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1.
J Med Chem ; 66(1): 413-434, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36573286

RESUMO

Dry eye disease (DED) is one of the most prevalent ocular diseases but has limited treatment options. Cystic fibrosis transmembrane conductance regulator (CFTR), a major chloride channel that stimulates fluid secretion in the ocular surface, may pave the way for new therapeutic strategies for DED. Herein, we report the optimization of Cact-3, a potent CFTR activator with poor solubility, to 16d, a potent CFTR activator with suitable solubility for eye drop formulation. Notably, 16d was well distributed in target tissues including cornea and conjunctiva with minimal systemic exposure in rabbit. Topical ocular instillation of 16d significantly enhanced tear secretion and improved corneal erosion in a mouse model of DED. In addition, 16d significantly reduced mRNA expression of pro-inflammatory cytokines including IL-1ß, IL-17, and TNF-α and MMP2 in cornea and conjunctiva of DED mice.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Síndromes do Olho Seco , Animais , Camundongos , Coelhos , Túnica Conjuntiva/metabolismo , Córnea , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/genética , Síndromes do Olho Seco/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/metabolismo , Solubilidade , Lágrimas/metabolismo
2.
Int J Mol Sci ; 23(16)2022 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-36012741

RESUMO

Meibomian gland dysfunction is one of the main causes of dry eye disease and has limited therapeutic options. In this study, we investigated the biological function of the beta 2-adrenergic receptor (ADRB2)/protein kinase A (PKA) pathway in lipid synthesis and its underlying mechanisms in human meibomian gland epithelial cells (HMGECs). HMGECs were cultured in differentiation media with or without forskolin (an activator of adenylate cyclase), salbutamol (an ADRB2 agonist), or timolol (an ADRB2 antagonist) for up to 4 days. The phosphorylation of the cAMP-response element-binding protein (CREB) and the expression of peroxisome proliferator activator receptor (PPAR)γ and sterol regulatory element-binding protein (SREBP)-1 were measured by immunoblotting and quantitative PCR. Lipid synthesis was examined by LipidTOX immunostaining, AdipoRed assay, and Oil Red O staining. PKA pathway activation enhanced PPARγ expression and lipid synthesis in differentiated HMGECs. When treated with agonists of ADBR2 (upstream of the PKA signaling system), PPARγ expression and lipid synthesis were enhanced in HMGECs. The ADRB2 antagonist timolol showed the opposite effect. The activation of the ADRB2/PKA signaling pathway enhances lipid synthesis in HMGECs. These results provide a potential mechanism and therapeutic target for meibomian gland dysfunction, particularly in cases induced by beta-blocker glaucoma drugs.


Assuntos
Antagonistas Adrenérgicos beta , Proteínas Quinases Dependentes de AMP Cíclico , Glaucoma , Disfunção da Glândula Tarsal , Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Glaucoma/tratamento farmacológico , Humanos , Lipídeos/biossíntese , PPAR gama/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais , Timolol/farmacologia
3.
Int J Mol Sci ; 23(9)2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35563294

RESUMO

Interleukin (IL)-1ß plays an important role in atherosclerosis pathogenesis. We aimed to investigate the effect of anakinra, a recombinant human IL-1 receptor antagonist, on the progression of atherosclerosis in apolipoprotein E knockout (ApoE−/−) mice. ApoE−/− mice (8-week male) were treated with saline (control), anakinra 10, 25, and 50 mg/kg, respectively (n = 10 in each group). Mice were fed a standard chow (4 weeks) followed by an atherogenic diet (35kcal% fat, 1.25% cholesterol, 12 weeks). Atheromatous plaques in ApoE−/− mice and the expression of inflammatory genes and signaling pathways in human umbilical vein endothelial cells (HUVECs), rat aortic smooth muscle cells (RAOSMCs), and 3T3-L1 adipocytes were assessed. Anakinra reduced the plaque size of the aortic arch (30.6% and 25.2% at the 25 mg/kg and 50 mg/kg doses, both p < 0.05) and serum triglyceride in ApoE−/− mice and suppressed inflammatory genes (IL-1ß and IL-6) expressions in HUVECs and RAOSMCs (all p < 0.05). In RAOSMCs, anakinra reduced metalloproteinase-9 expression in a dose-dependent manner and inhibited cell migration. Anakinra-treated mice exhibited trends of lower CD68+ macrophage infiltration in visceral fat and monocyte chemoattractant protein-1 expression was reduced in 3T3-L1 adipocytes. Anakinra could be a useful component for complementary treatment with a standard regimen to reduce the residual cardiovascular risk.


