1

Giycerol-3-phosphate

O-acyt-iransterasa

Acyl-CoA

t-CH

1-Acyt-sn-glycerol phosphate

1 -Acyigiyceroi-

3-phosphate acyttransf erase

Acyl-CoA

1,2-Diacy(-sn-gtycerol phosphate H.,0

Phosphatide phosphatase r v.

Hfro_cvAAAAAAA AcylCûA CoA

I,2-Diacyt-sn-giyce<wl Figure 6.19 Fat storage

Diacyiglycerol O-acyltransf erase

Tnacyl-sn-glycerol m water means thai it does not excrl osmotic pressure and is chemically quite inert. Adipocytes are specialized cells that arc able to store large amounts of fatty acids as triglyceride. Fatty acids in adipocytes and other tissues arc converted into acyl-CoA by several ligases specific for short-chain, medium-chain, and long-chain fatty acids as outlined above. Triglyceride synthesis occurs at the cvtosolic face of the microsomal membrane in most tissues, most extensively in adipose tissue, liver, and muscle. The initial steps can also lead to phospholipid synthesis. Only the last step, that adds a third fatty acid commits the fatty acids to triglyceride synthesis.

Cilyccro 1-3-phosphate O-acyltransferase (EC2.3.I.I5) links the first acyl-CoA to glyecrol-3-phosphate. An alternative peroxisomal pathway with gly Cerone - phosphate O-acyltransferase (di hydroxy acetone phosphate acv I transferase. EC2.3.1.42), which supports mainly the synthesis of etherlipids and plasmalogens. uses dihydroxyacetone phosphate as the initial fatly acid acceptor. In this case the product is converted to I -acy [glycerol-3-phosphate by acylglycerone-phosphate reductase (acyldihydroxyace-lone phosphate reductase. EC 1.1.1.101). l-Acylglycerol-3-phosphate acy I transferase (EC2.3,1.51) then adds a second activated fatty acid. At least live different genes code lor tins enzyme, and additional isofonns arise from alternative splicing. Phosphaiidate phosphatase (EC3.I.3.4), the regulatory enzyme of triglyceride synthesis, removes the phosphate group. Triglyceride synthesis is completed when diacylglyccrol O-acyltransferase (EC2.3.1.20) adds a third fatty acid. A wide range of fatty acids can be incorporated ai positions I and 3. but palmitate is preferred. The second fatty acid is often unsaturated. Overall, the fatty acid composition reflects long-term fatty acid intake patterns (Kohlmeierand Kohlmeter, 1995)-

Stored triglycerides can be released again into blood circulation by the combined activity of hormone-sensitive lipase and monoglyceride lipase. Activity of hormonesensitive lipase is under hormonal and neuronal control ihrough the cAMP-mediated phosphorylation of serine 563; the enzyme is activated by adrenaline (epinephrine) and inactivated by insulin.

Regulation

Intake regulation: Adipose tissue produces several hormone-like factors and cytokines, some of which signal fat content to the brain and other tissues. Leptin crosses the blood brain barrier and stimulates neuropeptide V (NPY) secretion in brain. NPY induces satiety and thereby slows food-seeking behavior. Leptin also affects numerous metabolic processes in other tissues. The rate of fat utilization by muscle depends to a considerable extent on the rate of uptake, which is decreased by leptin (Steinberg et at.. 2002).

fat storage: Energy metabolism depends to a large extent on fat stores to buffer variation in the availability of fuel energy from dietary sources. Storage and mobilization are largely under the control of insulin, glucagon, and adrenaline. Insulin slows the mobilization of fatty acids from adipocytes by inhibiting hormone-sensitive lipase (through cAMP-mediated phosphorylation by protein kinase A). Insulin also promotes fatty acid synthesis, though net production seems to be minor, as pointed out above. Glucagon and adrenaline slow fatty acid synthesis. Sterol regulatory element-binding proteins

(SRFBPs) mediate some of the effects by modulating the expression of genes involved in fatty acid synthesis. The more important adrenaline effect is, however, its strong promotion of lipolysis.

Peroxisomal metabolism: Fatty acid oxidation in peroxisomes, which may help to cope with excess, is regulated by the nuclear peroxisome pro I ¡feral or-activated receptors (PPARl, These receptors are inducible by a wide range of compounds including lipid-lowering (clolibrate and related fibrates) and glucose-lowering drugs (thia/olidine-dionesl, phthahte plastici/ers, leukotriene antagonists, and herbicides. At least three genetically distinct forms exist (alpha, beta, and delta) with different patterns of tissue expression and inducibility by specific compounds. PPAR delta is induced by unsaturated fatty acids.

Fatty acid composition: I he ratio of saturated to unsaturated fatty acids in membrane lipids is maintained within a narrow range, since this determines membrane lluidity. Transforming growth factor (i and other cytokines contribute to the control of membrane fluidity by increasing stearyl-CoA desaturase (EC 1.14,99.5) expression.

Function

Fuel energy: Its high energy content makes fat (triglycerides) a central player in fuel metabolism. On average, fats provide about 9kcal g. Their full oxidation depends 011 adequate supplies of thiamin, riboflavin, niacin, vitamin B12. biotin. pantothenate, carnitine, ubiquinone, iron, and magnesium. Additional nutrients are needed for the metabolism of some fatty acids, such as \ itamin BI2 for odd-chain fatty acids, or thiamin for phytanic acid. Since fat contains much less oxygen than carbohydrate, the ratio of carbon dioxide production to oxygen consumption (respiratory quotient) is much lower (0,7), At the same time, slightiv more oxygen is needed to produce the same amount of energy from a fatty acid than from sugar.

