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J. Biol. Chem., Vol. 277, Issue 11, 8755-8758, March 15, 2002

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MINIREVIEW
The Biochemistry of n-3 Polyunsaturated Fatty Acids^*,

Donald B. Jump

From the Departments of Physiology, Biochemistry, and Molecular Biology, Michigan State University, East Lansing, Michigan 48824

	INTRODUCTION

TOP INTRODUCTION Synthesis and Metabolism of... n-3 PUFA Effects on... n-3 PUFA Effects on... n-3 PUFA Effects on... Concluding Remarks REFERENCES

Dietary n-3 polyunsaturated fatty acids (n-3 PUFA)¹ have effects on diverse physiological processes impacting normal health and chronic disease, such as the regulation of plasma lipid levels (1-4), cardiovascular (5-7) and immune function (8), insulin action (9, 10), and neuronal development and visual function (11) (see Table I, supplemental material). Ingestion of n-3 PUFA will lead to their distribution to virtually every cell in the body with effects on membrane composition and function, eicosanoid synthesis, and signaling as well as the regulation of gene expression (11-14). However, cell-specific lipid metabolism as well as the expression of fatty acid-regulated transcription factors likely plays an important role in determining how cells respond to changes in PUFA composition. In this minireview I will highlight some of the recent advances in our understanding of n-3 PUFA effects on cells with an emphasis on those mechanisms likely to have a broad physiological impact.

	Synthesis and Metabolism of n-3 and n-6 PUFA in Mammals

TOP INTRODUCTION Synthesis and Metabolism of... n-3 PUFA Effects on... n-3 PUFA Effects on... n-3 PUFA Effects on... Concluding Remarks REFERENCES

n-3 and n-6 PUFA are the two major classes of PUFA encountered in the diet, and both classes of fatty acids are required for normal human health (15). Linoleic acid (18:2n-6) is the predominant plant-derived dietary PUFA and is a precursor for arachidonic acid (20:4n-6) and eicosanoids (see Fig. 1, supplemental material). -Linolenic acid (18:3n-3) is the predominant plant-derived dietary n-3 PUFA and is a precursor for 22:6n-3. Linoleic acid, 20:4n-6 and 22:6n-3, are prominent PUFA in cellular phospholipids (11).

Non-esterified fatty acids (NEFA) enter cells via fatty acid transporters and are rapidly converted to fatty acyl-CoA thioesters (FA-CoA) by acyl-CoA synthetases (see Fig. 2, supplemental material). Intracellular NEFA and FA-CoA are low (<10 µM), and a major fraction of these lipids is bound to specific proteins, i.e. fatty acid-binding protein and FA-CoA-binding protein. FA-CoAs are substrates for neutral lipid (triglycerides, cholesterol esters) and polar lipid (phospholipids (PS, PE, PC), sphingolipids, and plasmalogens) synthesis as well as elongation, desaturation, -oxidation, and protein acylation reactions.

22:6n-3 is the most abundant n-3 PUFA in most tissues and is found at the sn-2 position of phospholipids (11, 16). Deficiencies of n-3 PUFA lead to a loss of 22:6n-3 from brain and retina rod outer segment (ROS) phospholipids with a compensatory replacement by 22:5n-6 (11, 17-19). This minor change in membrane phospholipid structure is sufficient to lead to memory loss, learning disabilities, and impaired visual acuity. Metabolic studies with healthy humans have shown that in contrast to 20:5n-3, 18:3n-3 is not efficiently converted to 22:6n-3. 18:3n-3 is preferentially utilized by the skin and is more rapidly oxidized than the 20- and 22-carbon n-3 PUFA (20). 22-Carbon PUFA requires prior peroxisomal -oxidation before entering the mitochondrial -oxidation spiral (21). This metabolic partitioning decreases the availability of 18:3n-3 for conversion to the 20- and 22-carbon PUFA in the liver (20).

