Am J Clin Nutr 1993 Mayes 754S 65S

7/28/2019 Am J Clin Nutr 1993 Mayes 754S 65S

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754S Am J C /in N utr 1993 ;58 (su ppl):75 4S -65S . P rin ted in U SA . 1993 Am e rican S ociety fo r C lin ica l N utritio n

In te rm ed ia ry m e tabo lism o f fru c to se 3P ete r A M a yes

ABSTRACT M ost of the m etabo lic effe cts o f fru cto se a rcdue to its rap id u tilization b y the live r and it by -pass ing the p hos-phofru c to k inase regu la to ry step in g lyco lysis , lead ing to fa rreach ing conseq uences to carbo hydra te an d lip id m etabo lism .T hese co nsequ en ces inc lude imm edia te hepa tic inc reases in py -ruva te and lacta te p ro duc tion , ac tiva tion of pyruv ate dehydro -genase , and a sh ift in ba lance f rom oxida tion to es ter ifica tion ofnones te rified fa tty ac ids , resu lting in inc reased secretion of very -low -d en sity -lipopro tein (V LDL ). T hese effec ts a re augm ented b ylo ng-te rm absorp tion of fru ctose , w hich causes en zym e adap ta -tion s tha t in crease lipo genesis and V LDL secre tion , lead ing totrig ly ceridem ia , decreased g luco se to le rance , an d hyperinsu li-nem ia. A cu te load in g of the l iver w ith f ruc tose cause s sequ estra-tion of in organ ic p ho sph ate in fructose -l-p ho sph ate an d d im in-ished A TP syn thes is. C onseq uen tly , the inh ib ition by A l? of theen zym es of aden ine nuc leo tide degrad ation is rem oved an d uricacid form ation a cce lerates w ith co nsequ en t hy peruricem ia. Th eseef fects a re o f particu la r s ig n ificance to p o ten tia lly hypertrig ly -ce ridem ic o r hyp e ru ricem ic ind iv iduals. Am J C lin N u tr1993;58(suppl):754S-765S.

KEY WORDS Fru cto se, in te rm ediary m e tab o lism , sucrose ,imm edia te e ffec ts , long- te rm effec ts , live r, ca rboh ydra te m etab-olism , lip id m e tab o lism , enzym e adap tation , lipo gen esis , v ery -low -dens ity lipopro te ins , in su lin , no neste rified fatty ac ids, hy -p ertrig lyc eride mia , hyp eru rice mia

In troduct ion

V irtua lly a ll the un ique m etab o lic p ro pertie s o f fruc tose a red ue to tw o prim ary fac to rs: its rap id up take by the live r, and itsen try to the pa thw ay of g lyco lys is o r g luconeogenes is a t the tn -o se ph ospha te lev el a fte r b ypa ssing the pho sph ofructok inase reg-u la to ry step . T h e m etabo lic con sequence is the prov is ion o f in -c reased sub stra te in a ll th e m etab o lic pa thw ay s lead ing from tn-o se phospha te (F ig 1) .

Curren t in te rest in fru ctose m etabo lism has ar isen becau se o fits in cre ased use a s a sw eetener in the fo od ind ustry in the fo rmof h ig h-fruc tose corn syrup (H FS). A lso , w he ther based on soundsc ien ce or no t, fruc tose h as been prom oted a s an app eti te de -pressan t, as a food fo r no n-insu lin -dependen t d iabe tics , fo r par-en te ra l feed in g , and as a food su pp lem en t fo r enduran ce a th letes .R epresen tin g ha lf o f the sucrose m olecu le , fru ctose has been red -ogn ized fo r m any years as be ing large ly respo nsib le fo r the m et-abo lic e ffec ts o f h igh-sucrose d ie ts . C oncern has a risen becauseof the realiza tion tha t fru ctose , at e lev ated concen tra tio ns, canprom o te m etabo lic ch an ges tha t are ac tu a lly o r po ten tia lly d ele -

te rious , eg , h yperlip idem ia, hyp eru ricem ia , non en zym ic f ruc to -sy la tion of p ro te ins, lac tac idem ia , an d d is tu rbances in co pper m e-tabo lism . T he paper concen tra tes on the genera l m etabo lism offru c to se , p ar ticu la rly con cern ing its im pac t on carb ohyd ra te , lip idand pun ine m etabo lism . O ther asp ects re fe rred to are the sub jec tso f o ther rev iew s in th is vo lum e.

O f further cons ide ration is w h eth er augm ented insu lin sec ret ionis respo nsib le fo r som e of the m etab o lic e ffec ts o f fruc to se in take .Compared w ith g lucose , fruc tose feed in g doe s n o t d irec tly causean increase in p lasm a insu lin (1 ) w he reas sucrose feed in g do es (2) .Thu s w henever in take of fruc to se is accom pan ied by g lucose, theadded effec t o f in su lin sec re tion m ust be taken in to accoun t. N o tonly is th is th e c ase w ith sucrose i tse lf bu t som e H FS s are eq uiv -a len t to hydro ly zed su crose because they are - 50% gluco se and50% fruc tose (3 ). S im ila r co nside ra tions ap p ly to sup p lem en ts fo ra th le tes th a t con ta in bo th fruc tose and g luco se .

G en era l m etabo lismU tiliz a tio n o f b lo od fru c to se and up ta ke in to tiss ue s

T he consequ en ce of th e d iges tio n of sucrose an d o the r fructose -con ta in ing foods such as ho ney , fru its, and som e vege tab les , isab sorp tio n and tran sp ort o f fru cto se b y the in te stin al ep i thel iumin to the hep atic p orta l ve in . T herefo re , a ll fruc tose ab so rbed flow sthroug h the liver in itia lly . B ecause of th e pre sen ce of an ac tivehepa tic enzym e sys tem for m etabo liz in g fruc to se , fruc tose read ilypasses in to the liv er , accoun ting fo r a frac tion al up take of 55 %and 71% , resp ec tive ly , o f the fruc tose presen ted to the live r a ftertube feed ing fed o r s ta rv ed rats (4 ). In hum ans it w as shown tha tthe live r m etab o lized a t leas t ha lf o f the fruc tose in jected in trave-nous ly (5). In the p erfused rat liver w e fo und a v alu e o f 4 0% fo rthe frac tiona l ex trac tio n o f fruc to se (6 ). A s a conseq uence of th ehig h rate o f ex tract ion o f f ruc tose by the l iver , cor respon din g lylow concen tra tions of fruc to se are fo und in the system ic b loodvesse ls a fte r m ea ls con ta in ing fruc tose or su cro se are co nsum ed(4 , 7 , 8 ). Som e 20% of fru ctose adm in is te red in trav en ous ly is tak enup by the k idney (9 ). T hus , som ew hat less than th is am oun t w ouldbe expected to be tak en u p by th is o rgan afte r o ral fe ed ing w he reth e live r takes up som e 50% o f the in itia l in flux . A considerab lysm alle r frac tion would be ava ilab le fo r ad ipose tis sue (10) and