Complex lipid synthesis: The fatty acid-derived acyl chains in phospholipids and cholesterol esters provide more than half of the lipid mass in membranes. Phosphatidylcholine-sterol O-acy¡transferase (lecithin-cholesterol acy ¡transferase (IXAT): EC2.3. 1.43) transfers the middle (sn-2) fatty acid from phosphatidylcholine to cholesterol and other sterols. Since the sn-2 position of these phospholipids contains predominantly unsaturated fatty acids, more than half of the fatty acids in cholesterol esters are iinoleate. and more than 10% are other highly unsaturated fatty acids (Smedman etui.. 1999).

Phospholipids share the triglyceride synthesis pathway to the penultimate or the final step. Phosphatidate cytidyly I transferase (IZC2.7.7.41, magnesium-dependent) replaces the phosphate group of phosphatidate with cytidyl diphosphate (CDP). CDP-diacyl-glycerol-inositol 3-phosphatidy ¡transferase (EC2.7.8.11) ihen completes the synthesis of phosphatidyl inositol, Phosphatidy¡glycerol is produced from by sequential action of CD P-diacy Iglycero I-glycerol - phosphate 3-phosphatidvltransferase (glycerophosphate phosphatidy ¡transferase: EC2.7.K.5) and phosphatidylglycerophosphatase (EC3.1.3.27). The synthesis of other phospholipids starts from 1.2-diacylglyccrol, Cholincphospliate cytidyly [transferase (EC2.7.7.15) generates phosphatidylcholine.

Cholesterol

Phospha tidy Icholi ne-slerol O-acyltransterase

Phospha tidy Icholi ne-slerol O-acyltransterase h.C—O—C

:vVWVW\

HO-CH-O—P—C—C—N—CH3 Phosphatidylcholine OH * * CH3

CH-OH

o CH3 II I

HO-CH-O-P-C-C-N-CH3 1 -Acylglycero-OH * ' CHj phosphocholine

Chdtesla rylli notoale Figure 6.20 Synthesis of cholesterol esters

^vWWwW

Chdtesla rylli notoale Figure 6.20 Synthesis of cholesterol esters and etiianolamine-phosphate cytidylyltransferase (EC2.7.7,M) produces phosphati-dylethanolaniine. Two CDP-diacylglycerol-serine O-phosphatidyltransfcrase (phospha-tidylscrine synthase (PSS), base exchange enzyme: EC2.7.8.8) genes, PSS-I and PSS-2. encode enzymes that can replace ethanolamine with serine to generate phospiiat idyl serine. PSS-I can also replace choline with serine. Cardiolipid and other more complex phospholipids are generated from these basic phospholipids.

Protein acyiation: Myristic acid or palmitic acid can be attached to specific sites of numerous proteins. The hydrophobic side chain often is important for anchoring of receptors, transporters and enzymes to membranes. Examples for myristoylated proteins are alpha (KAPA) and beta (KAPB) catalytic subunits ofcAMP-dependent protein kinase (EC2.7.1.37). A cysteine residue in tumor necrosis factor (TNF) is linked to a palmityl residue (Utsumi el at., 2001).

Eicosanoidsynthesis: Polyunsaturated fatty acids are essential precursors for a multi-memhered group of signaling compounds that a fleet platelet aggregation, uterine contractions. inflammation, pain sensation, blood flow, bone repair, and numerous other effects. Many of these effects are initiated when an eicosanoid binds to one of many specific receptors and starts an intracellular signaling cascade, l ite term eicosanoids is derived from the Greek term for the number of carbons in arachidonic acid, one of the fatty acid precursors. Prostaglandin-cndoperoxide synthase (prostaglandin II synthase, Cox-1/Cox-2: ECt. 14.99.11 is responsible for ihe first step in the synthesis of prostaglandins, prostacyclin, and thromboxanes. Arachidonate 5-lipoxygenase (ECU3.11.34, iron-dependent) catalyzes the lirst step of leukotriene synthesis, Both enzymes accept arachidonic acid, linolenic acid, adrenie acid, gamma-linolenic acid, eicosapentaenoic acid and other long-chain polyunsaturated fatty acids. The structure of the reaction products depends on the substrate (Larsen et at., 1996), Each precursor fatty acid generates eicosanoids \\ ith characteristic activity profiles. The difference in acti\ ities of compounds derived from omega-6 fatty acids versus those derived from omega-3 fatty acids is considerable and has been investigated extensively.

References

Aarsland A. Chnikes D, Wolfe RR. Hepatic and whole-body fat synthesis in humans during carbohydrate overfeeding. Am J Clin Nutr I997;65:1774 X2 Ahmed Z. Ravandi A. Maguire GF. Emili A, Draganc* D, La Du BN. Kuksis A. Connelly PW. Apolipoprotein A-l promotes the formation of phosphatidylcholine core aldehydes that are hydrolyzed by pantoxonase (PON-11 during high intensity lipoprotein oxidation with a peroxynitrite donor. J Biol Chem 2001^76^4473-81 Alexander JJ. Snvdcr A, Tonsgard JH. Omega-oxidation of monocarboxylie acids in rat brain. Neurvchem Res 1998:23:227 33 Alonso L. Fontecha J. Lozada L. I raga MJ. Juarez M. Fatty acid composition of caprine milk: major, branched-ehain, and trans fatty acids. J Duin' Sc i 1999:82:878-84 de Antueno RJ. Knickle LC, Smith H, Elliot ML. Allen SJ. Nwaka S. Winther Ml). Activity of human Delta? and Delta6 desaturases on multiple n-3 and n-fi pofyunsat-urated fatty acids. FEBS Lett 2001:509:77-80 Brown ML, Ramprasad MP. Umcda PK. Tanaka A. Kobayashi V, Watanabc L Shimoyamada II, Kuo WL, Li R. Song R, Bradley WA. GiantureoSH A macrophage receptor for apolipoprotein B4S: cloning, expression, and atherosclerosis. Prnc Xarl Acad Sci 2000;97:7488-93 Cheng JZ. S harm a R. Yang V. Singhal SS. Shartna A. Saini MK. Singh SV. Zimniak P, Awasthi S. Awasthi YC. Accelerated metabolism and exclusion of 4-hydroxynonenal through induction of RLIP76 and hGSTi.N is an early adaptive response of cells to heat and oxidative stress. J Biol Chem 2001:276:41213 -23 Clandinin M L Chappell JE. Heim T. Swyer PR, Chance GW. Fatty acid accretion in fetal and neonatal liver: implications for fatty acid requirements. Eurlv Human Oev 1981:5:7 14

