Lipid Nutrition and the Brain

脂质营养与大脑

• 批准号: 8335861
• 负责人: Stanley I. Rapoport
• 金额: $ 67.82万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8335861
• 关键词: Acids; Address; Adult; Age; Aging; Animals; Antipsychotic Agents; Arachidonate 15-Lipoxygenase; Arachidonic Acids; Brain; Brassica rapa; Calcium; Carbon; Chemicals; Clinical Protocols; Clinical Research; Consumption; Cytosolic Phospholipase A2; Data; Diabetes Mellitus; Diet; Docosahexaenoate; Docosahexaenoic Acids; Eicosapentaenoic Acid; Electroconvulsive Shock; Enzymes; Epilepsy; Equation; Goals; Health; Heart; Homeostasis; Hour; Human; Hyperactive behavior; Infusion procedures; Intravenous; Intravenous infusion procedures; Isotope Labeling; Isotopes; Kinetics; Label; Linoleic Acids; Lipids; Liver; Liver diseases; Magnesium; Measures; Messenger RNA; Metabolic; Metabolic syndrome; Metabolism; Methods; Modeling; Mono-S; Mus; N-Methylaspartate; NF-kappa B; National Institute on Alcohol Abuse and Alcoholism; Nutrient; Nutritional Requirements; Obesity; Oils; Oleic Acids; Organ; Pharmaceutical Preparations; Plants; Plasma; Polyunsaturated Fatty Acids; Process; Proteins; Protocols documentation; Publishing; Rattus; Regulation; Reporting; Rodent; SRE-1 binding protein; Seizures; Sunflower Oil; Supplementation; Synthetic Diet; Techniques; Tissues; Unsaturated Fatty Acids; Up-Regulation; Weaning; Writing; alpha-Linolenic Acid; arachidonate; audiogenic seizure; base; cyclooxygenase 1; cyclooxygenase 2; deprivation; dietary requirement; docosapentaenoic acid; fat nutrition study; fatty acid biosynthesis; fatty acid metabolism; feeding; human PLA2G4A protein; human subject; in vivo; lipid metabolism; male; mathematical model; member; microwave electromagnetic radiation; mind control; neuroprotection; p65; radiotracer; response; transcription factor; uptake

DIET AND LIVER DETERMINE BRAIN ARACHIDONIC AND DOCOSAHEXAENOIC ACID METABOLISM Dietary requirements for maintaining brain and heart docosahexaenoic acid (DHA, 22:6n-3) homeostasis are not certain, because rates of liver DHA synthesis from circulating alpha-linolenic acid (alpha-LNA, 18:3n-3) have not been quantified. These rates can be estimated using intravenous radiotracer- or heavy isotope-labeled alpha-LNA infusion. In adult unanesthetized male rats, such infusion shows that liver synthesis-secretion rates of DHA from alpha-LNA markedly exceed brain and heart DHA synthesis rates and the brain DHA consumption rate, and that liver but not heart or brain synthesis is upregulated when dietary n-3 ply unsaturated fatty acid (PUFA) content is reduced. These rate differences reflect much higher expression of DHA-synthesizing enzymes in liver, and upregulation of liver but not heart or brain enzyme expression by n-3 PUFAs. The intravenous U-13Calpha-LNA infusion method could be extended for human studies (Rapoport et al., 2010). DIETARY N-6 PUFA