Assuntos
Aterosclerose , Proteína Antagonista do Receptor de Interleucina 1 , Placa Aterosclerótica , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/metabolismo , Ratos , Receptores de Interleucina-1/metabolismo
4.
Int J Mol Sci ; 23(9)2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35563597

RESUMO

Cystic fibrosis transmembrane conductance regulator (CFTR) is highly expressed on the ocular epithelium and plays a pivotal role in the fluid secretion driven by chloride transport. Dry eye disease is one of the most common diseases with limited therapeutic options. In this study, a high-throughput screening was performed to identify novel CFTR activators capable of inducing chloride secretion on the ocular surface. The screening of 50,000 small molecules revealed three novel CFTR activators. Among them, the most potent CFTR activator, Cact-3 (7-(3,4-dimethoxyphenyl)-N-(4-ethoxyphenyl)pyrazolo [1,5-α]pyrimidine-2-carboxamide), produced large and sustained Cl- currents in WT-CFTR-expressing FRT cells with no alterations of ANO1 and hERG channel activity. The application of Cact-3 strongly activated CFTR in the ocular epithelia of mice and it also significantly increased CFTR-mediated Cl- transport in a primary cultured human conjunctival epithelium. Cact-3 strongly stimulated tear secretion in normal mice. In addition, Cact-3 significantly reduced ocular surface damage and the expression of proinflammatory factors, including interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in an experimental mouse model of dry eye disease. These results suggest that Cact-3, a novel CFTR activator, may be a potential development candidate for the treatment of dry eye disease.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Síndromes do Olho Seco , Cloretos/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Síndromes do Olho Seco/tratamento farmacológico , Humanos , Transporte de Íons , Escopolamina
5.
Exp Mol Med ; 54(5): 573-584, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513574

RESUMO

Endoplasmic reticulum (ER) stress is induced by various conditions, such as inflammation and the presence of excess nutrients. Abnormal accumulation of unfolded proteins leads to the activation of a collective signaling cascade, termed the unfolded protein response (UPR). ER stress is reported to perturb hepatic insulin response metabolism while promoting insulin resistance. Here, we report that ER stress regulates the de novo biosynthesis of sphingolipids via the activation of serine palmitoyltransferase (SPT), a rate-limiting enzyme involved in the de novo biosynthesis of ceramides. We found that the expression levels of Sptlc1 and Sptlc2, the major SPT subunits, were upregulated and that the cellular concentrations of ceramide and dihydroceramide were elevated by acute ER stress inducers in primary hepatocytes and HepG2 cells. Sptlc2 was upregulated and ceramide levels were elevated by tunicamycin in the livers of C57BL/6J wild-type mice. Analysis of the Sptlc2 promoter demonstrated that the transcriptional activation of Sptlc2 was mediated by the spliced form of X-box binding protein 1 (sXBP1). Liver-specific Sptlc2 transgenic mice exhibited increased ceramide levels in the liver and elevated fasting glucose levels. The insulin response was reduced by the inhibition of the phosphorylation of insulin receptor ß (IRß). Collectively, these results demonstrate that ER stress induces activation of the de novo biosynthesis of ceramide and contributes to the progression of hepatic insulin resistance via the reduced phosphorylation of IRß in hepatocytes.