I F rom the D iv ision of B iochem istry , D ep artm en t o f V ete rina ry B as icS cience s, R oya l V e ter inary C ollege , U niv ers ity o f L ondon .2 S upported b y the B ri tish H ear t F ounda tion .3 Add ress rep rin t req uests to PA M ayes, D iv ision of B iochem istry ,

D ep artm en t o f V e terinary B a sic Scienc es, R oyal V ete rin ary C ollege ,U niv ersi ty o f London , London NW 1 0T h, U K .


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C o 2

M ET A B O L IS M O F FR UCT O S E 755S

H ex ok inase w ill cataly se th e pho spho ry latio n o f m os t hex osesugars , inc lud ing f ruc to se . H ow ev er, w hen f ru cto se is p resen t

F R UCT S E

F R U C T O S E 1 -P

G l y c e r a l d e h y d e

I c iucose 6.pase_cr3I G1uc:: : :L , .4G L UC O SE 6 - P . . # { 21 6 }. G l yc o ge n

FR UCT OS E 6-P

[ F RU CT O SE 1 .6 - b is .P ( ) I 4O 6PHOFRUCTOK I P 4A SEF R U C TO SE 1 ,6 -b is -P

FIG 1. Fructose uti liz atio n in th e liv e r show ing its in te rre lationship w ith gluco se and f atty acid m etabo lism . Pase ,phosphatase; P, pho sphate .

sk e le tal m usc le (11 ). A recen t s tudy (12 ) sh ow ed that w h en f ruc -to se is in f u sed into ex erc ising subjects to m ain tain a con cen trationof 5. 5 m m o l/L , w h ich is abov e phy s io logical con cen tration s andabov e th e g lu co se concen tration , there is co nsiderab ly m o re f ruc -to se ox idation by ex e rcis ing and re stin g m u scles.

In a p rev ious rev iew (13 ) w e p o in ted ou t th at m any inv es tiga-tions bo th in v iv o and in v itro h ad b een carried o u t u sing unp hy -s io log ical co ncen tration s o f f ru cto se and that dedu ctions m adef rom such o bserv ation s co u ld be m islead ing , particu larly w henapp lied to h um ans consum ing norm al quan titie s o f sucro se andf ructose . O f particular relev an ce to h epatic m etabolism arc th e con-centrations of f ructo se lik ely to be attained in the h epatic portalv e in . In hum an s (14 ) and baboo ns (8 ) m ax im al concen tration s o f2 .2 m m ol/L hav e been reco rd ed af ter a f ru cto se o r su cro se m eal.W e f oun d v alu es w ith in the rang e 1 .1 -2 .2 m m olf L , w hen f ed o rs tarv ed rats w ere g iv en a large f ruc to se m eal by gas tric in tubation(4 ). In hum an s a m ax im um concen tratio n o f 1 .0 m m ol f ruc to sc f Lw as record ed in pe rip heral b lo od (14 ). B ecause th e norm al b loodf ru c to se concen tratio n is z e ro w hen no f ruc to se is b e in g ab sorbed ,f ru c to se con cen trations in b lood w ill v ary f rom z ero up to them ax im um recorded abov e , accord ing to the quan tity in the d ie t.

Spec ific m e tabo lic pa thw ays o ffru c tose u til iza tio n in ind iv idu a lt issues

w ith g lucose at phy s io log ical co ncen tration s its pho sph ory latio nis large ly inh ib ited by g lucose (10 ). N ev erthe le ss , it is p robab lyv ia th is rou te that f ruc to se , af te r up tak e f rom the b loo d , en te rsth e m etab o lic p athw ay s in ad ipose tis sue and m uscle . O f f argreate r sign if icance is th e pathw ay d iscov ered by H ers (15 ) ,w h ich inv o lv es th ree particu lar en z y m es (f ruc tok inase , ald o laseB , and trio k inase ), tw o of w hich arc spec if ic for f ruc tose m etab -o lism (Fig 1 ). T hese en z y m es arc presen t in liv e r an d k idn ey andprob ab ly in the sm all in tes tine o f som e spec ie s-such as thego ld en h am s te r (16 ), g u inea p ig (1 7 ), and d og (18 ) -that are ab leto co nv ert som e ab sorb ed f ruc to se in to g lucose . H ow ev er, th is isno t poss ib le in the in te stin e o f ei the r hum an s (19) or rats (17 ),w hich d o no t con tain g lucose -6 -ph osp hatasc , the en z y m e nec -essary f or re leasing g lucose . T hu s in the se tw o spec ies the re isno co nv ers io n o f f ruc to se to g lucose durin g ab sorp tio n . In th isre sp ec t the rat is a g ood m ode l o f hum an f ruc to se m etabo lism .

Fruc to se is rap id ly p hosphory lated by A lP in the liv e r to f o rmf ru cto se 1 -p hosp hate, cataly z ed by the f irs t en z y m e o f th e f ruc to sepathw ay -f ruc tok in asc (20 ). T h is enz y m e is v irtu ally spec if ic f o rf ru cto se because it is a k c tohex o k inase , and f ruc to se is the on lyk e toh ex o se o f phy s io logical sig nif icance in th e die t. T he h igh ac -tiv ity o f f ruc tok inase u nderlies the ab ility o f the liv e r to ex trac t som u c h o f th e f ruc tose pass ing through it. Fructose -i-p ho sphate issp lit b y liv e r aldo lase (aldo lase B ) in to g ly ceraldehy de and d ihy -d ro x y ace to nc ph osph ate , a m em ber o f the g ly co ly sis seq uence o fin term ed iate s. A ldolase B also fun ctions in the liv er in g ly coly sis


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7 5 6 S M A Y E Sto sp lit f ruc to se -1 ,6 -b ispho sph ate to g ly ceraldeh y de -3 -p hosphateand d ihy dro x y ace to ne phosphate . T h e th ird en z y m e in the f ruc to sepathw ay is tn iok inase (21 ), w h ich cataly z es the phospho ry lation o fg ly ceraldehy de by A l? to f o rm g ly cerald eh y de -3 -p hosphate , an -o th er in te rm ed iate o f the g ly co ly tic pathw ay .