In rodents maintained on chow diets, 18:3n-3 and 20:5n-3 are minor PUFAs in the phospholipid fraction. However, supplementing diets with fish oil, a rich source of 20:5n-3 and 22:6n-3, significantly increases tissue levels of 20:5n-3, 22:5n-3, and 22:6n-3; these changes occur at the expense of 20:4n-6. Such diets also induce hepatic microsomal, peroxisomal, and mitochondrial fatty acid oxidation while suppressing fatty acid synthesis (12). Differences in how 18- versus 20- and 22-carbon n-3 PUFA are metabolized in cells likely contribute to their effects on cellular regulatory processes. These effects extend beyond differential -oxidation to include PUFA assimilation into neutral lipids. CoA thioesters of 20:5n-3 are poor substrates for diacylglycerol acyltransferase, the last step in triglyceride synthesis (22-24). Neither 20- nor 22-carbon n-3 PUFAs are good substrates for cholesterol ester synthesis.² Thus, the unique properties of 20:5n-3 and 22:5n-3 likely affect intracellular NEFA or CoA thioester levels, factors that will impact several regulatory mechanisms (see Fig. 2, supplemental material). Sorting out these mechanisms represents one of the major challenges in this field.

	n-3 PUFA Effects on Membrane Structure and Function

TOP INTRODUCTION Synthesis and Metabolism of... n-3 PUFA Effects on... n-3 PUFA Effects on... n-3 PUFA Effects on... Concluding Remarks REFERENCES

n-3 PUFA Effects on the Retina and CNS-- The retina contains very high levels of 22:6n-3. In fact, ~50% of all acyl chains in the ROS phospholipids (both sn-1 and sn-2) are 22:6n-3 (in PC, PE, and PS). Minor phospholipids, like phosphatidylinositol and phosphatidic acid, contain predominantly 20:4n-6 (25). Thus, ROS represents an excellent model to define the role of 22:6n-3 in membrane structure and function. Rhodopsin is an integral membrane protein in the ROS. When excited by light, rhodopsin enters a metastable equilibrium between two conformation states, i.e. MI and MII (26-28). MII binds and activates the G-protein, transducin (G_t), and catalyzes a GDP-GTP exchange that activates cGMP-specific phosphodiesterase. Activated phosphodiesterase catalyzes cGMP hydrolysis and triggers closure of the cGMP-gated Na⁺/Ca²⁺ channels leading to hyperpolarization of the ROS plasma membrane and the visual response.

Using reconstituted membranes, Litman and colleagues (26-28) reported that the equilibrium constant (K_eq) for the formation of MII is related directly to the degree of phospholipid acyl chain unsaturation. Phospholipids with one or more 22:6n-3 acyl chains increase both the formation of MII and binding to G_t. Moreover, 22:6n-3-containing phospholipids attenuated the inhibitory effect of cholesterol on both the formation of MII and MII-G_t association. Thus membrane composition plays a critical role in the temporal response of the G-protein-coupled signaling system in the retina ROS.

n-3 PUFA deficiency is associated with memory loss and diminished cognitive function (11, 17-20). Two observations might account for this effect. First, 22:6n-6 activates RXR in cultured neuronal cells (29). RXR is a heterodimer partner to many class II nuclear receptors, some of which, like T₃ receptors, have a major impact on CNS development. Astrocytes, but not neurons, make 22:6n-3, thus providing a potential source of 22:6n-3 to activate RXR (15). Second, n-3 PUFA deficiency is correlated with a decline in PS and increased neuronal apoptosis (11, 30, 31). Neuronal apoptosis is linked to Raf-1 and plasma membrane PS content. Neuro 2A cells treated with 22:6n-3 increase PS in the inner leaflet of the plasma membrane and enhance Raf-1 translocation to the membrane. Raf-1 association with the plasma membrane down-regulates caspase-3 activity and prevents apoptotic cell death (31).