Assuntos
Resistência à Insulina , Serina C-Palmitoiltransferase , Regulação para Cima , Animais , Ceramidas/metabolismo , Estresse do Retículo Endoplasmático , Insulina/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Serina C-Palmitoiltransferase/genética , Serina C-Palmitoiltransferase/metabolismo , Ativação Transcricional
6.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921231

RESUMO

Dry eye disease is one of the most common diseases, with increasing prevalence in many countries, but treatment options are limited. Cystic fibrosis transmembrane conductance regulator (CFTR) is a major ion channel that facilitates fluid secretion in ocular surface epithelium and is a potential target of therapeutic agent for the treatment of dry eye disease. In this study, we performed a cell-based, high-throughput screening for the identification of novel natural products that activate CFTR and restore the aqueous deficiency in dry eye. Screening of 1000 natural products revealed isorhamnetin, a flavonol aglycone, as a novel CFTR activator. Electrophysiological studies showed that isorhamnetin significantly increased CFTR chloride current, both wild type and ∆F508-CFTR. Isorhamnetin did not alter intracellular cAMP levels and the activity of other ion channels, including ANO1, ENaC, and hERG. Notably, application of isorhamnetin on mouse ocular surface induced CFTR activation and increased tear volume. In addition, isorhamnetin significantly reduced ocular surface damage and expression of interleukin (IL)-1ß, IL-8, and tumor necrosis factor (TNF)-α in an experimental mouse model of dry eye. These data suggest that isorhamnetin may be used to treat dry eye disease.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Síndromes do Olho Seco/tratamento farmacológico , Quercetina/análogos & derivados , Animais , Modelos Animais de Doenças , Síndromes do Olho Seco/genética , Síndromes do Olho Seco/patologia , Células Epiteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Interleucina-8/genética , Camundongos , Quercetina/farmacologia , Fator de Necrose Tumoral alfa/genética
7.
Endocrinol Metab (Seoul) ; 36(6): 1243-1253, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34986301

RESUMO

BACKGROUND: Farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency. METHODS: En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)-/- and ApoE-/-FXR-/- mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice. RESULTS: Compared with ApoE-/- mice, ApoE-/-FXR-/- mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE-/-FXR-/- mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver). CONCLUSION: Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, ß-oxidation, and triglyceride hydrolysis.


Assuntos
Aterosclerose , Hepatopatia Gordurosa não Alcoólica , Animais , Apolipoproteínas E/genética , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Ativados por Proliferador de Peroxissomo
8.
Ocul Surf ; 18(4): 575-582, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32360783

RESUMO

PURPOSE: This study was performed to investigate the effects of interleukin (IL)-4 on adipogenesis and the underlying molecular mechanisms in human meibomian gland epithelial cells (HMGECs). METHODS: HMGECs and human white preadipocytes (HWPs) were cultured and differentiated with or without IL-4. Oil-red O staining, Adipored assay, and LipidTox immunostaining were performed to examine the extent of lipid droplet formation. The expression of signal transducer and activator of transcription 6 (STAT6), phospho-STAT6, peroxisome proliferator activator receptor (PPAR)γ, and sterol regulatory element-binding protein (SREBP)-1 was measured through immunoblotting. Cells were treated with STAT6 inhibitor, which prevents the phosphorylation of STAT6 by IL-4, to determine whether the effects of IL-4 on lipogenesis were altered. RESULTS: Treatment with IL-4 significantly facilitated lipid production in differentiated HMGECs. Phosphorylation of STAT6 and expression of key adipogenesis-related molecules PPARγ and SREBP-1 were increased after IL-4 treatment. Inhibition of STAT6 phosphorylation suppressed IL-4-mediated lipid synthesis in HMGECs. In contrast, the lipid synthetic effects of IL-4 were not observed in differentiated HWPs. CONCLUSIONS: IL-4 appears to promote lipid synthesis in meibomian gland epithelial cells through the STAT6/PPARγ signaling pathway. This mechanism can serve as a potential therapeutic target for meibomian gland dysfunction.