T hus, the p athw ay s o f g lucose an d f ru c to se m e tabo lism in theliv e r conv erge at the trio se ph osph ate stage o f m etabo lism andf rom th is po in t on , th eir m etabo lism is qu alitativ ely s im ilar. Fruc -to se has arriv ed at th is stage in m e tab o lism , w ith ou t pass in gth rou gh the m ain rate -con tro lling step in g ly co ly sis cataly z ed bypho sph o f ruc tok inase (22 ). In th is w ay f ru c to se , on presen tationto the liv e r, is rap id ly p hosphory lated , p ro v id ing increased sub -s trate to the m e tabo lic pathw ay s lead in g f rom trio se pho sph ate(ie , g ly co ly sis, g ly cogenesis , g luconeog enesis, lipog en es is, andpo ssib ly f atty ac id estenif ication ). T hus, m ajor products o f f ruc-to se m e tabo lism in the liv e r are g luco se , g ly cogen , and lac tate(23 ). S m aller quan titie s arc ox id iz ed to carb on d iox id e, k eton cbod ie s o r con v erted to tn iacy lg ly ccro l (1 3 ). T he general d ispo -s ition o f f ruc to se carbo n b etw een its m ajor end p roduc ts is alte redby ch an ges in nu tritional and endocrine statu s, eg , g lu coneogen -es is f rom f ruc to se is increased du rin g s tarv ation , d iabe tes , o r ad -m in istration o f e thano l o r g lucag on (24 ).

B io s yn th e s is o ffru c to s e in m a m m a lia n tis s u e sA lthoug h the prim ary pu rpose o f th is paper is to rev iew the

e f f ec ts o f ex ogenou sly deriv ed f ru cto se , d iscuss ion o f the m e tab -o lism o f f ruc to se is no t com p le te w ith ou t a v ery brie f re f e renceto its sy n th es is in a f ew spec ializ ed tis sues .

Free f ruc to se is f ound in the lens, sem inal f lu id , and the f etalc ircu lation o f ung u late s and w hale s. I t is f o rm ed b y th e so rb ito l(po ly o l) p athw ay (25 ), w h ich is re spons ib le f o r f ruc to se f o rm a-tion f rom g lucose . T h is pathw ay is p resen t in the len s, sem inalv es ic le s, an d p lacen ta o f the g roup s m en tioned abov e . It inc reasesin ac tiv ity as g lucose con cen trations rise in d iabe tic s in tho setissues that are no t in su lin sens itiv e , such as the len s. G luco seund ergoes reduc tion by N A D PH to sorb ito l, cataly z ed by aldosereduc tase , f o llow ed by o x idation o f so rb ito l to f ruc to se by son -b ito l (p o ly o l) dehy d rogenase in the presence o f N A D . B o th son -b ito l an d f ruc to se accum u late in th e hum an lens in d iab etic s,causing osm o tic dam age , w h ich is p ro bab ly inv o lv ed in the path -ogen es is o f d iabe tic catarac t. S o rb ito l dehy d nogenase , bu t no tald ose reduc tase , is f ou nd in liv e r and is re spons ib le f o r th e con -v ers ion o f any ex o genous ly d eriv ed sorb ito l to f ruc to se .

E f f ec ts o f f ruc tose on carbohy drate m etabolismE ffe c ts o n th e c o n c e n tra tio n s o f im p o r ta n t in te rm e d ia te s

E x perim en ts w ith bo th the perf u sed liv en (2 3 , 26 , 27 ) and cath -e ten iz ed hum an sub jects (9 ) ind icate that in th e starv ed s tate , 6 6% of a f ru c to se dose is conv erted to g lucose and up to 25%is re leased as lactate . U p to a f u rther 8% m ay f orm g ly co gen(23 ). A f te r adm in istration o f f ru cto se e ith er orally o r by in tra-v eno us load ing th ere is a rap id and m ark ed increase in g lucose1 -p hosphate in those tis su es co n tain ing th e f ru cto se pathw ay , ie ,liv e r (28 -3 1 ), k idney (30 , 32 ), and sm all in te stine (3 3 , 3 4 ). R e -cen t inv es tigations u sing P m agne tic- re son an ce spectro scopyhav e con f irm ed the accum u lation o f f ruc to se 1 -ph osph ate in thehum an liv e r af te r in trav enou s adm in istratio n o f f ruc to se (3 5 ). A l-th ough m ost o f these e f f ec ts w ere o b tain ed by u sing unph y sio -log ical concen tratio ns o f f ruc to se, ex perim en ts w ith iso lated he -

p atocy te s us ing graded concen trations o f f ruc to se (31 ) d em on-strated that sign if ican t elev ations o f f ru cto se 1 -ph osp hateoccurred at concen tratio ns o f 0 .5 and 1 .0 m m o l f ruc to sc /L , w h ichare av ailab le in the portal v e in in v iv o af te r a f ruc to se m eal.Othe r im portan t in te rm ed iate s w hose concen tratio ns m ay alte r

as a resu lt o f f ruc to se adm in is tratio n inc lude g ly cero l 3 -p hos -phate , f ruc to se 2 ,6 -b ispho sphate , py ru v ate, lac tate , A T P, and in -o rgan ic phosphate (Pi). T hese w ill be d iscussed in f o llow ing 5cc -tions.

