H00CvWAAA

Figure 6.26 Mynscic acid

Nutritional summary

Function. Myristaic has one of the highest energy contents of any nutrient, prov iding about 9kcal/g. Complete oxidation depends on riboflavin, niacin, pantothenic acid, carnitine, ubiquinone, iron and magnesium.

Food sources: Milk fat and other animal fats are especially rich sources, hut many solid plant fats also contain mvnstate. especially alter hydrogenation. Requirements: Current recommendations suggest limiting total saturated fat intake to less than 10% of total energy intake.

Deficiency: There is no indication that a lack of myristate intake causes any untoward health consequences.

Excessive intake: Myristate intake strongly raises LDL cholesterol concentrations and increases cardiovascular risk.

Endogenous sources

The extent of de novo fatty acid synthesis, which occurs in eytosol of adipose tissue and liver, is still under dispute (Hcllerstein, 2001). Synthesis, as far as it takes place, tends to proceed to chain lengths of Hi or 1X carbons with little release of the intermediate metabolite myristate.

Dietary sources

Myristate is a minor, but very characteristic component of milk (X 12% of total fat) and ruminant fat (about 3%). The amounts in fats from other sources are much smaller. Intakes of healthy Swedish men were around 4 g d (Wolk et al.. 2001).

Digestion and absorption

Myristate-containing fats are absorbed to near completion from the small intestine. The myristate and other fatty acids from lipase-mediated hydrolysis combine with bile acids, monoglyeerides. and phospholipids into mixed micelles. The micellar lipids arc taken up into the small intestinal cnterocytes through a mechanism thai needs further elucidation. Myristate is then used mainly for the synthesis of triglycerides, which are secreted with chylomicrons into intestinal lymph ducts.

Transport and cellular uptake

Blood circulation: Myristate in plasma is mainly bound to cholesterol and other complex lipids in lipoproteins and taken up into cells with them. Muscles, liver, and adipose tissue readily take up free fatly acids through an incompletely understood mechanism. Blood-brain barrier: The transfer of fatty acids in general into brain is limited and involves largely receptor-mediated endocytosis of lipoproteins. Maternofetal transfer: While myristate, like most fatty acids, reaches the fetus, the amounts and responsible mechanisms are not well understood.

Metabolism

Cham elongation and desaturation: While some chain elongation and desaturation may occur, the extent is likely to he small.

Mitochondrial catabohsm- Long-chain fatty acid C'oA ligase I or 2 (EC6.2.1.3) activates myristale and the combined action of carnitine, palmitoyl-CoA:I.-carnitine O-palmi-toy I transferase I (EC2.3.I.21, on the outside), trans locase. and pahnitoyl-CoA:L-carni-tine O-pa I mitoy I transferase II (EC2.3.I.21, on the inside) shuttles it into mitochondria. The successive actions of long-chain acyl-CoA dehydrogenase (EC1.3.99.I3), enoyl-CoA hvdratase. L-3-hydroxy acyl-Co A dehydrogenase, and thiolase remove two carbons as acetyl-CoA and generate LAD and NAD! I. The acyl-CoA dehydrogenase forms a complex in the mitochondrial matrix with the electron-transfer flavoprotein (ETF, contains FAD), and the iron-sulfur protein electron-transferring-llavoprotein dehydrogenase (EC 1.5.5.1, also contains FAD), which hands off the reducing equivalents to ubiquinone for oxidative phosphorylation, i his sequence is repeated five times. The last cycle releases two acetyl-CoA molecules, of course.

Peroxisomal catabohsm: Myristale is less effectively catabolized in peroxisomes than longer fatty acids. If it is taken into peroxisomes at all. it will undergo only one or two beta-oxidation cycles, since medium-chain acyl-CoA molecules tend to leave peroxisomes and metabolism continues in mitochondria.

After activation by one of several available long-chain fatty acid CoA ligases (EC6.2.1.3), the beta-oxidation cycle in peroxisomes uses FAD-depende rtt acyl-CoA oxidase (EC 1.3.3 6), peroxisomal multifunctional protein 2 (MFP2, comprising activities EC4.2.I.I7. EC5.3.3.8. and EC1.1.1.35), and peroxisoine-spccific acetyl-CoA C-acyliransferase (3-ketoacyl-CoA thiolase; EC2.3.1.I6).

Storage

Adipose tissue typically contains 2- 5°depending strongly on dairy fat intake (Garaulet et (//.. 20(11: Wolk et oi. 2(H) 11, Myristatc is released with normal adipose tissue turnover (about 1 -2% of body fat per day).

Excretion

As vs ith all fatty acids, there is no mechanism that could mediate significant excretion of myristate even with significant excess.

Regulation

The total fat content of the body is protected by powerful appetite-inducing mechanisms that include ihe action of leptm and other humoral mediators. Adipocytes release the proieohormone leplin commensurate to their fat content. Leptin binds to a specific receptor in the brain and decreases appetite through a signaling cascade that involves neuropeptide Y. If the fat content of adipose tissue decreases, less leptin is sent to the brain and appetite increases.

HOOcWWW Myristic acid (14:0)

Long-chain latly acid-Co A tigase

Myristyl-CoA

Acyt-CoA dehydrogenase

wvwv

2-Trans-enoyl- H;0 CoA hydraiase (

O ii

acetyl-CoA C- X acyttrarisl erase /

Lo fig-chains'hydroxyacyl-CoA dehydrogenase

CoA-S

O' NADH

CoA-S-NAD

0 Ii

O' NADH

3-Keto-mynslyl-CoA

Dodecyl-CoA \

0 acetyl-CoA

Decyl-CoA \

Octyl-CoA

O II

Hexyl-CoA

acetyl-CoA

O ii

Butyryl-CoA

2 acetyl-CoA

Figure 6.27 Breakdown ormymtic Jod occurs via (itmdalton

There is no indication that the amounts of myristate in the body or concentrations in specific tissues or compartments are homeostalically controlled.

Function

Fuel energy. The oxidation of myristate supports the generation of about 92 ATP (6 X 2.5 from NADH. fix 1.5 from FADI \2, about 70 from acetyl-CoA, minus 2 for ligation to CoA). This corresponds to an energy yield of about 9kcal g. Complete oxidation of myrislale requires adequate supplies of riboflavin, niacin, pantothenic acid carnitine, ubiquinone, iron, and magnesium.

Membrane anchor for proteins: Some proteins, especially those with signaling function, are acvlated with mynstate as a substrate. Tins lipophilic side chain can nestle into membranes and thus anchor the attached proteins. The specific type of fatty aeid determines preference for membrane regions and precise protein positioning in regard to the membrane surface. A typical example for a myristoylated protein is eAMP-dependent protein kinase (EC2.7.1.37).