DEPRIVATION DOWNREGULATES ARACHIDONATE BUT UPREGULATES DOCOSAHEXAENOATE METABOLIZING ENZYMES IN RAT BRAIN. For maintaining metabolic homeostasis, we hypothesized that dietary n-6 PUFA deprivation would decrease expression of arachidonic acid (AA 20:4n-6)-selective cytosolic phospholipase A2 (cPLA2) IVA and cyclooxygenase (COX)-2 in rat brain, while increasing expression of docosahexaenoic acid (DHA 22:6n-3)-selective calcium-independent iPLA2 VIA. Brain expression of these enzymes and of their transcription factors was quantified in male rats fed an n-6 PUFA adequate or deficient diet for 15 weeks post-weaning. The deficient compared with adequate diet increased mRNA, protein and activity of iPLA2 VIA and 15-lipoxygenase (LOX), but decreased cPLA2 IVA and COX-2 expression. The protein level of the iPLA2 transcription factor SREBP-1 was elevated, while protein levels were decreased for AP-2alpha and NF-kappaB p65, cPLA2 and COX-2 transcription factors, respectively. These changes would be expected to homeostatically dampen reductions in brain n-6 PUFA concentrations and metabolism, while increasing n-3 PUFA metabolism (Kim et al., 2011). REGULATION OF RAT BRAIN POLYUNSATURATED FATTY ACID (PUFA) METABOLISM DURING GRADED DIETARY N-3 PUFA DEPRIVATION. Knowing threshold changes in brain lipids and lipid enzymes during dietary n-3 polyunsaturated fatty acid deprivation can elucidate regulation processes of brain lipid metabolism. To determine thresholds, rats were fed for 15 weeks DHA-free diets having graded reductions of &#945;-linolenic acid (alpha-LNA). Compared with control diet (4.6% alpha-LNA), plasma DHA fell significantly at < 1.7% dietary alpha-LNA. Brain DHA remained unchanged down to 0.8% alpha-LNA, when plasma and brain docosapentaenoic acid (DPAn-6) were increased and DHA-selective iPLA2 and COX-1 activities were downregulated. Brain AA was unchanged by deprivation, but AA selective-cPLA2, sPLA2 and COX-2 activities were increased at or below 0.8% dietary &#945;-LNA, likely in response to elevated brain DPAn-6. Homeostatic mechanisms appear to maintain a control brain DHA concentration down to 0.8% dietary alpha-LNA, despite reduced plasma DHA, to when DPAn-6 replaces DHA. At extreme deprivation, decreased brain iPLA2 and COX-1 activities likely reduce brain DHA loss (Kim et al., In Press). BRAIN PROTECTION BY RAPESEED OIL IN MAGNESIUM-DEFICIENT MICE. Diets given for 30 days having various mono-(MUFA) and poly-(PUFA) unsaturated fatty acid contents were evaluated for brain protection in magnesium-deficient mice: a commercial and three synthetic diets (n-6PUFA, n-3PUFA and MUFA-based chows enriched with 5% corn/sunflower oils 1:3, with 5% rapeseed oil and with 5% high oleic acid sunflower oil/sunflower oil 7:3, respectively). The n-3PUFA but not other diets protected magnesium-deficient mice against hyperactivity and electroshock- and NMDA-induced