E ffe c ts o n g ly c o lys is , g lyc o g e n e sis , a n d g lu c o n e o g e n e s isA s a resu lt o f the load ing o f the in itial p athw ay s o f f ruc to se

m e tabo lism th ere is a tend ency f o r in te rm ed iate s o f g ly co ly sis toincrease in concen tratio n , re su lting in an increased f lux th roug hth e pathw ay , ev idenced by increased lac tate f o rm atio n and raisedb lood lac tate con cen trations (36 , 37 ). In the sp an o f g ly co ly ticreac tions f rom g ly ceraldehy de -3 -pho sphate to py ruv ate an d lac-tate , the rate -con tro lling s tep is cataly z ed by p y ruv ate k inase .T h is enz y m e is norm ally under f eed -f o rw ard co n tro l b ecause o fallo s ten ic ac tiv ation b y f ruc to sc -1 ,6 -b isph osp hatc . A lth ough th ism e tabo lite m ay doub le in concen tratio n w hen f ruc to se is addedto hepatocy te s (31 ), o f m ore sign if icance are the large increasesin f ruc to se -1 -ph osp hate con cen trations , w h ich ex tend a s im ilarbu t m ore enh an ced ac tiv ation o f py ru v ate k inase (3 8 ), thus f a-c ilitating passage o f f ruc to se carb on to p y ruv ate an d lac tate .

G ly cog en sy n th esis and break dow n is con tro lled by a com p lexserie s o f reac tion s inv o lv ing cov alen t m od if ication by pro te inp hosphory lation an d deph osp hory lation . B rie f ly , regu lation cen -te rs arou nd tw o rate -con tro lling enz y m es-g ly cogcn sy n thaseand g ly co gen ph osp hory lase . (See re f 25 f o r a general rev iew .)T h e ac tiv e f o rm o f g ly cogen sy n thase (sy n th ase a) is the de -p hosphoenz y m e , w hereas th e in ac tiv e sy n thase b is ph osph ory l-ated . O n the o th er hand ac tiv e g ly cogen pho sph ory lase a is thep hosphoenz y m c , w hereas the in ac tiv e b f o rm is deph osp hory -lated . Pro te in k in ases carry ou t ph osph ory lations and pro te inp hosphatases carry ou t dephospho ry lation s o f th ese enz y m es .B o th processes are con tro lled by ho rm onal and allo s ten ic m od i-f ie rs . C o n tro l o f g ly co gen m etabo lism in liv e r d if f e rs in som ed etail f rom that o f g ly co gen m e tabo lism in m usc le and has beenrev iew ed by H ers (39 ).

A study of th e lite ratu re rev eals a d isparity in resu lts on w he therf ruc tose prom o tes liv en g ly cog en depos itio n , w ith the b alance o fs tu d ies in v iv o in the f ed cond ition ind icating th at f ruc to se is ab ette r p rom o ter o f g ly co genesis th an is g luco se (31 ). T he ne t dep -os ition o f g ly cogen appears to resu lt f rom bo th ac tiv ation o f g ly -cogen sy n thase (4 0 , 41 ) and inh ib ition o f g ly cogen pho sph ory lase(40 , 42 ). T h is appears to be broug h t abou t by sev eral m ech an ism s .Phosphory lase a is inh ib ited by f ruc to sc -1 -pho sphate (4 2 -44 ),w h ich accum u late s af te r adm in is tration o f f ru c to se . A lso , g lucose -6 -p hosphate in creases in con cen tration and ac tiv ate s g ly cogen sy n -thase and in h ib its phospho ry lase (45 ) . W e h av e carried ou t per-f u s ions w ith th e liv e r o f f ed rats, u s ing w ho le b lood co n tain ingph y sio log ical concen trations o f g lucose , am ino ac id s , and f ree f attyac id s in to w h ich w as in f u sed g lucose, f ruc to se , o r b o th su gars atph y sio log ical rate s (46 ) . W h en e ither sug ar w as in f u sed alone .there w as a ne t ou tpu t o f g lu co se f rom the liv e r, w ith no chang ein g ly cog en concen tratio n . H ow ev er, w hen g lu co se and f ru c to sew ere in f u sed toge ther, th ere w as a m ark ed up tak e o f g lucose andan increase in g ly cogen . Fruc to se u p tak e w as the sam e w ith orw ith ou t a concom itan t g lu co se in f u s ion .


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M ETABOLISM OF FRUCTO SE 7 5 7 SThu s, fruc tose on its ow n does n o t seem to be g ly co gen ic b u t

in the presence of ex tra g luco se , as w ould be the case afte r asucrose m ea l, fruc tose opens the door fo r hepa tic g lucose up-take an d syn thes is o f g ly cogen . T h is is ach ieved , p resum ably , byac tiv ation of g lycogen syn thase and inh ib ition of p hosphory lase ,bu t fruc tose itself is no t ab le to m ak e u se of the fac ility b ecausean in crease in fruc tose -1 ,6 -b isp hospha te inh ib its fruc tose -i,6 -b is -pho spha tase (22). It w as sign ifican t th at lacta te concen tra tions in -c reased on ly in the presence of a fruc tose in fus io n , th e up tak e ofw hich in to th e live r co u ld acco un t fo r the inc reased lac ta te p ro -du ction . In the presence of a s im u ltaneou s g lu cose in fu sion , the rew as an add itiona l sm all inc rem en t in lac ta te p roduc tion . T hus inthe fed s ta te , fru ctose w ould appear to be pred om inan tly g ly co -lyzed to lac ta te rath er th an converted to g lycog en o r g lucose . A nora l load of fruc tose or su crose , bu t no t g lucose , a lso leads toinc reases in b loo d lac tate co ncen tra tion in hum ans (47 , 4 8).