n-3 PUFA Effects on Lipid Rafts-- Outside the CNS, retina, and testes, 22:6n-3 rarely exceeds 10% of the total fatty acid in membrane phospholipids; 20:5n-3 and 22:5n-3 are at even lower levels. However, treating cells with 20:5n-3 increases 20:5n-3, 22:5n-3, and possibly 22:6n-3 in both the phospholipid and protein component of membranes. Lipids rafts are one target for n-3 PUFA effects on membrane function. Lipid rafts are regions within the exoplasmic leaflet of the plasma membrane that are enriched in cholesterol and sphingolipids (32). Rafts selectively incorporate proteins and govern protein-protein and protein-lipid interactions. These membrane microdomains contribute to the structure and function of caveolae, plasma membrane invaginations, signal transduction, endocytosis, transcytosis, and cholesterol trafficking as well as tyrosine kinase and sphingolipid cell signaling. Proteins acylated with saturated fatty acids (14:0 or 16:0) partition into the inner leaflet of the plasma membrane with high affinity for rafts, perhaps because of the unusually long saturated acyl chains on sphingolipids (33). In some cases palmitoylation of proteins requires prior myristoylation, and palmitoylation is required for membrane targeting. A number of proteins involved in cell signaling are found in lipid rafts, including G-proteins (_s, _q), members of the Src kinase family, caveolin, and Gap43. Lipid rafts are sensitive to modification by PUFA. These modifications occur to both the phospholipid component as well as to proteins associated with rafts.

A well defined model for studying PUFA effects on lipid rafts is T-cell activation (33-37). Both n-3 and n-6 PUFAs affect raft composition and function through an eicosanoid-independent mechanism (35). n-3 PUFAs (20:5n-3 and 22:6n-3) are used clinically as immunosuppressive agents because they rapidly alter cellular phospholipid compositions without enhancing inflammatory eicosanoid production associated with n-6 PUFA (see below) (38). Maximal T-cell activation requires the T-cell receptor (TCR)-CD3 complex plus other co-stimulatory signals. These co-stimulatory molecules are attached to the plasma membrane via glycosylphosphatidylinositol anchors clustered in lipid rafts (35). The Src kinase family of protein tyrosine kinases plays an important role in T-cell activation. All Src kinases have myristate (14:0) covalently attached through an amide linkage at a glycine at position 2 of the protein. Seven of the Src kinases are also palmitoylated (16:0) at a cysteine (Myr-Gly-Cys). Myristoylation and palmitoylation are required for targeting Src kinases to rafts (34, 37).

The two Src family kinases, Lck and Fyn, are concentrated on the cytoplasmic side of lipid rafts. Stimulation of the TCR triggers Lck and Fyn activation that leads to increased Ca²⁺ signaling, ERK activation, and other downstream signaling events (34-37). Lipid rafts from Jurkat T-cells treated with 20:4n-6 or 20:5n-3 display reduced Lck and Fyn content and a decline in both calcium signaling and ERK activation. In contrast, the glycosylphosphatidylinositol-anchored proteins, (CD59 and CD48), the ganglioside GM1, and caveolin remain in rafts after PUFA enrichment. Treatment of Jurkat T-cells with 20-carbon PUFA enriches both outer (sphingomyelin, PC) and inner leaflet (PE) phospholipids with 20- and 22-carbon PUFA. The more unsaturated lipid environment of rafts and, in particular, the cytoplasmic leaflet may account for the displacement of acylated proteins from rafts in PUFA-treated T-cells (36).

PUFA treatment of T-cells also results in PUFA acylation of Fyn (34, 37). In fact, the profile of Fyn acylation parallels the fatty acid composition supplied to the cells. Saturated (14:0, 16:0, 18:0), monounsaturated (18:1n9) and polyunsaturated (20:4n-6, or 20:5n-3) fatty acids can be covalently bound to Fyn. Apparently, palmitoyl acyltransferase is a promiscuous enzyme that will covalently attach a broad spectrum of fatty acids to proteins. Replacement of 16:0 with any PUFA results in the failure of Fyn to specifically interact with rafts. Failure of Fyn or other Src kinases to interact with rafts uncouples the TCR from activating downstream signaling pathways, e.g. calcium signaling or ERK activation.