seizures. This diet also inhibited audiogenic seizures by 50%. Because, matched control MUFA diet failed to provide protection, alpha-linolenate (ALA) rather than reduced n-6 PUFA diet content likely caused n-3PUFA neuroprotection. Our data ALA support supplementation for neuroprotection in epilepsy (Pages et al., 2011). CONVERSION OF LINOLEIC TO ARACHIDONIC AND OTHER N-6 POLYUNSATURATED FATTY ACIDS IN UNANESTHETIZED RATS. Isotope feeding studies report a wide range of conversion fractions of shorter-chain to long-chain PUFAs, which limits assessing nutritional requirements and organ effects of arachidonic (AA, 20:4n-6) or docosahexaenoic (DHA, 22:6n-3) acid. Knowing conversion rates can help to assess daily nutritional requirements. Using our in vivo infusion method, we determined rates and coefficients of conversion of circulating unesterified linoleic acid (LA, 18:2n-6) to esterified AA and to other n-6 PUFAs in unanesthetized adult rats on a high DHA but AA-free diet. The conversion rate of LA to AA equaled 16 micromol/day, exceeding the brain AA consumption rate 27-fold. The heavy-isotope intravenous infusion model could be used to quantify e liver synthesis-secretion of AA from LA under different conditions in rodents or humans (Gao et al., 2010). LIVER CONVERSION OF DOCOSAHEXAENOIC AND ARACHIDONIC ACIDS FROM THEIR 18-CARBON PRECURSORS IN RATS ON A DHA-FREE ALPHA-LNA-CONTAINING N-3 PUFA ADEQUATE DIET. The long-chain polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6), are critical for health. These PUFAs can be synthesized in liver from their plant-derived precursors, alpha-linolenic acid (alpha-LNA, 18:3n-3) and linoleic acid (LA, 18:2n-6). Vegetarians and vegans may have a suboptimal n-3 PUFA status, and the extent of the conversion of alpha-LNA to EPA and DHA by the liver is debatable. We quantified liver conversion to DHA and other n-3 PUFAs of circulating alpha-LNA in rats fed a DHA-free alpha-LNA adequate diet, and compared results to conversion of LA to AA. U-13CLA or U-13Calpha-LNA was infused intravenously for 2 hours at a constant rate into these unanesthetized rats. Using our published equations to calculate kinetic parameters, the conversion coefficient k* of DHA from alpha-LNA was shown to be much higher than of AA from LA, showing elongation-desaturation selectivity for n-3 PUFA biosynthesis. The net daily secretion rate of DHA exceeded the re brain DHA consumption rate by 50-fold, suggesting that the liver can maintain brain DHA metabolism with an adequate dietary supply solely of alpha-LNA. This infusion method could be used to determine minimal daily requirements of EPA and DHA in humans (Gao et al., 2011). WHOLE-BODY SYNTHESIS OF DOCOSAHEXAENOIC ACID IN HUMAN SUBJECTS. We are writing a clinical protocol with members of the NIAAA to characterize whole-body synthesis-secretion rates of long-chain n-3 polyunsaturated fatty acids (PUFAs) using infusion of deuterated alpha-linolenic acid (d5-LNA) in humans, to evaluate effects of lowering the dietary nutrient linoleic acid) as a controlled variable on synthesis-secretion rates. This protocol extends our method for animal studies (Gao et al., 2010).