In th e sta rved cond ition g lu co ncogenes is and g lucose prod uc-tion f rom fruc tose is an ac tive process . ev en exceed ing th e ra teso f g lucon eo genesis from lac ta te (23 , 49 ). U nfor tu na tely , m anystud ies on g luconcogen es is from fruc tose , pa rticu la rly in v itro ,have used unphysio log ica lly h igh concen tra tions o f fruc tose ( ic 5 mm ol/L ) and w ill no t be cons ide red in the p resen t d iscus-s io n . T he g ly co ly sis and g luconeog en ic pa thw ays m ake use ofm any comm on in te rm ed ia tes and enzym es bu t a rc con tro lled bysev eral n onequ ilib rium enzym es un iqu e to each pa thw ay (25 ).Tw o pivo tal reac tio ns, fo r w hich th e ac tiv itie s a rc rec ip roca l andcoo rd ina ted , dom in a te th ese pa thw ay s. T hese arc ca ta ly zed byphosph ofruc tok in ase in g lyco lys is and fruc tose- i,6 -b ispho spha-ta se in g luco neo genes is (F ig 1 ). The ir ac tiv i ties arc b o th indu cedby horm on es and also by a llos ten ic m odifie rs o ften ac ting on thekey regu la to ry m olecu le -fruc to sc -2 ,6 -b ispho spha tc -w hich ac-tiva tes p hosphofruc to k inase an d inh ib its fruc tosc -1 ,6 -b isp hos-ph atase (5 0). T he concen tra tio n of fruc tose -2 ,6 -b isph osp ha tc ise leva ted in live r from fed ra ts bu t fa lls during sta rva tion , thusac tiva tin g fruc tose -i ,6 -b ispho sph atase and the g lu co neogen icp athw ay and inh ib iting phosphofruc tok inasc and g lyco lys is . U n -d er these cond ition s, fru ctose - 1 ,6 -b ispho sph ate do es no t accu-m u la te even when the flux from fruc tose m etabo lite s a t the triosep hospha te leve l inc reases. T here fo re , the re is no inh ib itio n ofg lu co ncogenes is by fruc tose . In iso la ted hepa tocy tes the re issom e increase in fru ctose -2 ,6 -b isphospha te u nder phys io log icalcon cen tra tions o f fruc to se , w hich leads to inc reased subs tra te cy-c ling at th e lo cus of p hosph ofru cto k in asc and fructosc -i,6 -b is-phospha tase (51). H ow ever, the re is no ev idence tha t th is in h ib itsg lu co neogenes is from fruc tose.

Lo n g -te rm e ffe c ts o f a h ig h fru c to s e in ta k eExp erim en ta l da ta have b een ob ta ined from hum ans or an im als

consum ing be tw een 7 .5% and 70% of the ir energ y-in take re -q u irem en t as fruc tose. L ong- te rm feed ing of fruc tose -co n tain ingd ie ts lead s to adap tive inc reases in th e ac tiv ity o f m any en zym esin th e pa thw ay s o f fruc tose m etabo lism . T hese enzym es can begroup ed in to those invo lv ed in itia lly w ith fruc tose up take andm etabo lism and th ose invo lved in lipo genesis and trig lyceridesyn thes is (13 ). L ong-te rm e ffe cts of feed ing hig h-f ruc tose d ietsm ay diffe r from those of feed ing su crose , b ecause the g lucosem o ie ty of sucro se m ay cau se increased insu lin sec re tion . T h is intu rn w ou ld be exp ec ted to cau se ad ap tive ef fects . T he m ajo r ityo f op in io n , how ever, w ou ld reg ard the long -te rm effects o f asucrose d ie t as be ing due m ain ly to its fru ctose con ten t (52) .

G en erally , it has been the case tha t g lu co se to le rance has beenw orse un der a lon g-te rm sucrose reg im e com pared w ith a s ta rch -based d ie t, b o th in an im als (53) and hum ans (54 ). T he reason fo rthe decreased g lu co se to le rance d oes no t appear to be an insu f-ficiency in insu lin sec retion , ra th er the reverse . In creased p lasm ainsu lin con cen tra tions have b een reported afte r sucro se feed in g( 5 5 - 5 8 ) and insu lin sens itiv ity , as m easured by the h ypog lycem icrespo nse to adm in iste red in su lin , is le ss (59). T hus decreasedg lucose to le ran ce is due to inc reased in su lin res istance , b roug h tabou t m ost like ly b y in creased n onesten ified fatty acid (N EFA )concen tra tions and u tiliza tio n (6 0 , 61 ).

T he decreased u tiliza tion of g lu co se , as foun d in the w hole or-gan ism w hen p laced on a h igh -su crose or -fruc tose d iet, is a lsoexh ib ited in stud ies o f ind iv idu al tis sues . H ow ever, th is is usua llyaccom pan ied b y an in creased ab ility to m etab o lize fruc tose . T hus ,in the liv er the re is d ecreased u tiliza tio n and ox ida tion o f g lucose(62 , 63). T h is is no doub t due to depressed g lucok inase an d in -c reased ac tiv ity o f g lucose-6 -pho sph atasc in the live r af te r f ruc -tose -con ta in ing d ie ts a re co nsum ed (64). A s oppo sed to the im -m ediate e ffec t o f fruc tose in fac ilita ting co nversio n of g lucose tog lycogen in the live r (46), long-te rm feed ing o f fruc to sc -con ta in ingd ie ts reduces the con version of g lucose to live r g lyco gen (65 , 66).H ow ever, conv ers ion of fruc tose to live r g ly cogen is in creasedbecause o f en zym e adap ta tion (64 ). C onsum ption of a sucrose d ie tbe fo re consum ption of a sucro se lo ad d id no t elic it any ex tra in -c rease in b loo d lac ta te com pared w ith a s tarch d ie t (6 7).

M usc le tissue a lso show s decreased ab ility to m etabo lize g lu -cose and increased ab ility to ox id ize fa tty acids af te r an im alshave been fed h igh -fruc tose d ie ts (68). L ikew ise , the u tiliza tionof g lu co se in ad ipose tissue is im p aired w ith respec t to its up take ,ox ida tion , and convers ion to g lycogen (6 2 , 69 ).

E ffec ts o f fru cto se o n lip id m e tabo lismIm m e d ia te e ffe c ts o n th e in itia l p a th w a y s o f lip id m e ta b o lis ma nd o n lip og en es is

F ruc tose has b o th imm ed ia te an d long-te rm effec ts o n lip idm etab o lism . Short-te rm or acu te e ffec ts a rc tho se tha t occur as aresu l t of fru c to se m etabo lism by ex isting enzym e capac ity ,w hereas long -term effec ts resu lt m ain ly from en zym e adap ta tionto d iets con ta in ing h igh concen tra tions of sucrose o r fruc tose .B ecause of the im po rtan ce o f the live r in fruc to se u p tak e f romthe b lo od , m any of its e ffec ts on lip id m etabo lism arc foun d inth is o rg an . T h ey invo lve th e m ajo r pa thw ays of fa tty acid o x i-da tion and es tcn ifica tion , and lipogenes is. In th is respec t, dangerso f ap p ly ing resu lts in experim en ta l an im als to hum ans m ust b eapprec ia ted . Fo r exam ple , it is like ly tha t lipog en es is is a m o reim por tan t pa thw ay in ra ts than in hum ans , w here lipo genesis m aybe confined to the liv er and w here even there the k ey en zym esof lip ogenes is m ay b e low in ac tiv ity (70) .