These studies illustrate how changes in membrane phospholipid composition as well as protein acylation affect signaling from the plasma membrane. In particular, the effect of PUFA on membrane protein acylation and protein targeting to the membrane and microdomains, like rafts, is likely to have a broad impact on signaling pathways. It will be important to determine whether n-3 PUFA acylation of membrane proteins extends beyond Src kinases to include effects on G-protein receptors, membrane channels, or sphingolipid signaling.

	n-3 PUFA Effects on Eicosanoid Signaling

TOP INTRODUCTION Synthesis and Metabolism of... n-3 PUFA Effects on... n-3 PUFA Effects on... n-3 PUFA Effects on... Concluding Remarks REFERENCES

Non-esterified PUFAs released from the sn-2 position of the membrane phospholipids by the action of specific phospholipases (phospholipase A2) are substrates for cyclooxygenases (COX-1, a constitutive enzyme or COX-2, an inducible enzyme), lipoxygenases (5-, 12-, or 15-LOX), or cytochrome P450 monooxygenases (CYP) (6, 8, 14, 39-41). Cyclooxygenase products of 20:4n-6 give rise to prostanoids and thromboxanes (14, 41). The LOX pathway catalyzes the insertion of molecular oxygen into arachidonic acid as the first step in the formation of leukotrienes and hydroxyeicosatetraenoic acids. COX and LOX products exit cells and act locally at nanomolar levels through autocrine or paracrine processes on cell surface receptors linked to G-proteins. Activation of G-protein-associated receptor leads to changes in intracellular cAMP or calcium, which serve as second messengers that activate signaling mechanisms that have pronounced effects on various cellular functions. The COX products are modulators of thromboregulatory, inflammatory, and chemotaxic responses, whereas the LOX products are involved in vascular permeability, vasoconstriction, and bronchoconstriction (6, 8, 14).

When compared with 20:4n-6, 20:5n-3 and 22:6n-3 are poor substrates for the COX and LOX reactions (6, 8, 42, 43). Structural analysis of COX-1 reveals a strained configuration when 20:5n-3 binds (44). This configuration misaligns carbon 13 with respect to Tyr-385, the residue that abstracts hydrogen from substrate fatty acids and leads to a 7-fold reduction in oxygenation efficiency relative to 20:4n-6. Moreover, most eicosanoids resulting from COX and LOX action on 20:5n-3 have a bioactivity weaker than the 20:4n-6 product. n-3 PUFAs also enhance eicosanoid catabolism by increasing its peroxisomal degradation (43). Clearly n-3 PUFAs are important modulators of eicosanoid signaling through several mechanisms. The effects of n-3 PUFA on the synthesis, bioactivity, and metabolic clearance of eicosanoid (COX and LOX) products accounts, at least in part, for the anti-inflammatory properties of n-3 PUFA.

A third route for eicosanoid production involves microsomal cytochrome P450-linked monooxygenases. These enzymes are members of a large superfamily of enzymes that catalyzes the NADPH-dependent oxidation of a diverse array of lipophilic compounds including fatty acids, hormones, drugs, and xenobiotics (39, 40). CYP-mediated oxidation of 20:4n-6 yields a variety of eicosanoids, including epoxides, midchain hydroxy fatty acids, -hydroxy fatty acids, and dihydroxy fatty acids. Of these oxidized lipids, the epoxy derivatives of 20:4n-6 are reported to modulate calcium signaling, channel activity, transporter function, mitosis, and impact hypertension. n-3 PUFAs are converted to both epoxy and hydroxy fatty acids by cytochrome P450-linked monooxygenases (45). This mechanism may be important in cells where there is little COX or LOX activity, e.g. hepatic parenchymal cells (46). Unfortunately, little information is available on the bioactivity of 20:5n-3-derived monooxygenase products on biological systems.

	n-3 PUFA Effects on Gene Expression

TOP INTRODUCTION Synthesis and Metabolism of... n-3 PUFA Effects on... n-3 PUFA Effects on... n-3 PUFA Effects on... Concluding Remarks REFERENCES

The effects of fatty acids on gene expression have received considerable attention because this represents a direct route for fatty acids to regulate gene function (12, 13). n-3 PUFAs have rapid effects on gene expression; changes in mRNAs encoding several lipogenic enzymes can be detected within hours of feeding animals diets enriched in n-3 PUFA (47, 48). Moreover, these effects are sustained so long as the n-3 PUFAs remain in the diet. In these cases, the fatty acid acts like a hormone to control the activity or abundance of key transcription factors.

