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1.
J Mol Cell Cardiol ; 133: 1-11, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31145942

RESUMO

BACKGROUND: The fatty acid (FA) composition of membrane phospholipid reflects at least in part dietary fat composition. Saturated FA (SFA) suppress Sirt1 activity, while monounsaturated FA (MUFA) counteract this effect. OBJECTIVE: We explored a role of Sirt1 in homeostatic control of the fatty acid composition of membrane phospholipid in the presence of SFA overload. METHODS AND RESULTS: Sirt1 deficiency in cardiomyocytes decreased the expression levels of liver X receptor (LXR)-target genes, particularly stearoyl-CoA desaturase-1 (Scd1), a rate-limiting enzyme in the cellular synthesis of MUFA from SFA, increased membrane SFA/MUFA ratio, and worsened left ventricular (LV) diastolic function in mice fed an SFA-rich high fat diet. In cultured cardiomyocytes, Sirt1 knockdown (KD) exacerbated the palmitate overload-induced increase in membrane SFA/MUFA ratio, which was associated with decrease in the expression of LXR-target genes, including Scd1. Forced overexpression of Scd1 in palmitate-overloaded Sirt1KD cardiomyocytes lowered the SFA/MUFA ratio. Nicotinamide mononucleotide (NMN) increased Sirt1 activity and Scd1 expression, thereby lowering membrane SFA/MUFA ratio in palmitate-overloaded cardiomyocytes. These effects of NMN were not observed for Scd1KD cardiomyocytes. LXRα/ßKD exacerbated palmitate overload-induced increase in membrane SFA/MUFA ratio, while LXR agonist T0901317 alleviated it. NMN failed to rescue Scd1 protein expression and membrane SFA/MUFA ratio in palmitate-overloaded LXRα/ßKD cardiomyocytes. The administration of NMN or T0901317 showed a dramatic reversal in membrane SFA/MUFA ratio and LV diastolic function in SFA-rich HFD-fed mice. CONCLUSION: Cardiac Sirt1 counteracted SFA overload-induced decrease in membrane phospholipid unsaturation and diastolic dysfunction via regulating LXR-mediated transcription of the Scd1 gene.

2.
PLoS One ; 13(12): e0208396, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30533011

RESUMO

Increase in saturated fatty acid (SFA) content in membrane phospholipids dramatically affects membrane properties and cellular functioning. We sought to determine whether exogenous SFA from the diet directly affects the degree of membrane phospholipid unsaturation in adult hearts and if these changes correlate with contractile dysfunction. Although both SFA-rich high fat diets (HFDs) and monounsaturated FA (MUFA)-rich HFDs cause the same degree of activation of myocardial FA uptake, triglyceride turnover, and mitochondrial FA oxidation and accumulation of toxic lipid intermediates, the former induced more severe diastolic dysfunction than the latter, which was accompanied with a decrease in membrane phospholipid unsaturation, induction of unfolded protein response (UPR), and a decrease in the expression of Sirt1 and stearoyl-CoA desaturase-1 (SCD1), catalyzing the conversion of SFA to MUFA. When the SFA supply in the heart overwhelms the cellular capacity to use it for energy, excess exogenous SFA channels to membrane phospholipids, leading to UPR induction, and development of diastolic dysfunction.


Assuntos
Cardiomiopatias/metabolismo , Lipídeos de Membrana/metabolismo , Membranas/metabolismo , Fosfolipídeos/metabolismo , Animais , Cardiomiopatias/patologia , Células Cultivadas , Diástole , Dieta Hiperlipídica , Regulação para Baixo , Ácidos Graxos Monoinsaturados/análise , Ácidos Graxos Monoinsaturados/metabolismo , Masculino , Lipídeos de Membrana/análise , Membranas/química , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/química , Miocárdio/metabolismo , Fosfolipídeos/análise , Triglicerídeos/análise , Triglicerídeos/metabolismo , Resposta a Proteínas não Dobradas/fisiologia
3.
Biochem Biophys Res Commun ; 505(1): 81-86, 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30241938

RESUMO

Reelin is a secreted protein essential for the development and function of the mammalian brain. The receptors for Reelin, apolipoprotein E receptor 2 and very low-density lipoprotein receptor, belong to the low-density lipoprotein receptor family, but it is not known whether Reelin is involved in the brain lipid metabolism. In the present study, we performed lipidomic analysis of the cerebral cortex of wild-type and Reelin-deficient (reeler) mice, and found that reeler mice exhibited several compositional changes in phospholipids. First, the ratio of phospholipids containing one saturated fatty acid (FA) and one docosahexaenoic acid (DHA) or arachidonic acid (ARA) decreased. Secondly, the ratio of phospholipids containing one monounsaturated FA (MUFA) and one DHA or ARA increased. Thirdly, the ratio of phospholipids containing 5,8,11-eicosatrienoic acid, or Mead acid (MA), increased. Finally, the expression of stearoyl-CoA desaturase-1 (SCD-1) increased. As the increase of MA is seen as an index of polyunsaturated FA (PUFA) deficiency, and the expression of SCD-1 is suppressed by PUFA, these results strongly suggest that the loss of Reelin leads to PUFA deficiency. Hence, MUFA and MA are synthesized in response to this deficiency, in part by inducing SCD-1 expression. This is the first report of changes of FA composition in the reeler mouse brain and provides a basis for further investigating the new role of Reelin in the development and function of the brain.