In the live r, lip id m etab o lism is a ffec ted by fruc tose a t thed ihy droxy ace tone phosp ha te an d pyru va te loca tions . D ihy droxy -ace tone pho spha te is in equ ilib rium w ith g ly cero l-3 -ph osph a tc ,cosubs trate fo r es ter ifica tion o f long-cha in acy l-C oA in the sy n-thes is o f trig lyceride and pho spho lip id s. T rig lycerid e is the m ajo rp recurso r and d ete rm inan t o f very -low -density lipo pro tc ins(V LD Ls) sec re ted b y th e live r an d wh ich cons titu te the bu lk ofen dogenously derived p lasm a trig lycer id e (7 1). F ruc tose a lsogenera tes pyru va te , w h ich , b esides fo rm ing lac ta te, en te rs them itochondn ion to fo rm ace ty l-C oA as a resu lt o f pyruv ate d e-


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7 5 8 S M A Y E Shy dro genase (PDH ) ac tiv ity . H ere it can ac t as a carbon so urcef o r th ree produc ts: carb on d iox ide , af te r o x idatio n in the c itricac id cy c le ; long -chain f atty ac id s, af te r en terin g th e lipo genesissequ ence o f reac tion s; an d , k e tone bo d ies (72 , 73 ). A cety l-C oAis the m ajor carbo n source f o r lip ogenesis . H ow ev er, as lipogen -es is occurs in the cy to so l, acety l-C oA m ust b e tran spo rtedth rou gh the m itochond n ial m em bran e as c itrate, re f o rm in g ace ty l-CoA in the cy to so l by th e actio n o f the lipogenic enz ym e , A lT -c itrate ly ase . A ccty l-C oA is conv erted to lo ng -chain f atty ac idv ia th e im p ortan t cy to so lic in te rm ed iate m alo ny l-C oA . B y th esepathw ay s , f ruc to se pro v ides carbo n atom s f o r bo th th e g ly cero lan d the acy l po rtio ns o f the acy lg ly cero l m o lecu le .

T he ac tiv ity o f PD H is a k ey f ac to r in de te rm in ing the f ate o fpy ru v ate. I t is ac tiv ated by a decreased ratio o f [A lT ] to [A DP]and b y an increase in py ruv ate (74 ); it is inh ib ited b y increasedconcen tratio ns o f N EFA (74 , 7 5 ). A s d iscu ssed in ref e ren ce 7 6 ,f ruc to se adm in is tration , particu larly at h igh am oun ts , causes de -p le tio n n o t on ly o f A lT bu t o f all aden ine nuc leo tides; there f o re ,the ratio o f [A T P] to [A D P] m ay no t change app reciab ly . O raladm in is tratio n o f large am oun ts o f f ruc to se to hum ans produ ceshy pcruriccm ia, w h ich is k now n to f o llow dep le tion o f A l? ando ther adcn inc nuc leo tides (77 , 78 ) . H ow ev er, no decrease in he -patic [A T P] w as f oun d in f ru c to se -f ed rats (79 ). A den in e nud e-o tide concen tratio ns an d PDH ac tiv ity d id no t ch an ge w hen f ruc -to se w as ad ded to the perf u sed rat liv e r at ph y sio log ical co ncen -trations o f 1 .3 m m ol/L . H ow ev er, at 1 1 .0 m m ol/L bo th A lP andto tal ad en in e n uc leo tides w ere decreased and PDH w as ac tiv ated(80 ) . A t a f ruc to se con cen tration o f 1 .5 m m ol/L th ere w as a per-cep tib le increase in PDH ac tiv ity , w h ich w as no t accom pan iedby an y ch an ge in ad en in e nuc leo tid e con cen trations (1 3 ). O fm ore s ign if icance w as the f ac t th at at th is ph y sio log ical concen -tration o f f ruc to se , th e in h ib ito ry e f f ec t o f increased o leate (aN EFA ) on PDH activ ity w as rev ersed . G enerally , th ese resu ltssup port the v iew th at f ruc to se causes increases in PDH activ ityby increasing py ruv ate co ncen trations , rath er than by decreas ingthe ratio o f [A l?] to [A D P] (81 ). In sum m ary , it w ou ld appearth at som e ac tiv ation o f PD H occurs w ith h igh ph y sio log ical con -cen trations o f f ruc to se , e spec ially in an tagon ism to the depressan tef f ect o f increased co ncen tration s o f N EFA s .

W hen f ruc to se w as in jec ted in trav enous ly in to rats there w asan im med iate tho ugh trans ien t increase in g ly cero l-3 -phosphatean d p y ruv ate concen trations (82 ). In con tras t, af te r g lucose ad -m in is tratio n there w as no im m ed iate increase . W hen f ruc to se w asadm in is te red in trap en iton eally th ere w as an in crease in hepaticd ihy dro x y ace to ne phosphate , g ly cero l-3 -ph osp hate , p y ruv ate ,an d lac tate (83 ). S im ilar re su lts h av e been o b tain ed in the p er-f u sed liv er (27 , 84 , 85 ). A ce ty l-C oA concen tratio ns also increase(72 ). It is also lik ely that m alo ny l-C oA con cen trations rise w henf ruc to se is adm in is tered b ecause an increase has been record edin hepatocy te s in th e presen ce o f lac tate and p y ruv ate (86 ), bo tho f w h ich in crease in th e presence o f f ruc to se . T hu s, f ruc to secauses increased co ncen tration s o f its m e tabo lite s in bo th theg ly cero l-3 -ph osp hatc and g ly co ly tic and ace ty l-C oA b ranches o fits m e tabo lism . A lth ough m an y lipogen ic in te rm ed iates increasein concen tration af te r adm in is tration o f f ruc to se , there is littleev idence that f ruc to se o n its ow n has an im m ed iate e f f ec t onlipogenes is. T h us, f ruc to se stim u lated lipogenes is f rom ace tatein ch ick liv e r s lice s, bu t no t w h en f ruc to se w as added alone (87 ).U sing th e tn itiated w ate r tech n ique w e w ere unab le to d em on-s trate any increase in lipogenes is in perf u sed liv e rs f rom f ed ratsin th e presence o f phy s io log ical concen trations o f f ruc to se (13 ).