Costa CC, Dorland L, Kroon M. lava res de Almeida 1. Jakobs C, Duran M. 3-, (>- and 7-hydroxyoctanuic acids are metabolites of medium-chain triglycerides and excreted in urine as glucuronides. J Mass Spectrum 1996:31:633 8 DannouraAH, Berriot-Varoqueaux N, Amati P. Abadie Werthier N. Schmit/ j, Wetterau JR. Samson-Bouma ME, Aggerbeck I.P. Anderson's disease: exclusion of apolipoprotein and inmicellular lipid transport genes, irterioscl Thnmb fi/vt 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 22S

I dmond J. Essential polyunsaturated fatty acids and the barrier to the brain: the components of a model for transport. J Mol Neumsci 2001:16:181-93 El sing C, Kassncr A, Stremmel W. Effect of surface and intracellular pH on hepatocellular fatty acid uptake. Am J Physiol 1996:27I:GI067-<j1073 Enoiu M Herber Ii. Wennig R. Marson C. Bodaud II. Leroy P. Mitrea N. Siest G. Wcllman M. Gamma-glutamyllranspeptidasc-dependent metabolism of 4-hydrox-yrtonenal-glutalhionc conjugate, fnh Bun-hem Biophys 2002:397:18-27 Folcik VA, t at heart MK. Predominance of esteritied hydroperoxy-linoleic acid in human monocyte-oxidized LDL. J Lip Res 1994:35:1570-82 Foulon V. Antonenkov VD. Crocs k. Wae I kens !. Mannaerts GR Van Veldhoven PP. Casteels \L Purification, molecular cloning, and expression of 2-liydro\vphytanoyl-CoA lyase, a peroxisomal thiamine pyrophosphate-dependent enzyme that catalyzes the carbon-carbon bond cleavage during alpha-oxidation of 3-mcthyl-branched fatty acids. Proc Natl Acad Sei USA 1949:96:10039-44 Goti D. Hammer A, Galla 11.1. Malle E, Sattler W, Uptake of lipoprotcin-associated alpha-tocopherol by primary porcine brain capillary endothelial cells../ Nenrochem 2t.HH): 74:1374 83

Hellerstein MK. No common energy currency: de novo lipogenesis as I he road less traveled. Am J Clin Nutr 2001;74:707-8 Herrmann T. Buchkremer F. Gosch I. Hall AM, Bemlohr DA, Stremmel W. Mouse fatty acid transport protein 4 (EATP4): characterization of the gene and functional assessment as a very long chain acyl-CoA synthetase. Gene 2001:270:31 40 Jarvik GP. Tsai NT. Mckmsiry LA, Wani R. Brophy VH, Richter RJ. Schcllenbcrg GD. Heagcrty PJ, Hatsukami TS. Furlong CE. Vitamin C and E intake is associated with increased paraoxonase activity. Arteriascl Thromh Vase Biol 2002:22 1329-33

Jones I.N. Rivett DE. The role of 18-metliylcicosanic acid in the structure and formation of mammalian hair fibres. Micron 1997;28:469-85 Kohtmeier L. Kohlmeier M. Adipose tissue as a medium for epidemiologic exposure assessment. P.nv Health Persp 1995;103:99-106 l.nrsen L\:. Dahl F.. Bremer J. Pcroxidative oxidation of I euco»dichloro fluorescein by prostaglandin H synthase in prostaglandin biosynthesis from polyunsaturated (ally acids. Biachim Biophys U ta 1496:1299:47-53 Laurent A. Perdu-Durand E. Alary J. Debmuwer L. Cravedi JP. Metabolism of 4-hvdroxy-nonenal. a cytotoxic product of lipid peroxidation, in rat precision-cut liver slices. Toxicol Lett 2000; 114:203-14 Marnen L.J. Chemistry and biology of DNA damage by malondialdehydc. ¡ARC Sa Puhl 1999:150:17-27

Martin G, Nemolo M. Gclman L, Geffroy S, Najib J. Fruchart JC, Rocvcns P. de Man im ¡lie B. Deeb S, Auvverx J, The human fatty acid transpori prntein-1 (SLC27A1; FATP-I) cDNA and gene: organization, chromosomal localization, and expression. Genomics 2000:66:296-304

Moon YA. Shah NA, Mohapatra S. Warrington JA, Horton JD, Identification of a mammalian long chain fatty acvl elongase regulated by sterol regulatory element-binding proteins. J Bud Chem 2001:276:4535K- 66

Ne CJ. Wadleigh DJ. Gangopadbyay A, llama S. Grijalva VR. \avah M. Fogclman AM. Rcddy ST. Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein, J Biol l hem 2001;276:44444-9 Oliw EH. Oxygenation of polyunsaturated fatty acids by cytochrome P450 monooxyge-

nases. Pmgr Lipid Res 1994:33:329-54 Qureshy A. Kubnta K, Ono S. Sato T. Fukuda II. Thoracic duct scintigraphy by orally administered 1-12.1 BMIPP: normal tindings and a case report. Clin Muel Med 2001; 26:847-55