饮食和肝脏确定脑蛛形子和二十二碳六烯酸代谢 不确定的是，尚未量化饮食六烯酸（DHA，22：6n-3）的饮食要求，因为尚未量化循环α-烯醇酸（Alpha-lna，18：3n-3）的肝脏DHA合成速率的稳态。可以使用静脉放射性示例或重型同位素标记的α-LNA输注来估计这些速率。在成年的未安装雄性大鼠中，这种输注表明，来自α-LNA的DHA的肝合成率显着超过了脑和心脏DHA的合成率和脑DHA的消耗率，而肝脏或心脏或脑合成不是饮食N-3脂肪含量不饱和脂肪酸（PUFA）的含量可减少。这些速率差异反映了DHA合成酶在肝脏中的表达更高，而N-3 PUFAS的肝脏上调但不是心脏或脑酶表达。静脉注射U-13Calpha-LNA输注方法可以扩展到人类研究（Rapoport等，2010）。 膳食N-6 PUFA剥夺下调了蛛网酸，但上调了大鼠脑中的二十二碳六烯酸酯代谢酶。 为了维持代谢稳态，我们假设饮食中的N-6 PUFA剥夺会降低蛛网膜酸的表达（AA 20：4N-6） - 选择性的胞质磷脂酶A2（CPLA2）IVA（CPLA2）IVA IVA IVA和环氧酶（COX） - 222222222 cox）的表达。独立于钙的IPLA2通过。这些酶的脑表达及其转录因子的大鼠在喂食N-6 PUFA的雄性大鼠中被定量，在断奶后15周内饮食中有足够的饮食。与足够饮食相比，IPLA2通过和15-脂氧合酶（LOX）的mRNA，蛋白质和活性增加了，但CPLA2 IVA和COX-2表达降低。 IPLA2转录因子SREBP-1的蛋白质水平升高，而对于AP-2alpha和NF-KAPPAB P65，CPLA2和COX-2转录因子，蛋白水平分别降低。这些变化有望在脑N-6 PUFA浓度和代谢中降低稳态减少，同时增加N-3 PUFA代谢（Kim等，2011）。 调节大鼠脑多不饱和脂肪酸（PUFA）代谢在分级N-3 PUFA剥夺过程中的调节。 在饮食N-3多不饱和脂肪酸剥夺期间，了解阈值的阈值变化可以阐明脑脂质代谢的调节过程。为了确定阈值，将大鼠喂食15周无DHA饮食，而降低了α-烯醇酸（alpha-lna）的降低。与对照饮食（4.6％α-LNA）相比，血浆DHA显着下降<1.7％的饮食α-LNA。当血浆和脑docosapentaenoic酸（DPAN-6）增加，DHA选择性IPL​​A2和COX-1活性下调时，脑DHA保持不变至0.8％α-LNA。大脑AA因剥夺而没有改变，但是AA选择性CPLA2，SPLA2和COX-2活性在饮食中或低于0.8％的饮食α-LNA或低于0.8％，可能是响应升高的脑DPAN-6。尽管血浆DHA降低了，但稳态机制似乎将对照脑DHA浓度降低至膳食α-LNA，直到DPAN-6取代DHA时。在极端剥夺时，脑IPLA2和COX-1活动的减少可能会减少脑DHA损失（Kim等人，印刷中）。 镁缺陷小鼠中的菜籽油保护。 评估了30天的饮食30天，以各种单（MUFA）和多饱和（PUFA）不饱和脂肪酸的含量评估镁缺陷小鼠的脑部保护：一种商业和三种合成饮食（N-6PUFA，N-3PUFA，N-3PUFA，N-3PUFA和MUFA基于5％的玉米/阳光酸盐，含5％的Rapees Oce affer，含5％的copece confloe石油/向日葵石油分别为7：3）。 N-3PUFA，但没有其他饮食保护缺乏镁的小鼠免受多动症以及电击和NMDA诱导的癫痫发作。这种饮食还抑制了听觉性癫痫发作50％。因为，匹配的对照MUFA饮食无法提供保护，因此α-烯酸酯（ALA）而不是降低N-6 PUFA饮食含量可能会导致N-3PUFA神经保护作用。我们的数据ALA支持补充癫痫中神经保护作用（Pages等，2011）。 亚麻的大鼠将亚油酸转化为蛛网膜和其他N-6多不饱和脂肪酸。 同位素喂养研究报告说，较短链到长链PUFAS的各种转化部分限制了评估蛛网膜（AA，20：4N-6）或docosahexaenoic（DHA，22：6n-3）酸的营养需求和器官效应。了解转化率可以帮助评估日常营养需求。使用我们的体内输注方法，我们确定了循环未酯化的亚油酸（LA，18：2N-6）转化的速率和系数，以酯化AA和其他N-6 PUFAS在高DHA中未经洗涤的成年大鼠中的其他N-6 PUFA，但无AA饮食。 LA到AA的转化率相当于16 micromol/天，超过了大脑AA消耗率27倍。在啮齿动物或人类的不同条件下，重型异位静脉输注模型可用于量化AA的肝合成分泌（Gao等，2010）。 在无DHA含α-LNA的N-3 PUFA充足饮食中，大鼠中18碳前体中二十六烯酸和花生四烯酸的肝转化。 长链多不饱和脂肪酸（PUFAS），eicosapentaenoic酸（EPA，20：5N-3），二十二烷酰己烯酸（DHA，22：6N-3）和花生四烯酸（AA，20：4N-6）至关重要。这些PUFA可以通过其植物来源的前体，α-烯醇酸（Alpha-LNA，18：3N-3）和亚油酸（LA，18：2N-6）合成。素食主义者和素食主义者可能具有次优的N-3 PUFA状态，并且肝脏将α-LNA转化为EPA和DHA的程度值得商bat。我们将肝脏转化为DHA和其他N-3 PUFA的大鼠中循环α-LNA的其他N-3 PUFA，并将其与LA转化为AA的转化率相比。将U-13CLA或U-13CALPHA-LNA静脉注射2小时，以恒定的速度持续到这些未经麻醉的大鼠中。使用我们发布的方程计算动力学参数，显示出来自alpha-lna的DHA的转换系数k*比LA的AA高得多，显示了N-3 PUFA生物合成的伸长延伸性选择性。 DHA的净分泌率超过了RE Brain DHA的消耗率50倍，这表明肝脏可以仅使用Alpha-LNA的足够饮食供应来维持脑DHA代谢。这种输注方法可用于确定人类中EPA和DHA的最小每日需求（Gao等，2011）。 人类受试者中二十六烯酸的全身合成。 我们正在与NIAAA成员一起编写临床方案，以表征长链N-3 N-3多不饱和脂肪酸（PUFAS）的全身合成 - 分泌速率（PUFAS），使用脱硫α-内酚酸（D5-LNA）在人类中降低了饮食营养酸的影响，以评估降低饮食营养酸的影响的效果，以评估降低饮食营养酸的影响。 该协议扩展了我们的动物研究方法（Gao等，2010）。