It is lik e ly that if f ruc to se w ere adm in iste red w ith an equalam oun t o f g lucose , there m igh t w e ll be increased lip ogenesis ,particu larly if th is w as accom pan ied by a rise in in su lin concen -tration.

Im m e d ia te e ffe c ts o n fa tty a c id o x id a tio n a n d e s te rific a tio n a n do n lip o p ro te in fo rm atio n a n d u tiliz a tio n

A lthou gh f ru cto se d oes no t seem to cau se any m ark ed im m e-d iate in crease in lipogenes is b y itse lf , it does hav e m ark ed andim m ed iate e f f ec ts on th e f ate o f N EFA s . T hese f atty ac id s ariseas a resu lt o f lip id m ob iliz atio n in ad ipose tissue or f rom hy dro -ly sis o f trig ly ceride -rich lipop ro tc in s b y lipo pro tc in lipase . W ees tab lished in the perf u sed rat liv e r that N EFA s, w h ich are tak enup by the liv e r to th e ex ten t o f 3 0 -40% per pass, are e ither ox i-d iz ed or es te rif ied (88 , 89 ). A n inv erse relationsh ip w as dem -on strated be tw een the quan tity o f f atty ac id s ox id iz ed to carbond iox id e and k c tonc bod ie s on th e one hand , an d those es te rif iedin liv e r acy lg ly ccro ls an d in V L D L S o n th e o ther. R egu latio n o fth is balance co n tro lled bo th k e togenes is an d V L DL secre tio n ina rec ip ro cal m anner. For a g iv en load o f f atty ac id s tak en up b ythe liv e r, liv e rs f rom f ed an im als ox id iz ed le ss f atty acid s bu te s te rif ied m ore than d id liv e rs f rom s tarv ed an im als , d em onstrat-ing that a m echan ism ex is ts, w h ich is af f ec ted by the nu tritio nalstate , f o r reg u lating th e partition o f f atty acid s be tw een these tw om ajor pathw ay s . W e sh ow ed (89 ) that liv e rs f rom f asted an im alsm ain tain ed a cons tan t f rac tio nal rate o f c s tc rif ication irre spec tiv eo f the N EFA load , dem ons trating that g ly cero l-3 -pho sph ateav ailab ility co u ld no t h av e been rate lim iting in f atty ac id este r-if ication . I t has now been f irm ly es tab lished th at the regu lato rysite f o r co n tro llin g th e balance be tw een o x idation and este rif i-catio n lie s in the ox idativ e pathw ay , w here long -chain acy lg roups en te r th e m itochond rio n (90 ). T he rate -lim iting s tep inm itochond n ial ox idation o f lo ng -chain f atty ac id s is cataly z ed bypalm ito y ltran sf e rasc I. Fatty ac id s f ailing to en te r th e m ito ch on -dna f o r ox idation do no t accum u late bu t are es te rif ied im m ed i-ately . Palm itoy ltrans f c rasc I is inh ib ited b y m alony l-C oA (9 0 ),w hose concen tratio n increases in the f ed con d ition w hen there isac tiv e lip ogcnesis . T h is can ex p lain the change in balance b e-tw ecn es te rif icatio n and ox idation o f f atty acid s be tw een liv e rso f f ed an d s tarv ed an im als .

T o test w he ther f ruc tose and in su lin had d irec t and im m ediatee f f ec ts o n V L D L secre tion by the liv e r, w e p erf u sed liv ers f romf ed rats w ith w ho le b loo d in to w h ich [4C ]o leate N EFA w as in -f u sed to m ain tain a cons tan t ph y sio log ical concen tration (46 , 91 ).Increased con cen trations o f in su lin or an in f u s io n o f a ph y sio -lo g ical quan tity o f f ruc to se decreased ox id ation and in creasedesten if ication o f f atty ac id s and secre tio n o f V L D L trig ly ceridef rom the liv e r. W hen in su lin w as added tog e th er w ith f ruc to se ,the separate e f f ec ts w ere ad d itiv e w ith a f u rther decrease in ox -id ation and en hancem en t o f e sten if ication an d V L D L secre tio n .M alony l-C oA is the product o f accty l-C oA carbox y lase ac tiv ityan d it is k now n that th is enz y m e is ac tiv ated by co v alen t m od i-f ication b y in su lin and inh ib ited by g lucagon (92 ). T here f o re ,in su lin and f ruc to se can ind ep en den tly increase th e concen tratio nof m alony l-C oA . Fru c tose m ay also enhance esten if ication byrais ing the co ncen tration o f g ly ccro l-3 -phosphate (93 , 9 4 ) al-th ough th is seem s un lik e ly if ph y sio log ical concen tratio ns o ff ruc to se do no t in f ac t in f luence the con cen tration o f th is in te r-m ed iate (8 2 ). A lso , w e hav e show n th at m itocho ndn ial g ly cero lphosphate acy ltrans f e rase ac tiv ity is enhanced by in su lin (95 ) ,


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M ETABOL ISM OF FRUCTO SE 759Sand th is cou ld a lso acco un t fo r a d irec t e ffec t o f insu lin in p ro -m o ting es te rifica tion and V LDL secre tion .

T hese effec ts o f fruc tose o n N EFA m etabo lism are u n ique toth is su gar. In a d irec t com parison w ith g lu co se , the e ffec t o f anin fu sion pro v id ing phys io log ica l concen tra tio ns of fruc tose in theperfusate o f the perfused live r w ere com pared w ith a com parab lein fu sion of g lu co se . O nly th e fruc to se in fu sion boosted[4C ]N EFA es ten ifica tio n and [4C ]VLDL secre tion (46 ). W hens im ila r am oun ts o f th e tw o sug ars w ere then in fused sim u ltane-ously to s im ulate sucro se d iges tio n and absorp tion , the re w ereno fu rthe r inc reases in N EFA es te rifica tio n or sec re tion as VLD L .P erfus ions w ere a lso carried ou t (73) to tes t th e e ffec t o f a f ruc -tose concen tra tio n above the phys io log ica l rang e (8 .9 mm ollL )ag ains t a co ncen tra tion w ith in th e phy sio log ica l range (1 .5 mm ol/L ). A t th e h igh er co ncen tra tio n , V LD L p ro duc tion w as cu t toone-th ird of the am oun t fou nd und er th e p hys io log ical concen-tra tion . B ecause lipopro te in produc tion is a com plex en ergy-re -quin in g p roc ess , th e low e r A TP ava ila b ili ty associate d w ithh ig h-fruc tose concen tra tions (76 ) w as pro bab ly the reason fo r theredu ced V LDL ou tp u t u nder these cond itions .