Rognstad R On the estimation of alternative pathways of fatty acid oxidation in the liver in vivo Bull Math Biol 1995;57:191-203 Sandhir R, Khan M, Singh 1, Identification of the pathway of alpha-oxidation of cere-

hronic acid in peroxisomes. Lipids 2000:35:1127 33 Shachter NS. Apolipoproteins C-l and C-M as imponant modulators of lipoprotein metabolism, Curr Opin Lipid 2001 ¡12:297 304 Smcdman AE, Gustafsson IB, Bi;rglund LG, Vcssby BO. Pentadecanoic acid in serum as a marker for intake of milk fat: relations between intake of milk fat and metabolic risk factors. Am J Clin Nutr 1999:69:22 9 Staprans I. Ilardman DA, Pan XM. Feingold KR. Effect of oxidized lipids in the diet on oxidized lipid levels in postprandial serum chylomicrons of diabetic patients. Diabetes Care 1999:22:300 6 Steinberg GR. Dyck DJ. Calles-Escandon J. Tandon NN. Linken JJ, Glatz JF, Bönen A. Chronic leptin administration decreases fatty acid uptake and fatty acid transporters in rat skeletal muscle. J Biol Chew 2002:277:8854 60 Steward ME. Downing 1)1. Unusual cholesterol esters in the sebum of young children

J Invest Dermatol 1990;95:603-6 Storch J, Thumser AI . The fatty acid transport function of fatty acid-binding proteins.

Biochim Biophvs Acta 20011; 1486:28 44 facken PJ. Hofker MH, Havekcs I M, van Dijk K\\ Living up to a name: the role of the

VI.DL receptor in lipid metabolism, Curr Opin Lipid 2(H) 1:12:275 9 Tanaga K. Bujo IL Inouc M. Vlikami K, Komm K. Takahashi K, Kanno T. Saito Y. Increased circulating malondialdehyde-modified LDL levels in patients with coronary artery diseases and their association w ith peak sizes of LDL panicles. Art Thmmh Vase Biol 2002:22:662 6 Utsumi T. Takeshige T. Tanaka K. Takami K. Kira Y, Klostergaard J. Ishisaka R.

Transmembrane TNF (pro-TNF) is palmitoylated. FL BS Lett 2001:500; t -6 Vcrhoevcn NM, Wanders RJA, Poll-Tbc BT. Saudubray JM, Jacobs (.. 1 he metabolism of phytanic acid and pristanic acid in man: a review. J hiher Metab Dis 1948: 21:697-728

Wilson R. Lyall K, Smyth L, Fernie CE. Riemers ma RA. Dietary hydroxy fatty acids are absorbed in humans: implications for the measurement of'oxidative stress' in vivo. Free Rad Biol Med 2002;32:162 8 Wölk A. Furuheim M, Vcssby U. Fatty acid composition of adipose tissue and serum lipids are valid biological markers of dairy fat intake in men.,/ Nutr 2001:131:828 33

Overfeeding

Abbreviations

CoA coenzyme A

cAWP 3',5'-cyclic AMP

LDL low-density lipoprotein

VLDL very-low-density lipoprotein

The nature of overfeeding

Unheal(hfill expansion of fat stores due to persistent overfeeding is fast becoming the norm in the US and many other affluent countries. The major killers of older adults (type 2 diabetes and cardiovascular disease) hold their ground despite targe advances in medical technology and now reach into adolescent and even childhood populations. Common diseases associated with persistent overfeeding include insulin resistance and type 2 diabetes, hyper- and dyslipidemia. hypertension, hyperuricemia and gout, heart disease, stroke, sleep apnea, cancer, cholesterol gallstone disease, and osteoarthritis (Pi-Sunyer. 1999). Even high levels of energy intake without severe body fatness may be undesirable. Evidence is mounting, for instance, that suggests a lower cancer risk with energy restriction (Thompson et aL, 2002).

The principal consequence of overfeeding is the expansion of fat stores. Subcutaneous and intraabdominal adipose tissue arc the main sites of triglyceride storage, but fat accumulations also occur in other tissues, especially in diabetics and obese people (Ravussin and Smith, 2002). Large intraabdominal deposits (signaled by great abdominal girth) are associated with greater cardiovascular and other health risks than subcutaneous fat (Stev ens. 1995). Preferential distribution of excess fat, resulting more or less in apple-like shapes for men and pear-shapes for women, may explain some of the differences in health consequences between the genders (Bertrais et u/.. 1999).

The fate of excess carbohydrate

There has been a spirited debate about the question whether humans convert excess glucose into fat (Mellerstein, 2001). The more recent evidence indicates that such de now fat synthesis is very limited accounting for less than lOg per day under all but the most extraordinary circumstances. This finding should not detract from the obvious fact that de novo synthesis from carbohydrate is not needed to explain the storage of fat in overfed humans The carbohydrate is utilized preferentially, and the fat is left over to be stored. As long as people consume more than they expend, ihere wilt be enough fat to put into storage and expand the fat mass further.

A separate issue is the impact of overfeeding on lipoproteins in blood. The production rate of Iriglyeeride-eonlaining very-low-density lipoprotein (VLDL) is very low in healthy lean subjects. This is important, because the main atherogenic

(atherosclerosis-promoting) lipoprotein fraction, low-density lipoprotein (L.DL), derives exclusively from VLDL, Even modest overfeeding increases VLDL production and thereby raises harmful LDL concentration in blood. High sugar consumption is a particularly potent recipe for raising VLDL production. Conversion of carbohydrate to saturated fat is partially responsible for the additional VLDL triglyceride synthesis (Hudgins et of, 2000).

