Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver
Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver
Year: 2007
Authors: Rapoport , S.I. Rao, J.S. Igarashi, M.
Publication Name: Prostaglandins, Leukotrienes and Essential Fatty Acids
Publication Details: Volume 77; Pages 251�261.
Abstract:
Plasma alpja-linolenic acid (a-LNA, 18:3n-3) and linoleic acid (LA, 18:2n-6) do not contribute significantly to the brain content of docosahexaenoic acid(DHA,22:6n-3) or arachidonic acid (AA,20:4n-6), respectively, and neither DHA nor AA can be synthesized de novo in vertebrate tissue. Therefore, measured rates of incorporation of circulating DHA and AA into brain exactly represent their rates of consumption by brain. Positron emission tomography (PET) has been used to show, based on this information, that the adult human brain consumes AA and DHA at rates of 17.8 and 4.6 mg/day, respectively, and that AA consumption does not change significantly with age. In unanesthetized adult rats fed an n-3 PUFA ��adequate�� diet containing 4.6% a-LNA (of total fatty acids) as its only n-3 PUFA, the rate of liver synthesis of DHA was more than sufficient to maintain brain DHA, whereas the brain�s rate of DHA synthesis is very low and unable to do so. Reducing dietary a-LNA in the DHA-free diet led to up regulation of liver but not brain coefficients of a-LNA conversion to DHA and of liver expression of elongases and desaturases that catalyze this conversion. Concurrently, brain DHA loss slowed due to down regulation of several of its DHA-metabolizing enzymes. Dietary a-LNA deficiency also promoted accumulation of brain docosapentaenoic acid (22:5n-6), and up regulated expression of AA metabolizing enzymes, including cytosolic and secretory phospholipases A 2 and cyclooxygenase-2. These changes, plus reduced levels of brain derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) in n-3 PUFA diet deficient rats, likely render their brain more vulnerable to neuropathological insults. (Author�s abstract)
Brain structure and function, particularly neurotransmission, depend on interactions between arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3). Clinical studies indicate that low dietary consumption of n-3 PUFAs or a low plasma DHA concentration is correlated with a number of brain diseases and with cognitive and behavioral defects in development and aging, and that dietary n-3 PUFA supplementation may be beneficial in some of these conditions. The liver�s in vivo capacity to convert a-LNA or eicosapentaenoic acid (EPA, 20:5n-3) to DHA, or LA to AA, has not be quantified in animals or in humans. The objectives of this study were to address (1) What are the in vivo rates of brain consumption of AA and DHA in rats and humans? (2) How does brain DHA metabolism depend on dietary n-3 PUFA composition and the liver�s ability to convert a-LNA to DHA? (3) How do brain lipid enzymes and trophic factors respond to dietary n-3 PUFA deprivation? Kinetic methods and models including brain imaging with quantitative autoradiography or positron emission tomography (PET), intravenous injection of radiolabeled PUFAs were used to examine incorporation, turnover and synthesis rates of PUFAs in brain or liver, enzyme assays to evaluate lipid metabolizing enzymes, and molecular techniques to examine mRNA and protein levels of these enzymes. The data presented show that in the absence of dietary DHA, a normal brain DHA content can be maintained by liver conversion of a-LNA to circulating DHA, provided sufficient a-LNA is in the diet, as the brain�s capacity for conversion is quantitatively insignificant. Liver but not brain conversion coefficients are increased by additional a-LNA deprivation, in relation to increased expression of liver elongases and desaturases. Brain DHA depletion caused by 15 weeks of dietary n-3 PUFA deprivation in rats is associated with slowed DHA loss from brain and reduced expression of DHA-metabolizing enzymes, tending to conserve brain DHA. At the same time, increased brain expression of AA-metabolizing enzymes and a high DPAn-6 concentration, and reduced brain BDNF, phospho-CREB and p38 MAP kinase activity levels, suggest up regulated brain n-6 PUFA metabolism. Future studies using these techniques need to examine additional relevant questions: (1) To what extent does the liver convert EPA to DHA under different dietary conditions? (2) What are the effects of gradedn-3 PUFA dietary deprivation on the markers of brain metabolism and function presented in this paper? (3) What are the effects of dietary n-6 PUFA deprivation on these markers? (4) How do liver conversion rates of a-LNA and EPA to secreted DHA vary with age and liver disease in rats? (5) In humans, how do brain AA and DHA consumption rates change with aging or disease, and how might human diets be tailored to maintain normal consumption rates with these variable conditions? (Editor`s comments)
Brain structure and function, particularly neurotransmission, depend on interactions between arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3). Clinical studies indicate that low dietary consumption of n-3 PUFAs or a low plasma DHA concentration is correlated with a number of brain diseases and with cognitive and behavioral defects in development and aging, and that dietary n-3 PUFA supplementation may be beneficial in some of these conditions. The liver�s in vivo capacity to convert a-LNA or eicosapentaenoic acid (EPA, 20:5n-3) to DHA, or LA to AA, has not be quantified in animals or in humans. The objectives of this study were to address (1) What are the in vivo rates of brain consumption of AA and DHA in rats and humans? (2) How does brain DHA metabolism depend on dietary n-3 PUFA composition and the liver�s ability to convert a-LNA to DHA? (3) How do brain lipid enzymes and trophic factors respond to dietary n-3 PUFA deprivation? Kinetic methods and models including brain imaging with quantitative autoradiography or positron emission tomography (PET), intravenous injection of radiolabeled PUFAs were used to examine incorporation, turnover and synthesis rates of PUFAs in brain or liver, enzyme assays to evaluate lipid metabolizing enzymes, and molecular techniques to examine mRNA and protein levels of these enzymes. The data presented show that in the absence of dietary DHA, a normal brain DHA content can be maintained by liver conversion of a-LNA to circulating DHA, provided sufficient a-LNA is in the diet, as the brain�s capacity for conversion is quantitatively insignificant. Liver but not brain conversion coefficients are increased by additional a-LNA deprivation, in relation to increased expression of liver elongases and desaturases. Brain DHA depletion caused by 15 weeks of dietary n-3 PUFA deprivation in rats is associated with slowed DHA loss from brain and reduced expression of DHA-metabolizing enzymes, tending to conserve brain DHA. At the same time, increased brain expression of AA-metabolizing enzymes and a high DPAn-6 concentration, and reduced brain BDNF, phospho-CREB and p38 MAP kinase activity levels, suggest up regulated brain n-6 PUFA metabolism. Future studies using these techniques need to examine additional relevant questions: (1) To what extent does the liver convert EPA to DHA under different dietary conditions? (2) What are the effects of gradedn-3 PUFA dietary deprivation on the markers of brain metabolism and function presented in this paper? (3) What are the effects of dietary n-6 PUFA deprivation on these markers? (4) How do liver conversion rates of a-LNA and EPA to secreted DHA vary with age and liver disease in rats? (5) In humans, how do brain AA and DHA consumption rates change with aging or disease, and how might human diets be tailored to maintain normal consumption rates with these variable conditions? (Editor`s comments)
