normoglycemic condition. POLDIP2 siRNA knockdown significantly impaired the H2O2 induction by insulin or leptin under normoglycemic condition, contributing the accumulation of cholesterol in cultured liver cells. The in vivo restoration of hepatic Poldip2 expression in T2DM mice remarkably rescued the moderate H2O2 generation in livers versus control mice, resulting in significant amelioration of hepatic cholesterol accumulation and plasma triglyceride levels. Importantly, the moderate induction of H2O2 in livers dramatically improved the hepatic PI3K-C1/AKT signaling or dampened PI3K-C2γ/AKT signaling through suppression of PTEN and PTP1B activities, thereby inhibiting the hepatic expression of HMGCR and SREBP2 for cholesterol synthesis. Moreover, the restitution of hepatic Poldip2 expression in diabetic mice significantly lowered the VLDL-cholesterol production rate, and substantially suppressed PEPCK and G6Pase expressions for gluconeogenesis, thus significantly improving the plasma insulin and glucose levels, and ITT and GTT outcomes in diabetic mice. Our findings suggest that hepatic dysregulation of Poldip2 may contribute to diabetic dyslipidemia and hyperglycemia.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Homeostase , Fígado/metabolismo , Proteínas Mitocondriais/deficiência , Proteínas Nucleares/deficiência , Animais , Células Cultivadas , Dislipidemias/etiologia , Gluconeogênese , Glucose/fisiologia , Hiperglicemia/etiologia , Metabolismo dos Lipídeos , Lipídeos/fisiologia , Fígado/citologia , Camundongos
14.
Plant Cell Physiol ; 60(7): 1556-1566, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31073607

RESUMO

Oil crop Brassica napus is subjected to environmental stresses such as drought, cold and salt. Phospholipase Ds (PLDs) have vital roles in regulation of plant growth, development and stress tolerance. In this study, 32 BnaPLD genes were identified and classified into six subgroups depending on the conserved protein structures. High similarity in gene and protein structures exists between BnaPLDs and AtPLDs. Gene expression analysis showed that BnaPLDα1s and BnaPLDδs had higher expression than other PLDs. BnaPLDα1 and BnaPLDδ were significantly induced by abiotic stresses including dehydration, NaCl, abscisic acid (ABA) and 4�C. Lipidomic analysis showed that the content of main membrane phospholipids decreased gradually under stresses, except phosphatidylglycerol increased under the treatment of ABA and phosphatidylethanolamine increased under 4�C. Correspondingly, their product of phosphatidic acid increased often with a transient peak at 8 h. The plant height of mutants of PLDα1 was significantly reduced. Agronomic traits such as yield, seed number, silique number and branches were significantly impaired in PLDα1 mutants. These results indicate that there is a large family of PLD genes in B. napus, especially BnaPLDα1s and BnaPLDδs may play important roles in membrane lipids remodeling and maintaining of the growth and stress tolerance of B. napus.


Assuntos
Brassica napus/genética , Genes de Plantas/genética , Fosfolipase D/genética , Fosfolipídeos/metabolismo , Brassica napus/enzimologia , Brassica napus/metabolismo , Regulação da Expressão Gênica de Plantas , Genes de Plantas/fisiologia , Estudo de Associação Genômica Ampla , Metabolismo dos Lipídeos , Lipídeos/fisiologia , Fosfolipase D/metabolismo , Fosfolipídeos/fisiologia , Filogenia , Folhas de Planta/metabolismo , Estresse Fisiológico , Transcriptoma
15.
Adv Exp Med Biol ; 1127: 181-194, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31140179

RESUMO

Despite the progress made over the last decades to understand the mechanisms underlying tissue damage and neurological deficits after neurotrauma, there are currently no effective treatments in the clinic. It is well accepted that the inflammatory response in the CNS after injury exacerbates tissue loss and functional impairments. Unfortunately, the use of potent anti-inflammatory drugs, such as methylprednisolone, fails to promote therapeutic recovery and also gives rise to several undesirable side effects related to immunosuppression. The injury-induced inflammatory response is complex, and understanding the mechanisms that regulate this inflammation is therefore crucial in the quest to develop effective treatments. Bioactive lipids have emerged as potent molecules in controlling the initiation, coordination, and resolution of inflammation and in promoting tissue repair and recovery of homeostasis. These bioactive lipids are produced by cells involved in the inflammatory response, and their defective synthesis leads to persistent chronic inflammation, tissue damage, and fibrosis. The present chapter discusses recent evidence for the role of some of these bioactive lipids, in particular, eicosanoid and pro-resolving lipid mediators, in the regulation of inflammation after neurotrauma and highlights the therapeutic potential of some of these lipids in enhancing neurological outcomes after CNS injuries.