Hyperlipidemic potential Myristate raises LDL cholesterol concentrations in plasma to a greater degree than other saturated fatty acids (Mensink el a I., 1W4), especially when polyunsaturated fatty acids contribute less than 5% of total energy. Ii is not known to what extent a concurrent increase in HDL cholesterol concentration can offset the known detrimental effect of higher LDL cholesterol levels.

References

Garaulet M, Perez-Llamas F. Perez-Ayah M, Martinez P. tie Medina FS, Tebar FJ, /amora S. Stte-spccilic differences in the fatty acid composition of abdominal adipose tissue in an obese population from a Mediterranean area: relation w ith dietary fatty acids, plasma lipid profile, serum insulin, and central obesity. Am J Clin Nutr 2001:74:585- 91 Hellerstein Mk. No common energy currency: de now lipogenesis as the road less traveled.

Am J Clin Nutr 2001: 74:707-8 Mensink RP, Temme FJ 1. Homstra i i. Dietary saturated and trans fatty acids and lipoprotein metabolism. Ann Med |994:26:46t 4 Wolk A. Furuheim M. Vessby B. Fatty acid composition of adipose tissue and scrum lipids are valid biological markers of dairy fat intake in men. J Nutr 2001; 131: 828 33

Conjugated linoleic acid

Conjugated hnoleic acid (CLA) is a term comprising 28 isomers of octadccadienoic acid I molecular weight 280) that have two double bonds separated by one single bond.

Abbreviations

Co A coenzyme A

ECl enoyl-CoA isomerase (EC5.3.3.8)

ETF electron-transferring ffavoprotein

FABPpm plasma membrane fatty acid binding protein

FATP-1 fatty acid transport protein 1 (CD36, 5LC27A1)

LPL lipoprotein lipase

MECI mitochondrial enoyl-CoA isomerase (EC5.3.3.8)

MTP microsomal triglyceride transfer protein

TVA rrans-vaccenic acid

VLDL very-low-density lipoprotein

O ii

Octadeca-9cis 1 llrans-dienic acid (conjugated)

Qctadeca-9cis.l2cis-dienic acid (not conjugated)

Figiir» 6,28 The double bonds are «parated by one single bond in CLA, but by two in linoleic acid

Nutritional summary

Function: The non-essential group of fatty acids collectively called conjugated linolcie acid (CLA) may have some cancer-preventive potential. CLA is used as an energy fuel like other fatty acids. Complete oxidation depends on thiamin, riboflavin, niacin, pantothenate, carnitine, lipoatc, ubiquinone, iron, and magnesium. Food sources, CLA is a normal component of ruminant fat in dairy products and meat. Deficiency: There is no indication for harmful effects in people with very low or absent CLA intake.

Excessive intake: The long-term health consequences of high-dose CLA supplement use are not known.

Endogenous sources

Metabolism of trans-11 octadccenoic acid (trans-vaccenie acid TVA) generates cis1), transl I linoleic acid in humans. The conversion occurs in the endoplasmic reticulum through the addition of a double bond by the stearoyl-CoA desalurase (delta-9-desamrase: ECI.14.W.5, contains iron) as originally observed in ruminants (Parodi, 1994; Santora eta}., 2000). The desaturasc uses cytochrome b5. which in turn is reduced by the flavoenzyme cytochrome-b5 reductase (EC'l.fO.2. contains HAD). About one-fifth of a moderate TVA dose (1.5g d) is converted to CLA, but individual metabolic capacities differ considerably (Turpeinen et al.. 2002), Typical daily intakes of TVA from dairy products are around 1.3 l.8g(Emken, l995;WolfT, 1995). High intake of polyunsaturated fatty acids decreases stearoyl-CoA desaturasc activity, whereas diets low in fat. high in carbohydrate or high in cholesterol decrease it (Turpeinen ei at.. 2002).

Dietary sources

CLA is consumed with fat-containing foods of ruminant origin, such as milk, butter, cheese, and beef. Cis9. transl 1 linoleic acid (cis1), iransl I octadecadienoicacid rumeme acid) accounts for three-quarters or more of total CLA in ruminant fat. Most of the remainder is trans7, cis9 ocladienoic acid and transit), cisl2 octadecadienoie acid-Synthetic products (e.g. Clarmol) contain a wider range of isomers.

Mean daily CLA intakes, mainly in ruminant fat including from dairy and beef, have been reported to be between 52 and 310 mg iRitzcnhaler et a!.. 1998; Salminen etaL 1998).

A/VWWW

trans-Vaccenie acid [Octadeca-11 trans-enoic acid)

Stearoy1-CoA A9-desatufase (Iron)

Cytochrome b5 reductase V (FAD)

Rumenic acid (Octadeca-9cis. 11trans-dienoic acid)

Figure 6.19 Dietary trans-vaccemc acid is a precursor for endogenous CLA synthevs

HO-C

Octadeca-9cis,l itrans-dienic acid (rumenic acid)

"^"VWWYA

Ocladeca-10trans, 12cis-dienic acid

Figure 6.M The main CLA isomers m ruminant fai

Digestion and absorption

Bilc-salt activated lipase (EC3.LU) from pancreas in conjunction with colipase is the major digestive enzyme for the hydrolysis of CLA-containing di- and triglycerides. Micelles form spontaneously from the mixture of fatty acids, monoglycerides, bile acids, and phospholipids. CLA is taken up into the small intestine by diffusion and facilitated transport from mixed micelles and is conjugated to CoA by long-chain fatty acid CoA ligasc (EC 6.2,1.3). Most of the acyl-C'oA is used for the synthesis of triglycerides, cholesterol esters, and phospholipids. Triglycerides are assembled into chylomicrons with cholesterol esters, phospholipids, and one molecule of ^»lipoprotein B4X per particle, and secreted into intestinal lymphatic v essels. The fatty acid binding proteins 1 and 2. microsomal triglyceride transfer protein IMTP), and presumably additional proteins are necessary for the intracellular transport of fatty acids and subsequent assembly and secretion of chylomicrons.

