Myristic acid

Myristic Acid 1 S3

Lhotta K, Holle G, Gasser R, Finkenstedt G. Hypokalemia. hyperreninemia and osteoporosis in a patient ingesting large amounts of cider vinegar. Nephron 1998;80:242-3 Liljeberg H, Bjorck I. Delayed gastric emptying rate may explain improved glycaemia in healthy subjects to a starchy meal with added vinegar. EliI' J Clin NutI' 1998; 52:368-71 Ogawa N. Satsu H, Watanabe H, Fukaya M. Tsukamoto Y. Miyamoto Y. Shimizu M. Acetic acid suppresses the increase in disaccharidase activity that occurs during culture of caco-2 cells . .J Nlltl' 2000; 130:507-13 Orsenigo MN. Tosco M, Bazzini C. Laforenza U, Faelli A. A monocarboxylate transporter MeT 1 is located at the basolateral pole of rat jejunum. Exp Physio/ 1999;84: 1033-42 Pouteau E. Piloquet H, Maugeais P. Kinetic aspects of acetate metabolism in healthy humans using [1-13C]acetate. Am .J Physio/ 1996;271 :E58-E64 Siler SQ, Neese RA, Hellerstein MK. De novo lipogenesis, lipid kinetics, and whole-body lipid balances in humans after acute alcohol consumption. Am J Clin Nlltr 1999; 70:928-36 Stein J, Zores M. Schroder O. Short-chain fatty acid (SCFA) uptake into Caco-2 cells by a pH-dependent and carrier mediated transport mechanism. EIII'.J Nlltl' 2000;39: 121-5 Tarnai I. Takanaga H, Maeda H. Sai Y. Ogihara T. Higashida H, Tsuji A. Participation of a proton-cotransporter, MCT I. in the intestinal transport of monocarboxylic acids. Biochem Biophys Res Comm 1995;214:482 9 Terasaki T, Takakuwa S, Moritani S, Tsuji A. Transport of monocarboxylic acids at the blood-brain barrier: studies with monolayers of primary cultured bovine brain capillary endothelial cells. J Phul'maco/ Exp Ther 1991 ;258:932-7 Watson AJ, Brennan EA. Farthing MJ, Fairclough PD. Acetate uptake by intestinal brush border membrane vesicles. Gilt 1991 ;32:383-5 Wolever TM, Trinidad TP, Thompson LU. Short chain fatty acid absorption from the human distal colon: interactions between acetate, propionate and calcium. JAm Coli NII/I' 1995; 14:393-8

Myristic acid Myristate (myristic acid tetradecanoic acid; molecular weight 228) is a saturated fatty acid with 14 carbons in a straight chain. Abbreviations

CoA ETF

coenzyme A electron-transfer flavoprotein

Figure 6.26

Myristic acid

1 S4 Fatty Acids

Nutritional summary Function: Myristate has one of the highest energy contents of any nutrient. providing about 9 kcal/g. Complete oxidation depends on riboflavin. niacin. pantothenic acid, carnitine. ubiquinone, iron and magnesium. Food sources: Milk fat and other animal fats are especial\y rich sources, but many solid plant fats also contain myristate, especially after 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 cytosol of adipose tissue and liver, is still under dispute (Hellerstein, 200 I). Synthesis. as far as it takes place, tends to proceed to chain lengths of 16 or 18 carbons with little release of the intermediate metabolite myristate.

Dietary sources Myristate is a minor, but very characteristic component of milk (8-12% of total fat) and ruminant fat (about 3%). The amounts in fats from other sources are much smaller. Intakes ofheaithy Swedish men were around 4 gld (Wolk et af.• 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, monoglycerides, and phospholipids into mixed micelles. The micellar lipids are taken up into the small intestinal enterocytes through a mechanism that needs further elucidation. Myristate is then used mainly for the synthesis oftriglycerides. 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 fatty 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. Materna-fetal transfer: While myristate, like most fatty acids, reaches the fetus, the amounts and responsible mechanisms are not well understood.