Insulin resistance and hyperlipidemia

One of the most persistent effects of overfeeding and obesity is the declining ability of tissues to increase glucose uptake upon stimulation with insulin. Insulin resistance is the conventional term for this phenomenon. The effect is particularly severe in muscle cells, because they import glucose largely via the insulin-stimulated transporter GLUT4 (SLC2A4). Glucose transfer into brain is little affected, because it proceeds mainly via GLUT! (SLC2A1). Several explanations for the high prevalence of increased insulin resistance in overfed and obese people have been put forward. One of these sees the problem in the typically elevated free fatty acid concentrations in blood (Kracgen et al. 2001). The rise in free fatty acid concentration, which is typical alter a lat-rieh meat, rapidly decreases insulin effectiveness in skeletal muscle. The same is seen with chronic elevation of free fatty acid concentration due to obesity. Another mechanism may involve the hexosamine nutrient-sensing pathway mentioned below. A third scenario focuses on the depressed production of adiponectin by expanded and overfed adipose tissue (Tsao et ui. 2002). Low circulating levels of this peptide hormone, which is produced only in adipose tissue, induce insulin resistance (Maeda et«/., 2002). Adiponectin blunts the typical rise of plasma free fatty acid after a fatty meal, which should relieve the free fatty acid-related resistance. A direct adiponcctin effect promoting insulin action is also possible.

Insulin serves in adipocytes to slow the release of fatty acids. The binding of circulating insulin to specific receptors activates adenylate cyclase (EC4.6.1.1) and the ensuing rise of intracellular 3',5'-cyclic AMP (eAMP) concentration inhibits the activity of hormone-sensitive lipase (fC3.lil.3J. The bottom line is that insulin resistance is associated w ith accelerated turnover of fat stores. The release of fatty acids from adipose tissue closely correlates with fat mass. The age-typical doubling of fat stores from about 9 kg in a lean young man of av erage weight {70 kg, BM121) to 18 kg thirty years later (77 kg. BMI 25) is likely to increase VLDL production several-fold. Insulin resistance then just adds to the quandary of the obese person by further ballooning VLDL output (Couillard et at.. I998|. On top of all this, an increase of fat intake adds to the fat load of the liver and cranks up VLDL synthesis all on its own. Since VLDL is the obligate precursor of LDL, both overfeeding and obesity raise the concentration of atherosclerosis-promoting lipoproteins in blood. Hyperlipidemia and cardiovascular disease are very common in obese people, therefore. \n illustration of the role of expanded fat stores in the genesis of hyperlipidemia is the close association between body fatness and LDL cholesterol concentration observed in patients with LDL receptor defects (Gaudet etui., 1998).

Nutrient sensing

Abundance liters the utilization of energy-rich nutrients in characteristic ways and modifies intake behav ior. One of the metabolites that serve as fuel sensors is malonyl-CoA. Since the acetyl-CoA for its synthesis comes from carbohydrate, fat, and protein breakdown, malonyl-CoA is well suited to signal fuel nutrient availability. A high malonyl-C'oA concentration slows the rate of fat oxidation by inhibiting carnitine patmitoyl transferase-mediated fatty acid import into mitochondria (Chien et ul.. 2(H)(1). At the same lime, fat storage increases with high levels of malonyl-CoA < Ahu-Flheiga etui.. 2001).

The hexosantine pathway provides another nutrient-sensing mechanism. A high level of hexosamine metabolites (particularly UDP-N-acetylglucosamine) increases the glycosylation of regulatory proteins and decreases the expression of mitochondrial genes for oxidative phosphorylation (Obici et at.. 2002). The hexosamine metabolites also down-regulate the insulin-dependent uptake of glucose and trigger the release of leptin and other satiety signals. The high free fatty acid concentrations in blood that are typical for overfeeding and obesity might cause insulin resistance through stimulation of the hexosamine pathway.

Blood coagulation

Large fat stores increase the risk of myocardial infarction and stroke partially due to an increased tendency to form thrombi (blood clots). This is not surprising, since adipose tissue, especially within the abdomen, plays an active role in fibrinolysis. Obese people have higher blood concentrations of coagulation factors VUI and VII, fibrinogen, von Willebrand factor, and plasminogen activator inhibitor (Mertcns and Van Gaal. 2(102).

Hyperuricemia

Elevated blood concentration of uric acid is a cardiovascular risk indicator that is closely related to overfeeding and obesity (Nakanishi eta!„ 2001). The hyperuricemia of most obese people is due to increased uric acid synthesis and not due to impaired renal elimination. Increased production from dietary nucleic acid precursors contributes to the uric acid burden. Many obese people with severe hyperuricemia suffer from gout. litis condition is characterized by the deposition of uric acid crystals in joints and connective tissue at other sties and the ensuing inflammation and pain.

References

Abu-Elheiga L. Matzuk MM, Abo-I lashema KA. Wakil SJ. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 2001. 291:2613-16

Bertrais S, Balkau B. Vol S. Forhan A. Calvet C. Mam.1 M. EscUwege E. Relationships between abdominal body fat distribution and cardiovascular risk factors: an explanation for women's healthier cardiovascular risk profile. The DFSIR Study, hit .1 Obes Re! MetabDis 1999;23:]Q85 94 Chien D. I Jean D. Saha Ak. Flan J P. Ruderman NB. Malonyl-CoA conteni and Fatty acid oxidation in rat muscle and liver in vivo. Am JPtnshf Endocrin Metab 2000;279: E259-65 Couillaid C, Bergeron N. Prud'homme D, Bergeron J, Tremblay A. Bouchard C. MauriegeP. Despres JP Postprandial triglyceride response in visceral obesity in men. Diabetes 199ft;47(6):9S$ 60