Transport and cellular uptake

Blood circulation: Most CLA in blood is a constituent of triglycerides in chy lomicrons, very-low-density lipoprotein (VLDL) and other lipoproteins. The relatively low percentage of cis9. trans 11 linoleic acid in scrum of people with low ruminant fat intake (about (U5% of total fatty acids) rapidly increases (to 0.3% or more with typical intakes} with higher consumption (Turpeinen el at2002). Lipoprotein lipase (LP! ..: EC3.1.1 3) on the endothelial surface of small arterioles and capillaries releases CLA from triglycerides within chylomicrons and VLDL. At least six distinct fatty acid transport proteins are expressed in various tissues. The uptake of the bulk office fatty acids into muscle cells and adipocytes depends on the fatty acid transport protein 1 (FATP-1, CD36. SLC27AI), either in conjunction with or augmented by plasma membrane fatty acid binding protein (FABPpm; Storch and Thumser, 2000) and fatty acid translocase I FAT). Transport across the cell membrane appears to be coupled to acyl-CoA synthase(EC6.2.1.3)activ ity. Apparently this activity does not always require a separate protein, since FATP4 in adipocytes functions as an acyl-CoA synthase (Herrmann end.. 2001). Fatty acids that remain in circulation bind to albumin. A proton-driven fatty aeid transporter mediates their uptake into liver cells {Elsing end.. 1996). Blood-brain barrier: It is not clear how extensive the transfer of non-essential fatty acids into brain is. Lipoprotein-mediated transfer tends to favor long-chain polyunsaturated essential fatty acids, but is likely to unspecifically tag along some CLA. Materw-fetal transfer: Albumin-bound fatty acids and fatty acids released from VLDL by 1 PI at the maternal face of the placenta can be transported to the fetus. FATP, FABPpm, and fatty acid translocase (FAT) on the maternal side, and FATP on the fetal side are likely to be involved (Dutta-Roy, 2000).

Metabolism

Beta-oxidation, both in mitochondria and in peroxisomes, is the main metabolic fate of CLA, discussed here with the example of cis9t trans! 1 linoleic acid.

CoA-linked CLA is transferred to carnitine by pal m i toy l-C'oA:L-carnitine O-palmitoyltransferase I (EC2.3.1.2I). Carnitine acylcamitine translocase (CACT, SLC25A20) then moves the conjugate across the inner mitochondrial membrane in exchange for a free carnitine. Palmitoyl-CoA:L-caraitine O-paImitoy(transferase I! (EC2.3.1.21) links the fatly acid again to CoA.

Long-chain acyl-CoA dehydrogenase (EC1.3.99.13) starts the first cycle of betaoxidation with the transfer of electrons from CLA via FAD and ubiquinone to the electron-transfer system. This FAD-containmg enzyme forms a complex with electron-transferring tlavoprolein (ETF. another FAD-containing protein) and electron-transferring flavoprotcin dehydrogenase (EC 1,5.5.1, contains both FAD and iron) in o

Ocladocn 9cis.11trans-(tioooy( CoA

wrjuj Acyl-CoA

aehydrogenj O

Ocladocn 9cis.11trans-(tioooy( CoA

OtlmfMM'2lrans 9cm,l Ifrani-trwnqyl-CoA

2-Trans-onayi-CoA hyifeatase 9

L- ¡J-HyOnnyociadecii

0 9ca. 1 itrarwaninoyi-CoA CoA-S-C-CH3 t-ortg-chain-3-

scelyi-CoA hydf<my»cyl.CoA J^ MD

1 SH-CoA 0 Q (iobydiogtinase,

ficyilidnstefassi /

/ 3-tieiooctadec®-9os.iitran3-ttenoyi-CoA nadh

Hcnndeca 7ct5,91rnnnUenQyl -CoA ■cotyl-CoA (

Teiraooca 60s Tiransdienoyt. CoA

s acetyl-CoA

Ooaecu 3cis SKans-iftenoyl-CoA Enoyl-CcA

DwJeca-21rans,5Ii flnntenayl-CoA acatyl-CoA

Dec-31ranfn?noylCQA eooyl coa

CoA-S

Doc-2irans-«ooyl CoA

acetyl-CoA

Wv acetyl.CoA acetyl-CoA acsiylCaA scoiyl CoA

Qetanoyt-CoA

Figure 6.31 Putative pathway for the metabolism of rumentc acid the mitochondrial matrix. Trans-enoyl-CoA hydratase (EC4.2.). 17) oxidizes the 2-trans metabolite. Another oxidation step, catalyzed by long-chain-3-hydroxyacyl-CoA dehydrogenase (EC1.1.1.211). generates the 3-kero intermediate. I biolysis by acetyl-CoA C-acy ¡transferase (thiolase: EC2.3.1.16) releases acetyl-CoA. Two more rounds of beta-oxidation with the same sequence of reactions follow.

The 3-cis double bond of the dodeca-3cis,51rans-dienoyI-CoA is not processed by trans-enoyl-CoA hydratase (EC4.2.1.17), w hich would normally act at this point of the cycle. It is likely that dodeeenoyl-CoA delta-isomcrase (enoyl-CoA isomerase; EC5.3.3.8) converts the intermediate dodeca-3.5lrans-dienoyl-CoA to its 2trans, ?cis isomer. Liver mitochondria contain the genetically distinct enzymes enoyl-CoA isomerase (ECI) and mitochondrial enoyl-CoA isomerase (MEC1) with dilferenl catalytic profiles (Zhang el al.. 2002). In peroxisomes both the multifunctional enzyme 1 and ECI have this enoyl-CoA isomerase activity. It is not clear, however, to what extent each of these three enzymes isomcrizes dodeca-3,5trans-dienoyl-CoA and analogous intermediates with conjugated double bonds. The successive actions of 2-trans-cnoyl-CoA hydratase. long-chain-3-hydroxyacyl-CoA dehydrogenase, and acetyl-CoA C-acyllransferase then shorten the molecule to dec-3-trans-cnoyl-CoA. Enoyl-CoA isomerase moves the double bond to the 2 position as discussed above. Among the three isomerases, ECI has the highest preference for this reaction (Zhang ei til., 2002). Completion of this round of beta-oxidation generates the saturated intermediate octanoyl-CoA and another three rounds finish off the breakdown of rumenic acid into nine two-carbon fragments. The acetyl-CoA moieties released with each cycle are utilized further through the Krebs cycle.

Just like other long-chain fatty acids. CLA may be modified by extension of chain length and addition of double bonds. The 18:3. 20:3. and 20:4 derivatives have been detected in adipose tissue. Especially the arachidonie acid analogs may be preferentially incorporated into phospholipids (Bannt et al., 2001 >. The 20 carbon metabolites may also give rise to eicosanoid-like compounds with as yet unknown properties.

Storage

The proportion of triglycerides with conjugated double bonds in adipose tissue correlates with the dietary intake of CLA (Sebedio et al.. 2001).

Excretion

As is the case with other fatty acids, \ irtually no CLA is lost with feces or urine. Function

Fuel metabolism; CLA can be utilized as an energy fuel providing about 9kcal/g, the low consumption levels notwithstanding. Complete oxidation requires adequate supplies of thiamin, riboflm in. niacin, pantothenate, carnitine, lipoate, ubiquinone, iron, and magnesium.

Other effects: Numerous metabolic changes are associated with increasing dietary intake of CLA. These include induction of lipid peroxidation (Basu el a!.. 2 (KM)) through acting as a peroxisome proliferator (Belury et ai. 1997). alteration of prostaglandin synthesis through an action on prostaglandin II synthase (Bulgareila etui., 2001). and promotion ofapoptosis (Park et ul.. 2001). The antioxidant capacity of CLA in vivo is less certain.