Assuntos
Mediadores da Inflamação/fisiologia , Inflamação , Lipídeos/fisiologia , Traumatismos do Sistema Nervoso , Eicosanoides/fisiologia , Humanos
16.
PLoS One ; 14(4): e0215102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31009484

RESUMO

The yeast dynamin-like protein Vps1 has roles at multiple stages of membrane trafficking including Golgi to vacuole transport, endosomal recycling, endocytosis and in peroxisomal fission. While the majority of the Vps1 amino acid sequence shows a high level of identity with the classical mammalian dynamins, it does not contain a pleckstrin homology domain (PH domain). The Dyn1 PH domain has been shown to bind to lipids with a preference for PI(4,5)P2 and it is considered central to the function of Dyn1 in endocytosis. The lack of a PH domain in Vps1 has raised questions as to whether the protein can function directly in membrane fusion or fission events. Here we demonstrate that the region Insert B, located in a position equivalent to the dynamin PH domain, is able to bind directly to lipids and that mutation of three lysine residues reduces its capacity to interact with lipids, and in particular with PI(4,5)P2. The Vps1 KKK-AAA mutant shows more diffuse staining but does still show some localization to compartments adjacent to vacuoles and to endocytic sites suggesting that other factors are also involved in its recruitment. This mutant selectively blocks endocytosis, but is functional in other processes tested. While mutant Vps1 can localise to endocytic sites, the mutation results in a significant increase in the lifetime of the endocytic reporter Sla2 and a high proportion of defective scission events. Together our data indicate that the lipid binding capacity of the Insert B region of Vps1 contributes to the ability of the protein to associate with membranes and that its capacity to interact with PI(4,5)P2 is important in facilitating endocytic scission.


Assuntos
Endocitose , Endossomos/patologia , Proteínas de Ligação ao GTP/genética , Lipídeos/fisiologia , Lisina/genética , Mutação , Saccharomyces cerevisiae/metabolismo , Proteínas de Transporte Vesicular/genética , Sequência de Aminoácidos , Endossomos/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Complexo de Golgi/metabolismo , Complexo de Golgi/patologia , Lisina/metabolismo , Transporte Proteico , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Homologia de Sequência , Vacúolos/metabolismo , Vacúolos/patologia , Proteínas de Transporte Vesicular/metabolismo
17.
Life Sci ; 227: 20-29, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30974116

RESUMO

AIMS: We previously reported that Hovenia dulcis Thunb. extract, a traditional Chinese medicine rich in dihydromyricetin (DHM), exhibited a significant hepatoprotective effect against acetaminophen (APAP)-induced liver injury. However, whether DHM plays a protective role in APAP hepatotoxicity and what mechanisms are involved remain unclear. In this study, we evaluated the hepatoprotective effects of DHM against APAP-induced liver injury. MAIN METHODS: Male C57BL/6 mice were used for the experiment. LC-MS, q-PCR, immunochemistry and western blot analysis were employed to mechanism analysis. KEY FINDINGS: DHM exhibited a protective effect against APAP-induced liver injury. Further mechanistic investigations revealed that the protective effect of DHM against APAP hepatotoxicity had multi-target and multi-pathway characteristics involving APAP metabolism, lipid regulation, and hepatocyte death and regeneration. DHM pretreatment resulted in cytochrome P450 2E1 inhibition and UDP-glucuronosyltransferase 1A1 activation, affecting APAP biotransformation. Moreover, DHM pretreatment significantly ameliorated lipid dysregulation via peroxisome proliferator-activated receptor and sterol regulatory element-binding protein-1c (SREBP-1c) signalling pathways. Furthermore, DHM regulated the expression of cell death- and liver regeneration-associated proteins. SIGNIFICANCE: These results suggested that DHM alleviated APAP-induced liver injury in mice by inhibiting hepatocyte death, promoting p53-related regeneration, and regulating lipid homeostatic imbalance and APAP transformation. Based on these findings, DHM provides a potential and novel approach for preventing and treating APAP-induced liver damage, and SREBP-1c signalling might be a new therapeutic target for APAP hepatotoxicity.


Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Flavonóis/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Flavonóis/uso terapêutico , Glutationa/metabolismo , Hepatócitos/metabolismo , Homeostase/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/fisiologia , Fígado/metabolismo , Regeneração Hepática/efeitos dos fármacos , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
18.
Life Sci ; 227: 201-211, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31002917

RESUMO

AIMS: Colorectal cancer syndrome has been one of the greatest concerns in the world. Although several epidemiological studies have shown that hepatic low lipoprotein lipase (LPL) mRNA expression may be associated with dyslipidemia and tumor progression, it is still not known whether the liver plays an essential role in hyperlipidemia of ApcMin/+ mice. MAIN METHODS: We measured the expression of metabolic enzymes that involved fatty acid uptake, de novo lipogenesis (DNL), ß-oxidation and investigated hepatic triglyceride production in the liver of wild-type and ApcMin/+ mice. KEY FINDINGS: We found that hepatic fatty acid uptake and DNL decreased, but there was no significant difference in fatty acid ß-oxidation. Interestingly, the production of hepatic very low-density lipoprotein-triglyceride (VLDL-TG) decreased at 20 weeks of age, but marked steatosis was observed in the livers of the ApcMin/+ mouse. To further explore hypertriglyceridemia, we assessed the function of hepatic glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) for the first time. GPIHBP1 is governed by the transcription factor octamer-binding transcription factor-1 (Oct-1) which are involved in the nuclear factor-κB (NF-κB) signaling pathway in the liver of ApcMin/+ mice. Importantly, it was also confirmed that sn50 (100 µg/mL, an inhibitor of the NF-κB) reversed the tumor necrosis factor α (TNFα)-induced Oct-1 and GPIHBP1 reduction in HepG2 cells. SIGNIFICANCE: Altogether, these findings highlighted a novel role of GPIHBP1 that might be responsible for hypertriglyceridemia in ApcMin/+ mice. Hypertriglyceridemia in these mice may be associated with their hepatic lipid metabolism development.