Assuntos
Transdução de Sinais , Humanos , Interleucina-4 , Lipogênese , PPAR gama , Fator de Transcrição STAT6
9.
Biochem Biophys Res Commun ; 497(4): 1149-1153, 2018 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-28131830

RESUMO

Adipogenesis is the process of differentiation from preadipocytes to adipocytes and is orchestrated by various transcription factors, such as the peroxisome proliferator-activated receptor gamma (PPARγ) and the CCAAT-enhancer-binding protein alpha (C/EBPα). Oxidative stress is also a crucial factor in adipogenesis, and adipocyte differentiation is affected by the cellular redox status. The nuclear factor E2-related factor 2 (Nrf2), which is a basic leucine zipper (bZIP) transcription factor, acts as a regulator of cellular oxidative stress. Although several previous studies examined the function of Nrf2 in adipogenesis, their results were controversial. In this study, we investigated whether the suppression of Nrf2 in 3T3-L1 cells affected adipogenesis. We found that adipogenesis master regulator genes, such as PPARγ and C/EBPα, were downregulated during the differentiation stage in Nrf2-knockdown 3T3-L1 cells. Moreover, the fibroblast growth factor 21 (FGF21) and manganese superoxide dismutase (MnSOD) were markedly downregulated in Nrf2-knockdown 3T3-L1 cells. Taken together, the results of the present study suggest that the suppression of Nrf2 attenuates adipogenesis and decreases FGF21 expression through PPARγ in 3T3-L1 cells.


Assuntos
Adipogenia/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/metabolismo , Inativação Gênica , Fator 2 Relacionado a NF-E2/genética , PPAR gama/metabolismo , Células 3T3-L1 , Animais , Regulação para Baixo/efeitos dos fármacos , Camundongos , Estresse Oxidativo , PPAR gama/genética , Superóxido Dismutase/efeitos dos fármacos
10.
Cardiovasc Diabetol ; 16(1): 92, 2017 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28728579

RESUMO

CONTEXT: A previous genome-wide association study showed that a genetic variant of sortilin was associated with the risk of coronary artery disease (CAD). However, the role of circulating sortilin is still unknown. We investigated the potential role of plasma sortilin as a biomarker for CAD and diabetes mellitus. METHODS: We enrolled statin-naïve subjects with CAD (n = 31) who underwent coronary artery bypass surgery and control subjects (n = 116) who were free from CAD as evaluated by coronary CT angiography. The presence of diabetes mellitus was evaluated and plasma sortilin levels were measured with a commercial ELISA kit. RESULTS: Plasma sortilin levels were higher in subjects with CAD and subjects with diabetes mellitus than in those without CAD or diabetes mellitus. Subjects in the highest sortilin tertile group were older and had higher glucose and HbA1c levels, but lipid profiles in the three tertile groups were comparable. Multivariable logistic regression analysis revealed that sortilin levels were independently associated with CAD. In addition, the receiver operating characteristic curve analysis showed that plasma sortilin levels could identify the presence of CAD or diabetes mellitus. CONCLUSIONS: Elevated circulating sortilin levels are associated with CAD and diabetes mellitus and can be used as a biomarker of both diseases in statin-naïve subjects.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/sangue , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Diabetes Mellitus Tipo 2/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Adulto , Idoso , Angiografia Coronária/métodos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Hemoglobinas Glicadas/biossíntese , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores de Risco
11.
Hepatology ; 62(1): 135-46, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25808625

RESUMO

UNLABELLED: The endoplasmic reticulum (ER) is the principal organelle in the cell for protein folding and trafficking, lipid synthesis, and cellular calcium homeostasis. Perturbation of ER function results in activation of the unfolded protein response (UPR) and is implicated in abnormal lipid biosynthesis and development of insulin resistance. In this study, we investigated whether transcription of sphingosine kinase (Sphk)2 is regulated by ER stress-mediated UPR pathways. Sphk2, a major isotype of sphingosine kinase in the liver, was transcriptionally up-regulated by tunicamycin and lipopolysaccharides. Transcriptional regulation of Sphk2 was mediated by activation of activating transcription factor (ATF)4 as demonstrated by promoter assays, immunoblotting, and small interfering RNA analyses. In primary hepatocytes, adenoviral Sphk2 expression elevated cellular sphingosine 1 phosphate (S1P) and activated protein kinase B phosphorylation, with no alteration of insulin receptor substrate phosphorylation. Hepatic overexpression of Sphk2 in mice fed a high-fat diet (HFD) led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and liver. Hepatic accumulation of lipid droplets by HFD feeding was reduced by Sphk2-mediated up-regulation of fatty acid (FA) oxidizing genes and increased FA oxidation in liver. In addition, glucose intolerance and insulin resistance were ameliorated by improved hepatic insulin signaling through Sphk2 up-regulation. CONCLUSION: Sphk2 is transcriptionally up-regulated by acute ER stress through activation of ATF4 and improves perturbed hepatic glucose and FA metabolism.