The presumed health consequences, possibly including anticancer action, cardiovascular disease prevention, and weight loss promotion (Riseruse/ al.. 2001). still require substantiation by further studies.

References

Banni S, Carta G. Angioni E, Murru E. Scanu P, Mclis MP, Bauman DK. Fischer SM, lp C. Distribution of conjugated linoleic acid and metabolites in different lipid fractions in the rat liver. J Lip Res 2001:42:1056-61 Basu S, Smedman A, Vesshy B. Conjugated linoleic acid induces lipid peroxidation in humans. FEBS Lett 2000:468:33 6 Bchirv MA. Moya-l amarena SY. Liu KI . Van den Hen vet .IP. Dietary conjugated linoleic acid induces perox¡some-specific enzyme accumulation and ornithine decarboxylase activity in mouse liver../ Sutr Biochem 1997:8:579 84 Bulgareila JA. Patton D. Bull AW Modulation «f prostaglandin 11 synthase activity by conjugated linoleic acid (CLA) and specific CLA isomers. Lipids 2001:36:407 12 Dutta-Roy Ak. Transport mechanisms for long-chain polyunsaturated fatty acids in the human placenta. Am J Clin AW2000;71:315S-322S Elsing C, Kassncr A. Stremmel W. LITect of surface and intracellular pi I on hepatocellular fatty acid uptake. Am J Physiol 1996;271 :G 1067-G1073 Emken LA. Trans fatty acids and coronary heart disease risk. Physicochcmical properties, intake and metabolism. Am J Clin Nutr 1995j62:659S-669S Herrmann T. Buchkremcr F. Gosch I, Mall AM, Bernlohr DA. Stremmel W. Mouse fatty acid transport protein 4 (FATP4); characterization of the gene and functional assessment as a very long chain acvl-CoA synthetase. Gene 2001:270:31 40 Park HS. Ryu Jl 1, Ha YL. Park JH. Dietary conjugated linoleic acid (CLA) induces apopto-sis of colonic mucosa in 1.2-dimethyl hydrazine-treated rats: a possible mechanism of the ant ¡carcinogenic elTcct by CLA. Br J Nutr 2001:86:549 55 Parodi PW. Conjugated linoleic acid: an antic arc inogenic fatty acid present in milk fat,

Aust J Dairy Techno! 1994:49:93 7 Riserus I . Berglund L, Vesshy B, Conjugated linoleic acid (CLA i reduced abdominal adipose tissue in obese middle-aged men with signs of the metabolic syndrome: a randomised controlled trial, IntJObesity 2001:25:1129 35 Ritzenhaler K. MeGuirc MK. Falen R, SchultzTD, McGuirs MA. Estimation of conjugated linoleic acid (CLA) intake. FASEB J I998:I2:A527 Salmincn I. Mutanen M, Jauhiaincn Aro A, Dieiarv trans fatty acids increase conjugated linoleic fatty acid levels in human serum. J Nutr Biochem 1998;9:93-8 San lord JE. Palmquist DL. Roehrig KL. Trans-vaccenie acid is desaturaied to conjugated linoleic acid in mice../ Nutr 2000; 130:208-15

Sebedio Jl. Angiont E. Chardigny J\|, Gregoirc S. Juaneda PT Bordeaux 0 I'hc effect of conjugated linoteic acid isomers on fatty acid profiles of liver and adipose tissues and their conversion to isomers of 16:2 and IX:3 conjugated fatty acids in rats. Lipids 2001;36:575-82

Storeh J. Thumscr AE. The fatty acid transport function of fatty acid-binding proteins.

Bioehim BiophysActa 2000;1486:28- -14 Turpeincn AM. Mutancn M, Aro A. Salminen I, Basu S, Palmquist 1)1.. Griinari JM. Bioconversion of vaccenic acid to conjugated linoleic acid in humans. Am J Clin Nurr 2002:76:504-10

Wolff RL. Content and distribution of trans-1H: I acids in ruminant milk and meat fats. Their importance in European diets and their effect on human milk. J Am Oil Chem Sot 1995:72:259-72

Zhang 1). Yu W. Geisbrccht BV. Gould SJ. Spreeher M. Schulz H. Functional characterization of Dclta3,Defta2-enoyl-CoA isomerases from rat liver. ./ Bud Chem 2002: 277: 9127-32

Docosahexaenoic acid

Docosahexaenoic acid t HI IA; molecular weight 328) ts an omega-3 polyunsaturated fatty acid.

Abbreviations

CoA coenzyme A

DHA docosahexaenoic acid

EPA eicosapentaenoic acid

ETF electron-transferring flavoprotein

Nutritional summary

Function: The essential fatty acid docosahexaenoic acid (DHA) becomes a component of complex lipids in membranes (especially of the retina), nerve insulation (myelin in brain), and other structures, is the precursor for signaling molecules (prostaglandins and other eicosanoids), and provides about 9kcal/g when used as an energy fuel. Complete oxidation depends on thiamin, riboflavin, niacin, pantothenate, carnitine, ubiquinone, iron, and magnesium.

o II

o II

Figure 6.32 Docos.ihexacnoic acid

Food sources: Salmon, herring, mackerel, and trout are good DHA sources. Fish-oil capsules are used by some as a dietary supplement. Some DHA can also be formed from alpha-linolenic acid in flaxseed (linseed) and other plant sources The synthesis requires adequate supplies of riboflavin, niacin, pantothenate, magnesium, and iron. Requirements: Canadian recommendations for daily consumption of total omega-3 fatty acids arc I.2-l.6g. UK recommendations are 1% of total energy intake as alpha-linolenic acid and 0.5% as EPA plus DHA. Omega-6 fatty acids cannot substitute for omega-3 fatty acids.

Deficiency: Inadequate omega-3 fatty acid intake impairs immune function and leads to the development (after many weeks) of dermatitis. Low intake increases the risk of sudden death due to heart disease and the risk for some cancers. Excessive intake: High omega-3 fatty acid consumption prolongs bleeding time (Dyerberg and Bang, 1979).

Endogenous sources

Alpha-linolenic acid eicosapentaenoic acid (EPA). and other omega-3 fatty acid can be converted into DHA, mainly in the liver. A series of elongation and desaturation steps in the endoplasmic reticulum generates the 2-1-carbon intermediate tetracosa-hexaenoic acid, which then has to be shortened to DHA by peroxisomal beta-oxidation (Ferdinandusse ft a!.. 2001). DHA synthesis requires adequate supplies of riboflavin, niacin, pantothenate, biotin, iron, and magnesium. The capacity for such conversion reactions is limited in the very young infant and adequate amounts of preformed DHA have to be supplied (Clandinin et «/., 19XI).