Assuntos
Fígado/metabolismo , Receptores de Lipoproteínas/fisiologia , Triglicerídeos/metabolismo , Animais , Caquexia/metabolismo , Caquexia/fisiopatologia , Neoplasias do Colo/fisiopatologia , Ácidos Graxos/metabolismo , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/genética , Células Hep G2 , Humanos , Hiperlipidemias/genética , Metabolismo dos Lipídeos/genética , Lipídeos/fisiologia , Lipogênese/fisiologia , Lipólise/fisiologia , Lipoproteínas VLDL/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 1 de Transcrição de Octâmero/fisiologia , Receptores de Lipoproteínas/genética , Receptores de Lipoproteínas/metabolismo , Triglicerídeos/genética , Fator de Necrose Tumoral alfa/fisiologia
19.
Environ Pollut ; 249: 99-108, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30884398

RESUMO

The analysis of lipid disruption in invertebrates is limited by our poor knowledge of their lipidomes and of the associated metabolic pathways. For example, the mechanism by which exposure of the crustacean Daphnia magna to tributyltin, juvenoids, or bisphenol A increase the accumulation of storage lipids into lipid droplets is largely unknown/presently unclear. Here we analyze transcriptome changes subsequent to this lipid accumulation effect induced by either the pesticide pyriproxyfen (a juvenoid agonist), the plasticizer bisphenol A, or the antifouling agent tributyltin. Changes in the whole transcriptome were assessed after 8 and 24 h of exposure, the period showing the greatest variation in storage lipid accumulation. The three compounds affected similarly to a total of 1388 genes (965 overexpressed and 423 underexpressed transcripts), but only after 24 h of exposure. In addition, 225 transcripts became up-regulated in samples exposed to tributyltin for both 8 h and 24 h. Using D. melanogaster functional annotation, we determined that upregulated genes were enriched in members of KEGG modules implicated in fatty acid, glycerophospholipid, and glycerolipid metabolic pathways, as well as in genes related to membrane constituents and to chitin and cuticle metabolic pathways. Conversely, down-regulated genes appeared mainly related to visual perception and to oocyte development signaling pathways. Many tributyltin specifically upregulated genes were related to neuro-active ligand receptor interaction signaling pathways. These changes were consistent with the phetotypic effects reported in this and in previous studies that exposure of D. magna to the tested compounds increased lipid accumulation and reduced egg quantity and quality.


Assuntos
Daphnia/efeitos dos fármacos , Lipídeos/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Compostos Benzidrílicos/toxicidade , Daphnia/fisiologia , Drosophila melanogaster/genética , Fenóis/toxicidade , Piridinas/toxicidade , Transdução de Sinais , Transcriptoma , Compostos de Trialquitina/toxicidade
20.
Dev Cell ; 49(2): 220-234.e8, 2019 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-30905771

RESUMO

Lipid transfer proteins (LTPs) acting at membrane contact sites (MCS) between the ER and other organelles contain domains involved in heterotypic (e.g., ER to Golgi) membrane tethering as well as domains involved in lipid transfer. Here, we show that a long ≈90 aa intrinsically unfolded sequence at the N terminus of oxysterol-binding protein (OSBP) controls OSBP orientation and dynamics at MCS. This Gly-Pro-Ala-rich sequence, whose hydrodynamic radius is twice as that of folded domains, prevents the two PH domains of the OSBP dimer from homotypically tethering two Golgi-like membranes and considerably facilitates OSBP in-plane diffusion and recycling at MCS. Although quite distant in sequence, the N terminus of OSBP-related protein-4 (ORP4) has similar effects. We propose that N-terminal sequences of low complexity in ORPs form an entropic barrier that restrains protein orientation, limits protein density, and facilitates protein mobility in the narrow and crowded MCS environment.


Assuntos
Proteínas de Transporte/metabolismo , Receptores de Esteroides/metabolismo , Proteínas de Transporte/fisiologia , Linhagem Celular , Membrana Celular/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Células HeLa , Humanos , Lipídeos/fisiologia , Membranas Mitocondriais/metabolismo , Organelas/metabolismo , Domínios Proteicos/fisiologia , Receptores de Esteroides/genética , Receptores de Esteroides/fisiologia , Esteróis/metabolismo
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