PPAR was the first transcription factor identified as a prospective fatty acid receptor (49, 50). Studies with PPAR knockout mice have shown that PPAR is required for many of the effects of fatty acids on gene expression (51-53). PPAR plays a role in the regulation of an extensive network of genes involved in glucose and lipid metabolism including fatty acid transport, fatty acid-binding proteins, fatty acyl-CoA synthesis, microsomal, peroxisomal, and mitochondrial oxidation, ketogenesis, and ⁵, ⁶, and ⁹ desaturation (50); the expression of genes for at least one glycolytic enzyme, i.e. L-pyruvate kinase (52) and several apolipoproteins, e.g. apoCII and -CIII, are influenced by PPAR (53). However, studies with the PPAR null mouse have shown that PPAR is not the sole transcription factor involved in mediating fatty acid effects on gene transcription. In addition to the PPAR family (PPAR, -, -1, and -2) several other transcription factors have been identified as targets for fatty acid regulation, including hepatic nuclear factor-4, SREBP-1c, LXR and -, RXR, and NFB (6, 12, 13, 29, 54-60).

At present, ligand binding and structural properties are best defined for the PPARs. All PPAR subtypes bind 20:5n-3 (IC₅₀ (or K_d) of ~1-4 µM). Structural analysis of PPAR shows that 20:5n-3 occupies 300 Å³ of the 1300 Å³ hydrophobic binding pocket (61). The acid group and the first 8 carbons are buried in the binding pocket. The hydrophobic -end is bent into the upper arm of the Y-shaped pocket, and 20:5n-3 is not exposed to solvent. Binding of 20:5n-3 or other natural ligands shifts the equilibrium to the active configuration, one that stabilizes the AF-2 helix (helix 12) through H-bonding and hydrophobic interactions with the ligand. This stable conformation of AF-2 permits co-activator recruitment to the receptor, a requisite event in ligand-mediated effects on gene activation. Fatty acids 14 carbons or longer than 20 carbons do not fit in this docking mode and would be exposed to solvent. These configurations do not stabilize the AF-2 helix, lessening the likelihood for co-activator recruitment. Based on this structural analysis, 20:5n-3 is an endogenous ligand for PPARs. Activation of PPARs by 22:6n-3 will likely require prior retro conversion to 20:5n-3, a process that requires peroxisomal -oxidation (21).

Although PPARs can bind many fatty acids in vitro, differential lipid metabolism imposes physiological discrimination at the cellular level. PPAR is the predominant PPAR subtype in rat hepatic parenchymal cells. PPAR binds 18:1n9 and 20:5n-3 with nearly equal affinity, i.e. 0.6 versus 1.1 µM (61). Yet, 20:5n-3, but not 18:1n9, activates PPAR in rat primary rat hepatocytes (51). The simplest explanation for this difference is that the intracellular NEFA pool available to activated PPAR is subject to metabolic regulation. When compared with 18:1n9-CoA, 20:5n-3-CoA is a poor substrate for diacylglycerol acyltransferase (24). A decrease in the rate of 20:5n-3 assimilation into neutral lipids might lead to an elevation in intracellular 20:5n-3 sufficient to activate PPAR. The notion that slowly or poorly metabolized fatty acids activate PPAR is supported by studies with modified fatty acids, e.g. bromo- and sulfur-substituted fatty acids (50). The fibrate class of lipid-lowering drugs (Lopid®, Pfizer; Tricor®, Abbott) was synthesized originally as metabolically stable analogs of branched chain fatty acids (62). When compared with 20:5n-3, fibrates are strong activators of PPAR (12, 50-52).

PPAR also binds 20:5n-3 (K_d ~4 µM) and is expressed in many tissues including adipose, muscle, and vascular cells. Activated PPAR induces lipoprotein lipase and fatty acid transporters (CD36) and enhances adipocyte differentiation as well as inhibiting NFB function and cytokine and COX-2 expression (8, 50). The glitazones, e.g. troglitazone, pioglitazone, and rosiglitazone, are pharmacological PPAR agonists and are used in the treatment of insulin resistance. Pharmacological activation of PPAR and PPAR reduces lipid levels in muscle and adipose tissue and improves insulin sensitivity in these tissues (63, 64). Although n-3 PUFAs are weak agonists of PPARs, when compared with pharmacological agonists n-3 PUFAs have significant effects on insulin sensitivity in various tissues, particularly skeletal muscle (9, 10). Thus n-3 PUFA action on insulin responsiveness in these tissues may extend beyond its regulation of PPAR activity.