The first step is the conjugation of the precursor to coenzyme A by the iron-enzyme long-chain-fatty-acid-CoA ligase (EC6.2.1.3). Linoleoyl-CoA desaturase (delta-6 desaturase: EC1.14.99,25) uses the cytochrome b5 system to add a double bond. FAD-containing cytochrome b5 reductase (EC1.6.2,2) can reactivate the b5 electron donor in an NADH-dependent reaction. A specific NADH-using long-chain fatty acyl elongase (no EC number assigned) adds malonyl-CoA to the aeyl-CoA and releases carbon dioxide and tree CoA. The biotin-enzyme acetyl-CoA carboxylase (F.C6.4.1.21 produces malonyl-CoA by earboxylating acclyl-CoA, Delta-5 desaturase (no EC number assigned) introduces another double bond. This enzyme is not yet well characterized. The next round of elongation generates EPA, which is functionally important itself. Apparently, there is no enzyme available which can introduce a double bond at position 4 of EPA. This difficulty is sidestepped by one more round of elongation and addition of the final double bond in position 6 by Imoleoyl-CoA desaturase. The reaction sequence generates a 24-carbon product tetracosahexaenoic acid, however. To produce DHA. the intermediate has to be moved into a peroxisome (by the peroxisomal ABC half-transporter ALDP. ABCD1) and shortened to 22-carbon length by one round of beta-oxidation (Su et al., 2001).

Peroxisomal beta-oxidation depends on the successive action of FAD-dependent acyl-CoA oxidase (EC 1.3.3.6) and peroxisomal multifunctional protein 2 (MFP2. comprising activities enoyl-CoA hydrata.se, Et 4,2.1.17: 3.2-trans-enoyl-CoA isomerase. EC5.3.3.8:

Alpha-linolenoyl-CoA

cyt. V Cytochrome öS

Linoleoyl-CoA

desaturase

CoA-S-C

CoA-S-C

CoA-S-C

Octadeca tetraenoyl -C o A

maionyl-CoA +2NADPH

Long-chain tatty acyl alongase

CoA-S-C

ElCOSatetraenoyl-CoA

Del ta-5 desaturase

E icosapentae noyl ■ Co A

malonyl-CoA Fatty acy! NADPH

elongase , COj + HaO • 2 NADP Docosa pe n taenoy I- CoA

malonyl-CoA f ■ 2NADPH

Fatty acyl etongase

Tetracosapentae noyl -Co A

CoA-S

CoA-S-C

CoA-S

Linoleoyt-CoA

desaturase

_ ^ NADH cyt. V Cytochrome t>5 reductase (FAD) ' - NAD

CoA-S-C

Tet racosafiexaenoyl-CoA

ALDP

transporter

Docosa he x a enoyl -Co A

peroxisomal fl-oxidation

Figure 6.33 A small percentage of alpha-linolcnic acid is converted into docosa h cïaenoir acid and 3-hydroxyacyl-CoA dehydrogenase. EC 1.1,1.35, and acetyl-CoA C-acyttransfera.se, EC2.3.1.16). Sterol carrier protein X also can catalyze the final step. Peroxisomes arc indispensable for this final activation of DtlA. since mitochondria can process only fatty acids with up to 22 carbons (Singh et at,, 19K4), Individuals with defective or absent peroxisomes can produce EPA, but not Dl IA, from omega-3 fatty acid precursors (Martinez el at., 2000).

Dietary sources

The few good dietary sources of DHA include salmon (14.6 mgg). herring (11.1 mgg). mackerel (7.0mg g). swordlish (ft.Xmgg), trout (5.2mg/g). and halibut (3.7mg.g), These fish also contain significant amounts of EPA and other omega-3 fatty acids. DHA is mainly present in the middle position tsn-2) of the fish-oil triglycerides (Yoshida et at,, 1999).

Flaxseed (linseed) is a particularly rich source of omega-3 fatly acids, because it contains 181 mg alpha-lmolenic acid per g. English walnuts can provide 68 mgg. Canola oil contains about 92 trig g and soybean oil about 78 mg g. Perilla oil has the exceptionally high alpha-linolenic acid content of 630mg g. but is rarely used. The combined omega-3 fatty acid content of most other animal- and plant-derived foods is well under lOmg/g.

Fish-oil capsules, used as dietary supplements, typically provide a combination of DHA. FPA. and other minor omega-3 fatty acids. Vitamin D can be a significant and welcome component of such supplements (particularly those containing cod-liver oil). Inn is not likely to increase intake to harmful levels, even in combination with other vitamin D-cotiiaining supplements. Rctinol is a concern, though.

Typical dietary omega-3 fat intakes depend lo a large extent on habitual use of the major sources. The daily dose of combined omega-3 fatty adds for Americans is about 1.hg. hut less than 200 mg of that is DHA (Kris-Etherton era/., 2000). People using a typical Mediterranean diet get about 0.3% oftheir total fat intake as DHA. and about 2.1 % as omega-3 fatty acids combined (Garaulct et at., 2001).

Digestion and absorption

Bile-salt activated lipase (EC3.U.3) from pancreas in conjunction with eolipase is the major digestive enzyme for the hydrolysis of DHA-containing di- and triglycerides and cholesterol esters. Phospholipase A2 (EC3JJ.4) from pancreas cleaves DHA-rich phospholipids. Micelles form spontaneously from the mixture of fattv acids, mo nog lye-erides, bile acids, and phospholipids. Dl IA enters enierocytes of the small intestine by diffusion and facilitated transport from mixed micelles and is conjugated to CoA by long-chain fatty acid CoA ligase (EC6.2.I.3). Most of the acvl-C'oA is Used for the synthesis of triglycerides, cholesterol esters, and phospholipids. Triglycerides arc assembled into chylomicrons with cholesterol esters, phospholipids, and one molecule ofapolipoprotein l)4K per particle, and secreted into intestinal lymphatic vessels. I lie fatty acid binding proteins I and 2, microsomal triglyceride transfer protein (M l P), and presumably additional proteins are necessary tor tiie intracellular transport of fatty acids and subsequent assembly and secretion of chylomicrons l Dannoura et a!.. 1999).