4.
Nat Med ; 23(11): 1287-1297, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29035365

RESUMO

Critical to the function of mast cells in immune responses including allergy is their production of lipid mediators, among which only omega-6 (ω-6) arachidonate-derived eicosanoids have been well characterized. Here, by employing comprehensive lipidomics, we identify omega-3 (ω-3) fatty acid epoxides as new mast cell-derived lipid mediators and show that they are produced by PAF-AH2, an oxidized-phospholipid-selective phospholipase A2. Genetic or pharmacological deletion of PAF-AH2 reduced the steady-state production of ω-3 epoxides, leading to attenuated mast cell activation and anaphylaxis following FcɛRI cross-linking. Mechanistically, the ω-3 epoxides promote IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein that counteracts FcɛRI signaling, through a pathway involving PPARg. Thus, the PAF-AH2-ω-3 epoxide-Srcin1 axis presents new potential drug targets for allergic diseases.


Assuntos
Compostos de Epóxi/química , Ácidos Graxos Ômega-3/farmacologia , Imunoglobulina E/imunologia , Mastócitos/imunologia , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Animais , Células Cultivadas , Meios de Cultivo Condicionados , Ácidos Graxos Ômega-3/química , Humanos , Lipídeos de Membrana/metabolismo , Camundongos , Camundongos Knockout , Fosfolipídeos/metabolismo
5.
EMBO J ; 36(12): 1719-1735, 2017 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-28495679

RESUMO

The autophagosome, a double-membrane structure mediating degradation of cytoplasmic materials by macroautophagy, is formed in close proximity to the endoplasmic reticulum (ER). However, how the ER membrane is involved in autophagy initiation and to which membrane structures the autophagy-initiation complex is localized have not been fully characterized. Here, we were able to biochemically analyze autophagic intermediate membranes and show that the autophagy-initiation complex containing ULK and FIP200 first associates with the ER membrane. To further characterize the ER subdomain, we screened phospholipid biosynthetic enzymes and found that the autophagy-initiation complex localizes to phosphatidylinositol synthase (PIS)-enriched ER subdomains. Then, the initiation complex translocates to the ATG9A-positive autophagosome precursors in a PI3P-dependent manner. Depletion of phosphatidylinositol (PI) by targeting bacterial PI-specific phospholipase C to the PIS domain impairs recruitment of downstream autophagy factors and autophagosome formation. These findings suggest that the autophagy-initiation complex, the PIS-enriched ER subdomain, and ATG9A vesicles together initiate autophagosome formation.


Assuntos
Autofagossomos/metabolismo , CDP-Diacilglicerol-Inositol 3-Fosfatidiltransferase/análise , Retículo Endoplasmático/enzimologia , Retículo Endoplasmático/metabolismo , Biogênese de Organelas , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Linhagem Celular , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Transporte Proteico
6.
J Biol Chem ; 287(4): 2926-34, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22147702

RESUMO

Chloroquine (CQ) is a widely prescribed anti-malarial agent and is also prescribed to treat autoimmune diseases. Clinical treatment with CQ is often accompanied by serious side effects such as hepatitis and retinopathy. As a weak base, CQ accumulates in intracellular acidic organelles, raises the pH, and induces osmotic swelling and permeabilization of acidic organelles, which account for CQ-induced cytotoxicity. We reported previously that CQ treatment caused α-tocopherol transfer protein (α-TTP), a gene product of familial vitamin E deficiency, to change its location from the cytosol to the surface of acidic organelles. Here we show that α-TTP plays a novel role in protecting against CQ toxicity both in vitro and in vivo. In the presence of CQ, rat hepatoma McARH7777 cells, which do not express α-TTP endogenously, showed more severe cytotoxicity, such as larger vacuolation of acidic organelles and caspase activation, than α-TTP transfectant cells. Similarly, α-TTP knockout mice showed more severe CQ toxicity, such as hepatotoxicity and retinopathy, than wild-type mice. These effects were not ameliorated by vitamin E supplementation. In contrast to bafilomycin A1 treatment, which prevents CQ accumulation in cells by raising the pH of acidic organelles, α-TTP expression prevented CQ accumulation without affecting the pH of acidic organelles. Taken together, our data suggest that α-TTP protects against CQ toxicity by preventing CQ accumulation in acidic organelles through a mechanism distinct from vitamin E transport.


Assuntos
Antimaláricos/efeitos adversos , Proteínas de Transporte/metabolismo , Cloroquina/efeitos adversos , Resistência a Medicamentos , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Cloroquina/farmacocinética , Cloroquina/farmacologia , Citosol , Citotoxinas/efeitos adversos , Citotoxinas/farmacocinética , Citotoxinas/farmacologia , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Knockout , Organelas/genética , Organelas/metabolismo , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/genética , Ratos , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/genética , Doenças Retinianas/metabolismo
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