tiaudet D, Vohl MC. Perron P, Tremblay G, Gagne C. Lesiege 13. Bergeron J. Moorjani S. Despres JP. Relationships of abdominal obesity and liyperinsulinemia to angiograph-ically assessed coronary artery disease in men with known mutations in the LDL receptor yene. Circulation 1998:97:871 7 Hellerstein MK. No common energy currency: de now» lipogenesis as the road less traveled. Am J C'lin \iar 2001;74:707-8 Hudgins LC. Hellerstem MK. Seidman CF. Neese KA. Tremaroli JD, Hirseh J. Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects. J Up Res 2000;41:595-604 Kraegen EW, Cooney GJ. Ye JM. Thompson AL. I urler SM. flic role of lipids in the pathogenesis of muscle insulin resistance and beta cell failure in type It diabetes and obesity. Exp Clin Endocrinol Diab 2001; 109:SIKY S2III Maeda N. Shimomura L Kishida K. Nishizawa II. Matsuda M. Nagaretani H. Furuyama N, Kondo H, lakahashi M, Arita Y. Komuro R, Ouchi N, Kihara S. Tochino Y, Okutomi K. Horie M. Takeda S. Aoyama T, Funahashi T. Matsuzawa Y. Diet-induced insulin resistance in mice lacking adiponectin ACRP30. Xatuiv Mai 2002:8:731 7

Mertens I, Van (iaal LF. Obesity, haemostasis and the fibrinolytic system. Obesity Rev 2002:3:85-101

Nakanishi N, Yoshida II, Nakamura K.. Suzuki k, Tatara K. Predictors for development of hyperuricemia: an 8-year longitudinal study in middle-aged Japanese men. Metab Clin Exp 2001:50:621 6 Obici S. Wang J, Chovvdury R. Feng Z, Siddhanta U. Morgan k. Rossetti L, Identification of a biochemical link between energy intake and energy expenditure ./ ( Ini Invest 2002:109:1599 605

Pi-Sunyer FX. Comorbidities of overweight and obesity: current evidence and research issues. Med Sci Sports Exercise 1999:31:8602-8 Ravussin F. Smith SR. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mcllitus. 4nn \'ew York Acad Sci 2002;967:363-78 Stevens J. Obesity, fat patterning and cardiovascular risk. Adv Exp Med Hiol 1995: 369:21-7

Thompson IIJ. Zhu Z. Jiang W, Protection against cancer by energy restriction: all experimental approaches are not equal../ Afutr 2002;132:1047 9 Tsao TS. Lodish III. Fruebis J, ACRP30. a new hormone controlling fat and glucose metabolism. Eur J Pharmacol 2002:440:213 21

Acetate

The term aceiate (acetic acid: molecular weight 60) refers to both the carbonic acid with a pungent odor and its salts.

Abbreviations

CoA coenzyme A MC monocarboxylate transporter

Nutritional summary

Function: Acetate and particularly it* conjugate with coenzyme A (acetyl-CoA) i» a critical intermediary metabolite for the utilization of carbohydrates, some amino acids ( lysine, leucine, isolencine, phenylalanine, tyrosine, tryptophan), fatty acids, and alcohol. It can be used as a precursor for fatty acid and cholesterol synthesis. Acetate can also lie utilized as an energy fuel: its complete oxidation requires thiamin, riboflavin, niacin, pantothenate, lipoalc. ubiquinone, iron and magnesium.

Food sources; Only very small amounts are consumed with foods, mainly with vinegar, fruits, and vegetables. Alcohol is converted completely into acetate. Several hundred grams of acetyl-CoA are generated daily from the breakdown of carbohydrates, fat. and protein,

Requirements; No dietary acetate intake is necessary, A beneficial effect of moderate vinegar intake on blood sugar control and chronic inflammatory polyarthritis has been claimed.

Excessive intake: High intakes of acetic acid (more than 10 20 g day) may induce gastric discomfort, alter pit balance (metabolic acidosis), cause the loss of bone minerals, and increase the risk of dental erosion.

Endogenous production

The metabolism of carbohydrates, amino acids, and fattv acids generates several hundred grams of acetate per day, mainly as acetyl-CoA. Depending on intakes, significant amounts of free actetatc may also be generated from ethanol. Most is utilized within the cells or tissues where the acetate or acetyl-CoA is generated, some is transported to other tissues and utilized there.

Carbohydrates; The amount of acetate generated from glucose depends on the proportion used for glycolysis (as opposed to the smaller fraction metabolized via the pentose phosphate pathway) and the proportion used for the generation of oxaloac-etate from pyruvate. Typically, about half a gram of acetate (as acetyl-CoA) is generated per gram of absorbed carbohydrate.

Amino acids: Aceivl-CoA is generated during the catabolism of isoleucine. leucine, and threonine. Lysine and tryptophan each generate two aeetvl-CoA molecules. Metabolism of cysteine, alanine, and tryptophan generates pyruvate, which may he

Figure 6.21 AcitJie

NH 1

CH OH

NH 1

CH OH

O OH

Figur* 6.22 Actt^-CoA is a crilical mu'rmediiitt; of fuel metaboliim converted into acetyl-CoA. Acetoacetate is generated by the cataboiism of phenylalanine. tyrosine, and leucine (for the latter in addition to one mole of acetyl-CoA). ! he acetoacetate can be activated by 3-oxoacid Co A-transferase (succinyl-CoA transferase. LC2.KJ.5t and then cleaved by acetyl-CoA C-acetyltransferase (thiolase, EC2.3.I.9) to generate two moles of acetyl-CoA. A minor pathway of threonine breakdown generates free acetate.

Fatty acids: One mole of acetyl-CoA is released with each cycle of fatty acid beta-oxidation.