Transport and cellular uptake

Blood circulation: DHA in fasting plasma (about 2.4% of total fatty acids or 30 lOOmg It is mainly a constituent of phospholipids and cholesterol in LDl. and other lipoproteins. Erythrocytes contain about II) 15ng 106 cells or 50 75mg l (Martínez et at., 2000). Lipoproteins arc taken up into muscle, liver and other tissues via specific receptor-mediated endocytosis. Lipoprotein lipase (LPL; EC3.1.U) on the endothelial surface of small arterioles and capillaries releases free DHA from triglycerides within chylomicrons and VI.DL. At least six distinct fatty acid transport proteins arc expressed in various tissues. The uptake of the hulk of free fatty acids into muscle cells and adipocytes depends on the fatty acid transport protein I (FATP-1. CD36. S1.C27A I: Martin et id.. 2000), either in conjunction with or augmented by plasma membrane fatty acid binding protein (FABPpm; Storeh andThumser, 200(1) and fatty acid transloca.se (FAT) Transport across the cell membrane appears to be coupled to aeyl-CoA synthase (EC'b.2.1.3) activity. Apparently this activ ity does not always require a separate protein, since FATP4 in adipocytes functions as an acyl-CoA synthetase (Herrmann et id.. 2001).

Fatty acids can also be taken up into some cells with the entire TRL. Specific receptors recognize chylomicron remnants I Brown eta!.. 2000) and VLDL (Tacken etui.. 2001).

Fatty acids that remain in circulation bind to albumin. Their main fate is uptake into the liver via a proton-driven fatty acid transporter t Llsing et at.. 1996). Blood-brain barrier; Transport of fatty acids from circulation into brain, via a poorly understood mechanism, favors DHA and other polyunsaturated fatty acids (Edmond. 2001). The mechanism for the specific transfer of essential fatty acids, which are needed for the synthesis of many brain-typical structural compounds, remains unclear. Small amounts may be transported with high-density lipoproteins (HDL). which enter brain capillary endothelium via a HDL-binding receptor (Goti et id.. 2000). Materno-fetal transfer: A third-trimester fetus requires about 3g of DHA per day for structures in the growing brain [Clandinin et al.. llJXI), Both albumin-bound fatty acids and fatty acids released from VLDL by LPL at the maternal face of the placenta arc available for transport. FATP. FABPpm. and fatty acid translocase (FAT) move DHA into the syntrophoblasl. FATP pro\ ides the main mechanism for export to the letal side (Dutta-Roy. 2000). The exact role and identity of these transporters remains to be clarified. The placental FABPpm, which is distinct from related transporters in other tissues, transports DHA more effectively than smaller and saturated fatty acids. Most DHA in fetal circulation is hound to alpha-fetoprotein (Calvo et ul.. I98X).

Metabolism

DI 1 A-C'oA can undergo beta-oxidation both in mitochondria and in peroxisomes. Nearly one-tenth of ingested DHA is shortened to EPA (Conquer and I lolub. 1997). which has its own specific functions. The enzyme that conjugates DI f A to CoA in brain for the

Annr\ /WWW

Docosahexae noyl -Co A

acyltnansf erase

CoA-S

acyltnansf erase

CoA-S

Acyl-CoA dehydrogenase

2t.4c.7c,10c,13c.16c.19c Docosaheptae noyl-CoA

Acyl-CoA dehydrogenase

2t.4c.7c,10c,13c.16c.19c Docosaheptae noyl-CoA

2.4-Dienoyl-CoA reductase

NAOPH -NADP

O II

CoA-S-C

3t.7e, 10c.t 3c. 1 6c,1 9c Docosa he xaenoyi-CoA

0 II

Dodecenoyt-CoA

isomerase

CoA-S

2t.7c. 10c. 13c 16c. 19c Docosahexaenoyl-CoA

O II

2-Trans-ertoyl-CoA hydratase

L-3-Hydroxy-7e.10c.13c.16c, 19c-docosapenlaenoyl-CoA

Long-ehai rv 3-hydroxyacy! CoA dehydrogenase

3-Keto-7c.10c,13c,16c.19cdocosapentaenoyl-CoA

Long-ehai rv 3-hydroxyacy! CoA dehydrogenase

NADH

NADH

3-Keto-7c.10c,13c,16c.19cdocosapentaenoyl-CoA

Sc.flc, 1 ic, 14c. 17c-eicosapeniaenoyi-CoA

Figurr 6.34 Docosa hcxa en trie acid ret reconversion to eicosapcntaenic acid initial activation step has a much lower Km than oilier long-chain fatty acid CoA ligascs (Bazan, 1990».

Palmitoyl-C. oA:L-camitine O-palmitoyI transferase I (EC2.3.1.21) replaces the CoA attached to DHA with carnitine and carnitine acylcamiUne translocase (CACT, SLC25A20) moves the conjugate across the inner mitochondrial membrane in exchange for a free carnitine. Palmitovl-CoA: [.-carnitine O-palm¡toy 1 transferase II (EC'2,3, 1.21) links DHA again to CoA.

The first cycle of DHA-CoA beta-oxidation, catalyzed by long-chain acyl-CoA dehydrogenase (ECL3.99.13). transfers electrons from the substrate via FAD and ubiquinone to the electron-transfer system. This FAD-containing enzyme forms a complex with electron-transferring flavoprolein (ETF. another FAD-containing protein) and cleclron-trdnsferring-flavoprotcin dehydrogenase (EC! .5.5.1, contains both FAD and iron) in the mitochondrial matrix. The conjugated delta2, deIta-1-double bond prevents the usual hydration step. 1 his barrier is sidestepped because NADPI l-dcpendent 2,4-dienoyl-CoA reductase (EC1.3.1.34) saturates the newly introduced double bond and dodecenoyl-CoA delta-isomerase (I.C5.3.3.S) converts the delta3-cis double bond into a delta2-trans double bond. The successive actions of 2-trans-enoyl-CoA hvdratase (FC4.2.1.I7). long-chain-3-hydroxyacyl-CoA dehydrogenase (EC 1.1,1.211). and acetyl-CoA C-acyl transferase (thiolase: EC'2.3.1.16) complete cycle I. The resulting EPA-CoA can either be used tor its own specific purposes or continue through beta-oxidation.

The breakdown of FPA-CoA takes nine cycles of beta-oxidation. Cycle 1 is catalyzed by long-chain acyl-CoA dehydrogenase, 2-trans-enoyl-CoA hydratase. long-chain-3-hydroxyacy 1 -CoA dehydrogenase, and acetvI-Co.A C-acyltransferase. Cycle 2 siart>-with conversion of the delta-3-cis double bond in 3e.6c.9c,l2c,l5c-octadecapentaenoate to a della-2-trans double bond (thus omitting the FADI^-generating step), 2-trans-enoyl-CoA hydratase. long-ehatu-3-hydroxyaeyl-CoA dehydrogenase, and acetyl-CoA C-acyl transferase complete this round. Cycle 3 comprises long-chain acyl-CoA dehydrogenase. 2.4-dienoyl-CoA reductase, dodecenoyl-CoA delta-isomerase, 2-trans-enoy I-CoA hydratase, long-chain-3-hydroxyacyl-CoA dehydrogenase, and acetyl-CoA C-acyl transferase, just like the cycle for DHA to EPA conversion.

