Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver

Abstract

Plasma α-linolenic acid (α-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% α-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 α-LNA in the DHA-free diet led to upregulation of liver but not brain coefficients of α-LNA conversion to DHA and of liver expression of elongases and desaturases that catalyze this conversion. Concurrently, brain DHA loss slowed due to downregulation of several of its DHA-metabolizing enzymes. Dietary α-LNA deficiency also promoted accumulation of brain docosapentaenoic acid (22:5n-6), and upregulated expression of AA-metabolizing enzymes, including cytosolic and secretory phospholipases A₂ 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.

Introduction

Brain structure and function, particularly neurotransmission, depend on interactions between arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3) at multiple target sites [1], [2], [3], [4], [5], [6]. These long-chain polyunsaturated fatty acids (PUFAs) and their respective shorter-chain PUFA precursors, linoleic acid (LA, 18:2n-6) and α-linolenic acid (α-LNA, 18:3n-3), are nutritionally essential and cannot be synthesized de novo in vertebrate tissue [7].

Animal studies with different proportions of PUFAs in the diet have identified broad dietary requirements for maintaining optimal brain function [8], and have demonstrated that metabolic and behavioral defects arise from severe long-term n-3 PUFA dietary deprivation. Additionally, 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 [9], [10], [11], and that dietary n-3 PUFA supplementation may be beneficial in some of these conditions [6], [12].

Effects on the brain of minor n-3 PUFA dietary deprivation associated with small declines in plasma DHA concentrations of the order found in human subjects have rarely been studied in animal models. Additionally, controversy exists about which dietary PUFA compositions are optimal for human brain function [6], [12], [13], [14], [15], [16]. The liver's in vivo capacity to convert α-LNA or eicosapentaenoic acid (EPA, 20:5n-3) to DHA, or LA to AA, has not be quantified in animals or in humans, although changes in this capacity with development, aging or disease likely impact brain PUFA metabolism [17], [18], [19], [20], [21].

Several important questions regarding the relation of brain PUFA metabolism to diet and liver PUFA metabolism have recently been partially resolved, and we shall discuss them in this brief review. These are: (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 α-LNA to DHA? (3) How do brain lipid enzymes and trophic factors respond to dietary n-3 PUFA deprivation?

We have developed kinetic methods and models to address these questions in the intact awake organism. The methods include brain imaging with quantitative autoradiography or positron emission tomography (PET), intravenous injection of radiolabeled PUFAs 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.