Alcohol: Lthanol is oxidized by various alcohol dehydrogenases (EC 1.1.1.1) or the microsomal ethanol oxidizing system ( Ml'.OS. unspeciik monooxygenases of the cytochrome P-450 family. LCI .14.14.1 ) in conjunction with several types of aldehyde dehydrogenases (EC 1.2.1.3, LCI.2.1.4, and EC 1.2 J .5) or ncetaldehyde oxidase (LCI.2.3.11. Ethanol metabolism occurs mainly in the liver, and most of the resulting acetate is released into circulation (Siler et «/,, 1999). One gram of ethanol generates about 1,3 g of acetate.

Fiber: Normal intestinal bacteria break down non-digestible carbohydrates and release significant amounts of short-chain fatty acids including acetate.

Cysteine. Tryptophan. Alanine v

Glucose. Fructose. Galactose

Tryptophan (2), Lysine (2), Leucine, isoieucine

Acetoacetaie

Pyruvate

O II

(Threonine)

Ha Ethanol

Dietary liber (bacterial fermentation)

Figure Û.13 Endttjjenoui sources uf ai.cl au and its metabolite*

Dietary sources

Acetate is ingested mostly as vinegar (content typically 5-6%) and with pickled, marinated or fermented foods. Typical intake is likely to be less than I g-day corresponding to about one tablespoon (15ml) of vinegar. Much smaller amounts are present in a wide range of plant- and animal-derived foods as acetyl-Co A.

Intestinal absorption

Absorption of acetate from the small intestine (Watson et at., 1991; Tamai et til.. 1495), especially the jejunum, appears to proceed mainly via the proton-monoear-boxylic acid cotransporter (MCT1. SLC16A11, which is possibly present in the apical and certainly in the basolateral enteroeyte membrane (Garcia et til.. 1994: Orsenigo et til., 1999). Acetate can also be absorbed from colon and rectum, which is an important site of bacterial production from dietary liber (Wolever et at., 1995). MCT I and possibly the SCFA HC03" antiporter contribute to this uptake (Stein et ui. 2000), The flow of protons across the luminal membrane of the proximal colon via the sodium hydrogen exchanger also promotes the protonation of the acetate anion and its subsequent passage into the enteroeyte by non-ionic diffusion (von Engelhardt et ul.. 1993).

Transport and cellular uptake

Blood circulation: The proton/monocarboxy Iic acid cotransporter (MCT1, SLC16A11 is the main carrier for uptake of acetate, aceloacetate. and beta-hydroxybutyrate by the liver and other critical tissues. The related carriers MCT2. MCT3. and MCT4 have much more limited distribution.

Blood-brain barrier: Limited transport of acetate occurs across the epithelial eclls of the blood brain barrier (Terasaki et at., 1991 ) \ ia MCT1 on both sides of the brain capillary endothelial cell (Halesttap and Price. 1999). Interestingly, the foot processes of astroglial cell, which form part of the blood brain barrier, express M<rT2. This carrier has much higher affinity for monocarboxylates than MCT I {Halestrap and Price, 1999). Permeability of the blood brain barrier increases greatly after several days of starvation and in diabetes mellitus.

Metabolism

Acetate can be utilized by muscle and other peripheral tissues (Pouteau et at,, 1996), Complete oxidation of acetate requires thiamin, riboflavin, niacin, pantothenate, lipoatc, ubiquinone, iron, and magnesium.

First, free acetate must be conjugated to coenzyme A by acetate-CoA ligase (thio-kinasc: EC6.2.1.1). Most acetyl-CoA is utilized in mitochondria via the tricarboxylic acid I Krebs) cycle. Citrate synthase (EC4.1.3.7) joins acetyl CoA to oxaloacetate. The citrate from this reaction can then be metabolized further providing FADI I, NADU, and succinate for oxidative phosphorylation and ATP or GTP from succmyl CoA.

The production rate of acetyl-CoA from fatty acid beta-oxidation in the liver with prolonged fasting usually exceeds the capacity of the Krebs cycle. The coenzyme A for continued beta-oxidation and other functions can be released through the production of aceloacetate in three steps. The typical odor of a fasting indiv idual is partially related to exhaled acetone formed from aceloacetate The conversion of aceloacetate into bet a-hydroxy butyrate taxes the body's acid-buffering capacity and may cause a drop in blood pll (acidosis) in diabetics and similarly susceptible patients. None of these events is related 10 dietary intake of acetate.

Ketogenesis lakes place in the mitochondria where fatty acid catabolism generates acetyl-CoA. Acetyl-CoA C-accly I transferase (Ihtolasc: EC2.3.I.9) joins iwo aectyl-CoA molecules, and hydroxymcthylglularyl-CoA synthase {HMG-CoA synthase: EC4.1.3.5) adds another one. The mitochondrial isoform of HMG-CoA synthase is genetically distinct from the cytosolic one. which generales the precursor for cholesterol

Acetyl-CoA

CoA-S

Acetaie-CoA ligase (magnesium)

Acetate

Acetyl-CoA

Figur* 6.24 Acetate most be activated before it can be utilized

Acetyl-CoA C-acetyttransferase

Acetoacetyi-CoA

HMG-CoA synthase

O OH

3-Hydroxy-3- methytgluiaryl -CoA

HMG-CoA synthase

HMG-CoA lyase

NAD NADH

II M2

[t-hydroxyDutyraie

OH 3-HydroxytJutyrate dehydrogenase

\ non-enzymlc OH

HjC C CR

Acetoacelate

Acetone

Figur* 6.25 Ketogenesii fries up coenzyme A from acetyl-CoA

synthesis. Hydroxymethy Igl utary l-Co A lyase (HMG-CoA lyase. (-.( 4.1.3.4} finally generates acetoacetate by cleaving off acetyl-CoA from the HMG-CoA intermediate. Spontaneous decarboxylation of acetoacetate generates the dead-end product acetone.