The next three cycles are analogous to 1. 2, and 3. Another tw o cycles are analogous to I and 2. except that acyl-CoA dehydrogenase (EC1.3.99.3} catalyzes the initial oxidation step. The successive actions i »f butyryl-CoA dehydrogenase (EC 1.3,99.2). 2-trans-enoyl-CoA hydratase. long-chain-3-hydroxyacyl-CoA dehydrogenase, and acetyl-CoA C-acyltransferase complete one final round of beta-oxidation. The acetyl-CoA moieties released with each cycle are utilized further through the Krcbs cycle.

Storage

Wood carries about 400 -800 mg DMA. much of which becomes available for other uses upon uptake of lipoproteins and degradation of red cell membranes. Adipose tissue at all sites contain some DHA (about 0.25% in a Mediterranean obese population), though the percentage tends to be lower than in the diet (Garaulet era!,, 2001 >. Adipose tissue near the intestines may contain slightly more than at other sites (0.35%). Assuming 10% total body fat. an average-sized (70kg), lean man may be expected to

CoA-S

CoA-S

etf:fad

ETF:FAOH?

acetyl-Co A

etf:fad

ETF:FAOH?

acetyl-Co A

NAOH

NAOH

3c.6c.9c,12c.15c* Ocla decapen raen oy)-Co A

acetyl-CoA

3c.6c.9c,12c.15c* Ocla decapen raen oy)-Co A

acetyl-CoA

NADH

NADH

ETF:FAD

ETF:FAD

NADPH

NADPH

NADP

NADH

5c,8c. 11c-Tet radeca trienoyl-CoA

acetyl-Co A

NADH

5c,8c. 11c-Tet radeca trienoyl-CoA

Figure 6.35 Eicoiapentacnic acid breakdown carry about I8g DHA. of which ¡-2% (i.e. 180-360 mg) are mobilized per day. Women tend to have slightly higher DMA stores due to their higher body fat mass. Lipids in other tissues, especially brain, contain a high percentage of DHA, but slow tissue turnover is likely to Itmti the amounts available for reuse at other sites.

Excretion

Losses of DHA. as of any other laity acid, are minimal and occur mainly with skin, feces, and body Hinds.

Function

Energy fuel: While Dl IA and other omega-3 fatty acids are not an important energy source, most is ev entually utilized through beta-oxidation, providing about 9 kcal/g. Full oxidation depends on adequate supplies of thiamin, riboflavin, niacin, pantothenate, carnitine, ubiquinone, iron, and magnesium.

Precursor for complex brain lipids: DHA is indispensable for the myelin izat ion of neurons in brain and for the functioning of photoreceptor cells in the eve (Martinez ci ul„ 2000). While DHA comprises one-third of the fatty acids in aminophospholipids of gray matter (Bazan and Scott. 1990), the exact functional significance of these and other complex lipids remains to be elucidated further. In particular, DHA is the precursor of a series of very long hexaenoic acids in brain <24:0,26:6, 2X:6. 30:6.32:6.34:6. 36:6) with elusive functions.

Prostanoid synthesis: DMA is a precursor of EPA. which gives rise to the synthesis of 3-scries prostaglandins and 5-scrics leukotrienes I Belch and Hill, 2000), Both DHA and EPA inhibit the synthesis of omega-6 fatty acid-derived prostaglandins, such as P(iF.2 and P(.iF2a (Noguchi et <>!.. 1905). Non-enzymic peroxidation of DHA in the brain produces a large scries of prostaglandin-like compounds, ncuroprosiancs. that may induce neuronal injury, bat also have functional significance (Bernoud-Hubac et aL 2001).

Cardiovascular disease: DHA and other omega-3 fatly acids slow the development of heart disease and its sequelae (Bucher et a!.. 2002) through several mechanisms. Important effects include lowering elevated concentrations of both cholcstcrol- and triglyceride-rich lipoproteins in HI<kkI (possibly through preferential utilization: Madsen ei aL, 1999), decreasing platelet aggregation, and stabilizing heart rhythm (Harper and Jacobson, 2001). The latter is particularly important in older people with significant coronary pathology. A large prospective study found that DHA stores were a strong predictor for sudden death from cardiac causcs (Albert et id.. 20021. L ontrary to some earlier expectations, raising DHA intakes moderately does not appear to increase oxidative stress in humans (Mori et a!.. 2000)

Cancer DHA and other omega-3 fatty acids appear to decrease risk of some cancers. The involved mechanisms arc not well understood. Women with relatively high Dl IA content of their adipose tissue were found to have much lower than average breast cancer risk (odds ratio of 0.31, Mai Hard et til.. 2002). The anticancer potential may be partially explained by the well-established ability of DHA to induce apopiosis (Chen and Istfan, 2000).

Mental health; It has been suggested that low intake of omega-3 fatty acids increases the risk of depression and suicide iBrunncr ei al„ 2002). DHA may also affect appetite and mood through a decrease in leptin production (Reseland et a!.. 2001),

References

Albert CM. Campos H, Stampfcr MJ. Ridker PM. Manson JE, VVilleit WC. Ma J. Blood levels of long-chain n-3 fatty acids and the risk Of sudden dealh. N Engl J Med 2002; 346:1) 13—18

Ra/an N(_i. Supply of h-3 polyunsaturated fatty acids and their significance in the central nervous system. In Nutrition and the Brain. vol. 8, Raven Press. New York. 1990. pp. I-24 '

Ba/an Nti. Scott BL. Dietary omega-3 fatly acids and accumulation of docosahexaenoic acid in rod photoreceptor cells of the retina and at synapses. I psala J Med Set Suppl ] 990:48:97-107

Belch JJI\ Hill A. Evening primrose oil and borage oil in rfieumatologic conditions. Am J

Clin Nutr 2000:7 U52S-35 ft S Bernoud-Hubac N, Davies SS. Boutaud O, Montine TJ. Roberts LJ 2nd. Formation of highly reactive gamma-kctoaldehydes (ncurokeials) as products of the neuroprosiane pathway. J Bial Chem 200l;276:30964 70 Brown Ml.. Ram prasad MP. Umeda PK. Tanaka A. Kobayashl V. Watanabe T. Shimoyumada H. Kuo WL, fi R. Song R. Bradley WA.Gianturco Sll. A macrophage receptor for apolipoprotein R4S: cloning, expression, and atherosclerosis. Proc Natl AcadSei 2000:97:7488 93 Brunner J. Parhofer KG. Schwandt P. Broniseh T. Cholesterol, essential fatly acids, and suicide. Pharmacopsychiatry 2002:35:1 5 Bucher HC. Hengstler P. Schindler C. Meier C. N-3 polyunsaturated fatty acids in coronary' heart disease: a meta-analysis of randomized controlled trials. I m J Med 2002: 112:298-304