Assuntos
Estresse do Retículo Endoplasmático , Fígado Gorduroso/metabolismo , Resistência à Insulina , Fígado/enzimologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Animais , Células Cultivadas , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Hepatócitos/enzimologia , Gotículas Lipídicas/metabolismo , Lipídeos/sangue , Lisofosfolipídeos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Oxirredução , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Resposta a Proteínas não Dobradas , Regulação para Cima
12.
J Food Sci ; 79(10): H2132-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25220663

RESUMO

UNLABELLED: Resveratrol has a beneficial effect of lowering reactive oxygen species (ROS) and reduces cellular oxidative stress. We hypothesized that ethanol extract of Smilax china root (EESC) rich in resveratrol (RES) and oxyresveratrol (OXY) could reduce ROS caused by nicotine and promoting nicotine turnover by induction of CYP2A6. The amount of cotinine converted from nicotine was quantified by the direct barbiturate assay method. Expression of CYP2A6 was unregulated by RES, OXY, or EESC, respectively. Pretreatment of RES (50, 100, and 250 µM), OXY (50, 100, and 250 µM), and RES+OXY (50 and 100 µM) inhibited cytotoxicity and ROS production caused by nicotine in a dose-dependent manner. EESC pretreatment (1.8 mg/mL) increased cell viability by 1.5-fold higher than the control (nicotine only), and lowered cellular ROS levels. A significant amount of the conversion of nicotine to cotinine was observed in EESC pretreatment by CYP2A6 induction in HepG2 cells. These results suggested that hepatic induction of CYP2A6 and ROS reduction by EESC activate nicotine metabolism and reduce cellular oxidative stress. PRACTICAL APPLICATION: Nicotine exposure due to smoking is very concerning because it is the major factor for lung diseases and cardiovascular disorders. It is necessary to examine natural ingredients that can detoxify from nicotine to cotinine as well as neutralize free radicals induced from nicotine. Results from the current study suggest potential applications of Smilax china root for detoxification of nicotine in the food industry.


Assuntos
Citocromo P-450 CYP2A6/metabolismo , Nicotina/toxicidade , Raízes de Plantas/química , Espécies Reativas de Oxigênio/química , Smilax/química , Cotinina/química , Cotinina/metabolismo , Citocromo P-450 CYP2A6/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Nicotina/química , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , RNA/genética , RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Artigo em Inglês | MEDLINE | ID: mdl-23761785

RESUMO

Obesity is a metabolic disorder developed by overnutrition and a major cause for insulin resistance and cardiovascular events. Since adipose tissue is one of the major sites for the synthesis and secretion of cytokines, enlarged adipose tissue in obese condition alters inflammatory state leading to pathophysiological conditions such as type 2 diabetes and increased cardiovascular risk. A plausible theory for development of metabolic dysregulation is that obesity increases secretion of inflammatory cytokines from adipose tissue and causes a chronic inflammation in the whole body. Additionally accumulation of lipids in non-adipose tissues elevates the cellular levels of bioactive lipids that inhibit the signaling pathways implicated in metabolic regulation together with activated inflammatory response. Recent findings suggest that obesity-induced inflammatory response leads to modulation of sphingolipid metabolism and these bioactive lipids may function as mediators for increased risk of metabolic dysfunction. Importantly, elucidation of mechanism regarding sphingolipid metabolism and inflammatory disease will provide crucial information to development of new therapeutic strategies for the treatment of obesity-induced pathological inflammation.

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