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

Abstract

Plasma alpha-linolenic acid (alpha-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% alpha-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 alpha-LNA in the DHA-free diet led to upregulation of liver but not brain coefficients of alpha-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 alpha-LNA deficiency also promoted accumulation of brain docosapentaenoic acid (22:5n-6), and upregulated 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.

Figure 1. Model of brain docosahexaenoic acid cascade at the synapse

Docosahexaenoic acid (DHA), esterified at the sn-2 position of a phospholipid, is liberated by activation (star) of PLA₂ at the synapse, secondary to neuroreceptor activation , . A fraction of the unesterified DHA is converted to docosanoids by COX, lipoxygenase or P450 enzymes, whereas the remainder is transported by a fatty acid binding protein (FABP) to the endoplasmic reticulum. From there, DHA is activated to docosahexaenoyl-CoA by an acyl-CoA synthetase with the consumption of two ATPs, then esterified into an available lysophospholipid by an acyltransferase. Unesterified DHA also can be lost by β-oxidation in mitochondria or peroxisomes, or by other pathways (not shown). The endoplasmic reticulum compartment is in very rapid equilibrium with unesterified plasma DHA that has been dissociated from circulating albumin, whereas the synaptic compartment does not exchange with plasma DHA . This allows injecting radiolabeled DHA* intravenously and determining the incorporation rates J_in (circled), a critical parameter, of unesterified unlabeled plasma DHA into individual membrane phospholipids, as well as DHA turnover rates and half-lives in those phospholipids. Adapted from .

Figure 2. Fractional distribution of [1-¹⁴C]α-LNA in different lipid compartments of rat brain, following 5 min of intravenous its intravenous infusion in unanesthetized rats on a high 2.3% DHA containing diet

Less than of the tracer has been elongated to EPA or DHA in the acyl-CoA, phospholipid(PL) or triacylglycerol (TG) pools. From .

Figure 3. Fifteen weeks of dietary n-3 PUFA deprivation in post-weaning rats prolongs half-life and slows DHA loss in rat brain phospholipid

[4,5-³H]DHA was injected into the brain radioactivity due to it was followed in individual phospholipids for 60 days, from which half-lives t_1/2 were calculated (Eq. J_loss was calculated from half-life as illustrated in figure (Eq. 3). From Demar et al. .

Figure 4. Horizontal section of regional incorporation rates of plasma unesterified arachidonic acid into human brain, after correction for partial voluming

. Rates are given in terms of color-coding. The global rate, obtained by integrating regional rates for whole brain, equaled 17.8 mg/1500 g brain/day. From .

Figure 5. Fifteen weeks of n-3 PUFA dietary deprivation, compared with an n-3 PUFA “adequate” diet, decreases rat frontal cortex iPLA₂ and COX-1 protein but increases sPLA₂, cPLA₂ and COX-2 protein

From .

Figure 6. Fifteen weeks of n-3 PUFA dietary deprivation, compared with an n-3 PUFA adequate diet, downregulates rat frontal cortex expression of p38 MAP kinase activity and phospho p38 MAP kinase protein, CREB DNA binding activity and phospho-CREB protein, and BDNF protein and mRNA. From