Acetoacetate can also be reduced to beta-hydroxyhuiyrate by NAD! [-dependent 3-hydroxybutyrate dehydrogenase (EC 1.1.1.30). This enzyme is allosterically activated by phosphatidyl choline. The reaction is fully reversible. Net flux depends on substrate concentrations. Acetoacetate and beta-hvdroxybutyrate (but not acetone) can become a significant energy fuel for brain after several days of adaptation to starvation conditions.

Storage

Other than the rapidly metabolized amounts in cellular cytosol and body fluids, acetate is not stored to a significant extent.

Excretion

Owing to its small molecular size, the renal glomerular membrane does not retain acetate. Nearly all Of the filtered acetate is recovered from the proximal renal tubular lumen.

Much of the uptake from the tubular lumen is mediated by the proton ntonocar-boxylic acid cotransporter 2 (MCT2. SLCI6A2), which has a several-fold higher affinity for Us ligands than MCTl, Additional transporters, including MCTl, are likely to play a role in acetate salvage from renal u it rali Urate,

Regulation

Acetyl-CoA activates allosterically the biotin-dependent enzyme pyruvate carboxylase (EC6.4.1.11 and thereby stimulates krebs cycle throughput.

Dietary effects

Acetate inhibits lipolysis and replaces fat in the fuel mixture (Silcr et ul.. I999). Acetic acid also lowers blood sugar levels (Ogawa el ul.. 2000), possibly by decreasing the activities of sucrase, maltose, trehalase. and lactase (Ogawa et ul.. 2000). or by delaying gasiric emptying (L iljeberg and Bjorck. 1998).

Dietary vinegar was found to enhance intestinal calcium absorption in rats (Ktshi et ul.. !999). but may at the same time increase urinary mineral Ions and cause osteoporosis {Lliotta ei ul., 1998),

A combination of vinegar and honey has been claimed to be effective for the self-treaunent of chronic inflammatory polyarthritis {Comara and Danao-Camara. 1999).

Drinking vinegar )usl once a week appears to be sufficient to increase the risk of dental erosion (Jar\iticti et ul.. 1991).

References

Camara K, Danao-Camara T. Awareness of. use and perception of efficacy of alternative therapies hy patients with inflammatory arthropathies. Hawaii Mai J 1999:58: 329-32 vim Fn gel hard t W. Burmester M. Hansen K. Becker G. Rechkemmer G, Effects of amiloride and ouabain on short-chain tarty acid transport in guinea-pig large intestine. ./Physiol 1993:460:455 66 Garcia CK, Goldstein JF. PalhaJt liK. Anderson RG. Brown MS, Molecular characterization of a membrane transporter for lactatc, pyruvate, and other monocarbox> lates: implications for the Con cycle. Cell 1994:76:865 73 Malestrap AP, Price N't The proton-linked monocarboxylate transporter (MC11 family:

structure, function and regulation. BiuchemJ 1999:343 Pt 2:281-99 Jan men VK, Rytomaa 11, llemonen OP Risk factors in dental erosion. J Dent Res 1991; 70:942-7

Ki>hi M. Fukaya M. TsukamotoY. Nagasawa T, lakehana K. Ni>,hiza\va V Enhancing effect of dietary vinegar on the intestinal absorption of calcium in ovaricctomized rats. Biosci Biotech Bioehem 1999:63:905-10

Lhotta K. Mode G. Gasser R. Fiiikenstcdt G. Hypokalemia, hyperrenincmia and osteoporosis in a patient ingesting large amounts of cider vinegar. Nephron 1948;80:242 3 Liljeberg H, Bjorck I. Delayed gastric emptying rate may explain improved gtycaemia in healthy subjects to a starchy meal with added vinegar. Eur J Clin Nutr 1998; 52:368-71

Ogawis N, Satsu H. Watanabe H. Kukaya M. Tsukamoto Y, Miyamoto Y, Shimizu M, Acetic acid suppresses the increase in disaccharidase activity that occurs during culture of caco-2 cells.,/ Nutr 2000; 130:507-13 Orsenigo MN. Tosco M. Bazzini C. Laforenza U. Faelli A, A monoearboxylate transporter MC'Tl is located at the basotateral pole of rat jejunum. Exp Physiol 1999;84:1033 42 Pouteau E, Piloquet H, Maugeais P. Kinetic aspects of acetate metabolism in healthy-

humans using [ I -13€]acetatc. Am J Physiol 1996;271:E58-E64 SilerSQ, Neese RA, Hell crate in MK. /><■ novo llpogencsts, lipid kinetics, and whole-body lipid balances in humans after acute alcohol consumption. Am J Clin Nutr 1999; 70:928-36

Stein J. Aires M. Schroder O. Short-chain fatty acid (SCFA) uptake into Caco-2 cells by a pM-dependent and carrier mediated transport mechanism. Eur J Nutr 2000:39:121 5 Tamai I, Takanaga II. Maeda H. Sai Y, Ogihara T. Higashida 11. Tsuji A. Participation of a proton-coinmsporter, MCTl, in the intestinal transport of monocarboxylic acids Biochem Biophys Res Comm 1995:214:482 9 Tcrasaki T, fakakuwa S. Moritant S, Tsuji A. Transport of monocarboxylic acids at the blood brain harrier: studies with monolayers of primary cultured bovine brain capillary endothelial cells. J Pharmacol Exp Ther 1991:258:932 7 Watson AJ. Brennan EA. Farthing M.I. Fairclough PD. Acetate uptake by intestinal brush border membrane vesicles. Gut 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../ Im Coll Nutr 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

Co A coenzyme A

ETF electron-transfer flavoprotein

Understanding And Treating Autism

Understanding And Treating Autism

Whenever a doctor informs the parents that their child is suffering with Autism, the first & foremost question that is thrown over him is - How did it happen? How did my child get this disease? Well, there is no definite answer to what are the exact causes of Autism.

Get My Free Ebook


Post a comment