Myristic Acid 155

Metabolism Chain elongation and desaturation: While some chain elongation and desaturation may occur, the extent is likely to be small. Mitochondrial catabolism: Long-chain fatty acid CoA ligase I or 2 (EC6.2.1.3) activates myristate and the combined action of carnitine, palmitoyl-CoA:L-carnitine O-palmitoyltransferase I (EC2.3.1.21, on the outside), translocase, and palmitoyl-CoA:L-carnitine O-palmitoyltransferase II (EC2.3.1.21, on the inside) shuttles it into mitochondria. The successive actions of long-chain acyl-CoA dehydrogenase (EC1.3.99.13), enoylCoA hydratase, L-3-hydroxyacyl-CoA dehydrogenase, and thiolase remove two carbons as acetyl-CoA and generate FAD and NADH. 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-flavoprotein dehydrogenase (EC 1.5.5.1, also contains FAD), which hands off the reducing equivalents to ubiquinone for oxidative phosphorylation. This sequence is repeated five times. The last cycle releases two acetyl-CoA molecules, of course. Peroxisomal catabolism: Myristate 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-dependent acyl-CoA oxidase (EC 1.3.3.6), peroxisomal multi functional protein 2 (M FP2, comprising activities EC4.2.1.l7, EC5.3.3.8, and EC 1.1.1.35), and peroxisome-specific acetyl-CoA C-acyltransferase (3-ketoacyl-CoA thiolase; EC2.3.1.16).

Storage Adipose tissue typically contains 2-5%, depending strongly on dairy fat intake (Garaulet et al., 200 I; Wolk et al., 200 I). Myristate is released with normal adipose tissue turnover (about 1-2% of body fat per day).

Excretion As with 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 the action of leptin and other humoral mediators. Adipocytes release the proteohormone leptin 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.

1 S6 Fatty Acids

HOOC"Vv\/'VVV

Myristic acid (14:0)

Long-chain fatty acid-CoA ligase

~

o

ATP + CoA AMP+ PP,

ETF:FAD

II

ETF:FADH2

\ )

COA-S-C-CH~

Acyl-CoA dehydrogenase

Myristyl-CoA

o

II H COA-S-C-~=C~

TranS-,1,2-enoyl-myristyl-CoA 2-Trans-enoyl-l/" H20 CoA hYdrataSe!

o II

CoA-S-C-C-CH ~ /\ /\ /\ /\ / H2 I v v v v V NAD OH

o II

9

COA·S-C- CH 3

acetyl-CoA

SH-CoA

acetyl-CoA Cacyltransferase o II

CoA-S-C~

L-3-Hydroxy-myristyl-CoA

0

0

COA-S-~-C-~

H

~

3-Kefo-myristyl-COA

Dodecyl-CoA

~

NADH

acetYIy'

J

COA-S-C~

Decyl-CoA acetyl-CoA

o

~

II

CoA-S-C-vvv

Octyl-CoA

o

acetYI-~

J

acetYI-~

J

II

COA-S-C----y\j

Hexyl-CoA

o II

COA.S-C-y

Butyryl-CoA

-\ ~

Figure 6.27

Breakdown of myristic acid occurs via

-

2 acetyl-CoA

~·oxidation

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

Function Fuel energ)': The oxidation of myristate supports the generation of about 92 ATP (6 x 2.5 from NADH, 6 X 1.5 from FADH 2, about 70 from acetyl-CoA, minus 2 for

Conjugated Linoleic Acid 157

ligation to CoA). This corresponds to an energy yield of about 9 kcal/g. Complete oxidation of myristate 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 aeylated with myristate as a substrate. This lipophilic side chain can nestle into membranes and thus anchor the attached proteins. The specific type of fatty acid determines preference for membrane regions and precise protein positioning in regard to the membrane surface. A typical example for a myristoylated protein is cAMPdependent 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 et al., 1994), especially when polyunsaturated fatty acids contribute less than 5% of total energy. It 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-Ayala M, Martinez P, de Medina FS, Tebar 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 J Clin Nut,. 2001;74: 585-91 Hellerstein MK. No common energy currency: de novo lipogenesis as the road less traveled. Am J Clin NlIIr 200 1;74:707-8 Mensink RP, Temme EH, Homstra G. Dietary saturated and trans fatty acids and lipoprotein metabolism. Ann Med 1994;26:461-4 Wolk A, Furuheim M, Vessby B. Fatty acid composition of adipose tissue and serum lipids are valid biological markers of dairy fat intake in men. J NlIIr 200 I; 131: 828-33

Conjugated linoleic acid Conjugated linoleic acid (CLA) is a term comprising 28 isomers of octadecadienoic acid (molecular weight 280) that have two double bonds separated by one single bond. Abbreviations CoA ECI ETF FABPpm FATP-1 LPL MECI MTP

TVA

VLDL

coenzyme A enoyl-CoA isomerase (ECS.3.3.8) electron-transferring flavoprotein plasma membrane fatty acid binding protein fatty acid transport protein 1 (CD36, SLC27A1 ) lipoprotein lipase mitochondrial enoyl-CoA isomerase (ECS.3.3.8) microsomal triglyceride transfer protein trans-vaccenic acid very-low-density lipoprotein