Recently, the liver X receptors (LXR and LXR) were identified as targets for fatty acid regulation (60, 64). LXRs bind oxysterols and regulate the expression of genes involved in hepatic bile acid synthesis (65). Unsaturated fatty acids antagonize oxysterol activation by LXR in Hek 293 and hepatoma cell lines by interfering with oxysterol binding. Although such studies suggest that changes in hepatic PUFA levels might affect bile acid synthesis in vivo, feeding studies with mice have yet to support this view. Acting through LXR, oxysterols induce CYP7A1, the rate-limiting enzyme for bile acid synthesis (66). Interestingly, hepatic 7-hydroxylase (CYP7A) activity or mRNA_CYP7A levels are not suppressed in mice fed diets supplemented with unsaturated fatty acids (67, 68).

LXRs also play a major role in lipogenesis through the regulation of transcription of the gene encoding sterol regulatory element-binding protein-1c (SREBP-1c) (69-71). SREBP-1c is a helix-loop-helix transcription factor required for the insulin-mediated induction of hepatic fatty acid and triglyceride synthesis (71-75). SREBP-1c binds sterol regulatory elements in promoters of many genes involved in fatty acid and triglyceride synthesis, including citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase-1, S14 protein, and glycerophosphate acyltransferase but not L-pyruvate kinase (58, 75). In contrast to bile acid synthesis, there is ample evidence for PUFA suppression of hepatic lipogenic gene expression (12). Feeding animals diets supplemented with corn oil, walnut oil, or fish oils suppresses the transcription of many genes involved in de novo lipogenesis including fatty acid synthase, stearoyl-CoA desaturase-1, L-pyruvate kinase, and S14 protein (48, 56-59). PUFA suppresses the nuclear content of SREBP-1c (56, 58). Overexpression of the nuclear form of SREBP-1c overrides the suppressive effect of PUFA on lipogenic gene expression (58, 59). Thus, PUFA regulation of nuclear form SREBP-1c levels may account for many of the suppressive effects of PUFA on hepatic lipogenesis. PPAR is not required for PUFA suppression of SREBP-1c or the mRNAs encoding the lipogenic genes (58).

In contrast to PPAR and LXR, fatty acid regulation of SREBP-1c may not involve direct fatty acid binding but rather control the nuclear abundance of SREBP-1c. Like other members of the SREBP family, SREBP-1c is translated as a large precursor protein (~125 kDa) tethered to the endoplasmic reticulum and Golgi complex (75, 76). The precursor is proteolytically processed to a mature form that moves to the nucleus where it binds as a dimer to sterol regulatory elements in promoters of responsive genes. In rat liver, both n-3 and n-6 PUFAs suppress the cellular level of mRNA_SREBP-1c as well as the precursor and nuclear forms of SREBP-1c (56-59). The hierarchy for fatty acid regulation of mRNA_SREBP-1c is 20:5n-3 = 20:4n-6 > 18:2n-6 > 18:1n-9. The mechanism for PUFA regulation of hepatic mRNA_SREBP-1c involves an enhanced rate of mRNA_SREBP-1c turnover rather than inhibition of gene transcription (77). Specific cis-regulatory elements within the transcript that are targeted by unsaturated fatty acids have eluded identification.² In contrast to liver and primary hepatocytes, established cell lines display a more complicated response to PUFA that involves effects at the transcriptional level, mRNA_SREBP-1c turnover, and conversion of precursor SREBP-1c to the nuclear form (60, 65). PUFA functions as a feedback regulator of fatty acid synthesis. Coupling this action with the PUFA-mediated induction of PPAR-regulated genes shifts hepatic metabolism away from lipid synthesis and storage to lipid oxidation (51, 58). This mechanism prevents lipotoxicity associated with lipid overload.