Calvo M. Naval J. Lamprcav e I, Uriel J, Pineiro A. Fatty acids bound to alpha-fetoprotein and albumin during rat development. Biochim Biophys tela 1988:959:238 46 Chen ZY. Istfan NW. Docosahexaenoic acid is a potent inducer of apoptosis in HT-29

colon cancer cells. Pmstagl Leukotr Ess Fatty Acids 2000;63:3t)l -8 Clandinin MT. Chap pell JE. HeimT, Swyer PR. Chance GW. Fatty acid accretion in fetal and neonatal li^er: implications for fatly acid requirements. Ear!) Human Per 1981:5:7-14 Conquer JA. Holub BJ. Dietary docosahexaenoic acid as a source of cicosapentaenoic acid in vegetarians and omnivores. Lipids 1997:32:341 5 Dannoura AH. Bcrriot-V'aroqueauv N, Amati P. Abadie V Verthier N. Schmit/ J, Wenetau JR. Samson-Bouma ME. Aggerbeck LR Anderson's disease: exclusion Of apolipoprotein and intracellular lipid transport genes. Arterioscl Thromb I'asc Biol 1999;19: 2494 508

Dutta-Roy AK. Transport mechanisms for long-chain polyunsaturated fatty acids in the human placenta. Am J Clin Nutr 2000;71:315S-322S Dyerbcig J, Bang HO. Haemostatic function and platelet polyunsaturated fatty acids in

Fskimos. Lancet l979;2(KI4f»:433-5 Edmond J. Essential polyunsaturated fatty acids and the barrier to the brain: the components of a model for transport. J Mai Neurosci 2001;16:181-93 Elsing C, Kassner A, Stremmel W. Effect of surface and intracellular pi! on hepatocellular tatty acid uptake. Am J Physiol 1996:271 :G 1067-73

Ferdinandussc S, Denis S. Muoijcr PA. /hang /. Rcddy JK. SpcctorAA, Wanders RJ. Identification of the peroxisomal beta-oxidation enzymes involved in the biosynthesis of docosahexaenoic acid. J Lipid Res 2001;42:1987-95 Garaulet M Perez-Llamas F, Pere?-Ayal3 M. Martinez P, de Medina FS. Tehar FJ, Zamora S, Site-specific differences in the fatty acid composition of abdominal adipose tissue in an obese population from a Mediterranean area: relation with dietary fatty acids, plasma lipid profile, serum insulin, and central obesity. Am./ din Nutr 2001 ¡74:585-91

Goti D, Hammer A, Galla HJ. Malle E, Sattler W, Uptake of lipoproiein-associaled alpha-tocopherol by primary porcine brain capillary endothelial cells, J Neurvchem 20(H); 74:1374 83

Harper CR, Jacobson TA. The fats of life: the role ofomega-3 fatty acids in the prevention of coronary heart disease. Arch Intern Med 2001 ;161:2185- 92 Herrmann T, Buchkremer F. Gosch I, Hall AM. üernlohr DA. Streinmel W. Mouse fatty acid transport protein 4 (FATP4): characterization of the gene and functional assessment as a very long chain acyl-CoA synthetase. Gene 2001 ;270:31 -40 Kris-Etherton PM, Taylor DS, Yu-Poth S. Huth P. Moriarty K. Fishell V. Hargrove RL. Zhao G, Etherton TD. Polyunsaturated fatty acids in the food chain in the United States, ,4/f) J Clin Star 2000:71:179S-188S Madsen L. Rustan AC, Vaagenes Fl. Berge K. Dyroy H. Berge RK. Eieosapcntaenoic and docosahexaenoic acid affect mitochondrial and peroxisomal fatty acid oxidation in relation to substrate preference. Lipids 1999:34:951 63 Matllard V Bougnoux P. Ferrari P. Jourdan ML. Pinault M. Lavillormierc F. Body G. Lc FlochO, Chajes V N-3 and N-6 fatty acids in breast adipose tissue and relative risk of breast cancer in a case-control study in Tours, France. Int J Cancer 2002;98:78-83 Martin G. Nemoto M. Gelmiin L, Geffrey S. Najib J. Fruchart JC. Roevens P. de Maninville B. Deeb S, Auwerx J. The human fatty acid transport protein-1 (SLC27A1: FATP-! I cDNA and gene: organization, chromosomal localization, and expression. Genomics 2000;66:296-304 Martinez M. Vazquez E. Garcia-Silva MT, Manzanares J, Bertnin JM, Casiellö F. Mougan I. Therapeutic effects of docosahexaenoic acid ethyl ester in patients with generalized peroxisomal disorders. Am J Clin Nutr 2000:71:376S-385S Mori TA, Puddey IB. Burke V. Croft KD. Dunslan DW. Rivera JH, Beilin LJ. EITeet of omega 3 fatty acids on oxidative stress in humans: GC-MS measurement of urinary 1' 2-isuprostane excretion. Redox Report 2000:5:45-6 Noguehi M. Earashi M. Minami M. Kinoshita K. Miyazaki 1. Effectsofeicosapcntaenoic and docosahexaenoic acid on cell growth and prostaglandin E and leukotricne B production by a human breast cancer cell line (MDA-MB-231). Oncology 1995; 52:458 64

Resetand JE. Haugen F, Hollung K. Solvoll K. Halvorsen B. Brude 1R. Nenseter MS. Christiansen EN, Drevon CA. Reduction of leptin gene expression by dietary polyunsaturated fatty acids../ Lipid Res 2001:42:743 50 Singh I. Moser AE. Goldfischer S. Moser HW. Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy, Pmc Natl Acad Set USA 1984:81:4203 7

Storch J. I humscr Ali The fatty acid transport function of fatty acid-binding proteins.

Biochim Rwphys Acta 2000; 1486:28-44 Su HM. MoserAB, W oser 11W, Walk ins PA Peroxisomal straight-chain acyl-CoA oxidase and I )-bi functional protein are essential for the ret roeon vers ion step in docosa-hexaenoic acid synthesis. J Biol Chem 2001:276:38115 20 Taekcn PJ, Hofker MH, Havekcs LM, van Dijk KVV. Living up to a name: the role of the

VLDL receptor in lipid metabolism. Curr Opin Lipid 2001:12:275-9 Yoshida 1L Mavvatan M. Ikeda I, Imaizumi K. Scto A. Tsuji II. Effect of dietary seal and fish oils on triacy (glycerol metabolism in rats. JNutr Set Vmminot (999;45:411 -21

Drop Fat + Stay Fat Free

Drop Fat + Stay Fat Free

I know you’ve tried everything. Every diet and exercise plan going. At first, everything goes great. You plunge in, full of determination that this time it’s going to be different.

Get My Free Ebook


Post a comment