	Concluding Remarks

TOP INTRODUCTION Synthesis and Metabolism of... n-3 PUFA Effects on... n-3 PUFA Effects on... n-3 PUFA Effects on... Concluding Remarks REFERENCES

The 20- and 22-carbon n-3 PUFAs are unique lipids that when added to the diet or to cells can alter membrane phospholipid composition, impact eicosanoid synthesis and action, and regulate transcription factor activity and abundance. n-3 PUFAs affect diverse physiological processes including cognitive functions and visual acuity, immunosuppressive and anti-inflammatory actions, and anti-thrombotic and anti-arrhythmia activities along with having major effects on whole body glucose and lipid metabolism (see Table I, supplemental material). It is important to distinguish those effects that are specific for n-3 PUFA from those effects that are seen with unsaturated fatty acids in general. Whereas n-6 PUFAs stimulate, n-3 PUFAs inhibit eicosanoid synthesis and signaling and NFB activation. This feature accounts for the anti-inflammatory and anti-thrombotic action of n-3 PUFA. There is also a strict requirement for 22:6n-3 over 22:5n-6 for normal CNS development and function. In contrast, PUFA effects on membrane raft composition as well as the regulation of transcription factors like PPARs, LXRs, or SREBP-1c are determined more by changes in cellular levels of unsaturated fatty acids rather than specific effects of n-3 PUFA. The modest resistance of n-3 PUFA to -oxidation or assimilation into neutral lipids might be sufficient to elevate intracellular n-3 NEFA or PUFA-CoA levels allowing these factors to serve as regulatory ligands for transcription factors or substrates for protein acylation. Unfortunately no direct evidence has been reported to support this concept.

Some effects of n-3 PUFA on physiological processes remain poorly defined. The rapid attenuation of arrhythmias in cardiomyocytes treated with n-3 PUFA involves changes in the activity of several membrane channels (7, 78). Whether this effect involves changes in membrane phospholipid composition or targeting of membrane channel proteins to specific microdomains is unknown. Nevertheless, considerable progress has been made in understanding how n-3 PUFAs affect cell function. Many mechanisms have been described, and new mechanisms are likely to be discovered that will better define how these unique lipids impact human health and disease.

	ACKNOWLEDGEMENTS

I am grateful for many members of the laboratory who have participated in this research. I thank Norman Salem Jr. at the National Institutes of Health and William Smith at Michigan State University for many helpful discussions and for a critical review of the manuscript.

	FOOTNOTES

^* This minireview will be reprinted in the 2002 Minireview Compendium, which will be available in December, 2002.

The on-line version of this article (available at http://www.jbc.org) contains Table I and Figs. 1 and 2.

To whom correspondence should be addressed: Dept. of Physiology, 115 Giltner Hall, Michigan State University, East Lansing, MI 48824. Tel.: 517-355-6475 (Ext. 1246); Fax: 517-355-5125; E-mail: Jump@msu.edu.

Published, JBC Papers in Press, December 17, 2001, DOI 10.1074/jbc.R100062200

² D. B. Jump, unpublished observation.

	ABBREVIATIONS

The abbreviations used are: PUFA, polyunsaturated fatty acid; CNS, central nervous system; FA-CoA, fatty acyl-CoA thioester; NEFA, non-esterified fatty acid; PS, phosphatidylserine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; ROS, rod outer segment; RXR, retinoid X receptor; LXR, liver X receptor; PPAR, peroxisome proliferator receptor; SREBP, sterol regulatory element-binding protein; NFB, nuclear factor B; COX, cyclooxygenase; LOX, lipoxygenase; CYP, cytochrome P450 monooxygenase; AF-2, activation function-2; IR, insulin receptor; TCR, T-cell receptor; ERK, extracellular signal-regulated kinase.

	REFERENCES

TOP INTRODUCTION Synthesis and Metabolism of... n-3 PUFA Effects on... n-3 PUFA Effects on... n-3 PUFA Effects on... Concluding Remarks REFERENCES

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				D. Maillet and J.-M. Weber Performance-enhancing role of dietary fatty acids in a long-distance migrant shorebird: the semipalmated sandpiper J. Exp. Biol., July 15, 2006; 209(14): 2686 - 2695. [Abstract] [Full Text] [PDF]

G. P. Zaloga, N. Ruzmetov, K. A. Harvey, C. Terry, N. Patel, W. Stillwell, and R. Siddiqui (n-3) Long-Chain Polyunsaturated Fatty Acids Prolong