W hen a 20% fruc to se so lu tion w as g iven in trav enous ly , serumtrig lycerides decreased in fem ale baboons bu t in creased in m ales,w hereas a com parab le so lu tion of g lucose caused a decrease inbo th sex es (96). A ltho ugh the increase in trig lycerid es is m os tl ikely the resu lt o f a d ire ct e ffe ct on th e liv er, a s d esc ribed ab ov e,the fall in trig lyce rid e co ncen tratio n is p rob ab ly du e to a d ecre asein NEFA concen tra tion , w hich in tu rn p rov ides less N EFA sub-stra te fo r the live r and there fo re less VLD L produc tion . In h u-m an s, fruc tose cau ses a d ecrease in NEFA s w ith little chang e inin su l in concen tra tion s (97), ind ica ting th at any reduced secre tio nof V LDL is d ue to decreased N EFA ava ilab ility and any in -creased secre tio n is m ost like ly due to the d irec t hepa tic ac tio nof fru ctose . T he n et ou tpu t o f V LDL by th e live r is the re fo re aba lance be tw een th ese tw o oppos in g effec ts o f f ruc tose .

F ruc tose is bo th an tik etog en ic and k etog en ic depend in g on thecircum stances . In v ivo , in th e sta rved s ta te , a ph ysio log ica l in takeof fru ctose is an tike to gen ic . T h is is nearly a lw ay s due to its in -h ib ition of N EFA m obiliza tion from ad ipose tis sue (9 7), w h ichresu lts in reduced up take of the m ain ke to gen ic subs tra te by thelive r. It app ears th at th e re is a lso a d irec t an tike togen ic e ffec t o ffruc tose o n th e live r, a s dem on stra ted in v ivo in th e presen ce ofa cons tan t p lasm a NEFA concen tra tion (98 ). S im ila r experim en tshave been carried ou t in the perfused liv er and iso la ted h ep ato -cy tes in the pre sen ce o f add ed N EFA (72 , 84 , 91 , 99 , 10 0). M o sto f these ex perim en ts w ere carried ou t in the sta rved sta te . It isunc lea r w he ther o r n o t m alony l-C oA inh ib ition of ca rn itine p a l-m itoy ltransfe rase I can exp la in these resu lts . It w ou ld requ ire theimm ed iate a ctiv ation o f acc ty l-C oA carb oxy lase , w h ich has no tbeen rep orted under these co nd itio ns. A ltho ugh g lyccro l-3 -phos-pha te av a ilab ility does no t ap pear to be rate -lim iting on este rifi-cation of N EFA S , it is possib le tha t b oos ting its concen tra tionabove th e norm al concen tra tion as a resu lt o f fruc tose m etabo lismcou ld cause a grea ter frac tiona l esten ifica tion of NEFA s and lessox ida tion to ke to nc b od ies (98).

T ha t fruc tose can a lso be ke togen ic w as firs t shown in perfu sedlive rs from sta rved ra ts in fused w ith the sugar a t 2 0 mm o llL (72) .T he phen om enon w as a lso dem onstra ted w ith live rs from fedan im als by us ing low er b u t still unphy sio log ica l concen tra tio nsof fruc tose (73 , 101). T o tes t w he ther th is ef fect cou ld be ob-tam ed w ith fruc tose w ith in phys io log ica l concen tra tions w e stud -ied ke togenes is in p erfused live rs from fed an im als and show ed

tha t ke togenes is p rogressive ly in creased as the con cen tra tion offru ctose w as ra ised (13 ). A t 1 .5 mm o l fru ctose /L , the re w as as ig n ifican t inc rease com pared w ith con tro l pe rfu sions in the ab-sen ce of fruc tose . S om e of th ese stud ies a lso u sed [4C ]fru c to sc .A t 20 mm o l/L , a ll o f th e ca rbon a tom s fou nd in k e to ne b od ie scam e from fruc tose (72) w hereas at 8 .9 mm ol/L , ha lf cam e fromfru ctose and a t the phy sio log ica l concen tra tio n of i .5 mm o l fru c-tose /L , 1 5% of the carbo n atom s orig ina ted from fru ctose (73).

R ad io lab eled fruc tose h as a lso b een used to fo llow the cou rsetaken by the sugar in the various m etabo lic pa thw ays . In itia lly ,the re is no d ilu tion of fru ctose labe l because the re is no endog-enou s poo l o f free fruc to se , bu t as fruc tose is conv erted in toin term ed ia tes comm on w ith g lu cose and fa tty ac id m etabo lism ,th e lab el is ex tensive ly d ilu ted . T here fo re , a lthough it is no t p os-s ib le to quan tify th e fa te o f fruc tose in a w hole an im al o r tissuew ithou t k now led ge of the spec ific rad ioac tiv ity o f in te rm ed ia rypo o ls, som e idea m ay b e ob tained of the fa te o f adm in iste redfru ctose . T hus , w hen the m etab o lism of sta rved ra ts g iven e ithe r[U -4C ]g lucosc o r [U -4C ]fruc to se by gas tric in tub ation w as com -pared , it w as show n th at a lthou gh 2 .5 tim es as m uch n ew lysyn thesized trig lyceride cam e from to ta l bo dy g lucose as fromadm in is te red fruc to se , tw ice as m uch of th e adm in iste red fruc tosefo rm ed tr ig ly cerid e com pared w ith a s im ila r quan tity o f adm in-iste red g lucose (102 ). T h ese da ta re flec t the fac t tha t fruc to se istaken up pred om inan tly by the live r w hereas g lucose is u tilizedm ain ly by th e ex trahepa tic tis sues . In live r slices , rad io labe ledfru ctose is co nverted to lac ta te , py ruva te , ca rbon d iox ide , andtrig lyceride m ore rap id ly th an is g lucose (1 03). S im ila r resu ltshave been rep orted fo r incorpo ra tion in to p lasm a lip ids ing u inea p igs (104) and b ab oons (105). A fte r adm in istra tio n of[4C }fruc tosc , m ore rad ioac tiv ity is foun d in g lyceride g ly cero lthan in the fa tty ac id portions of hepa tic trig lycer id e (10 2 , 103 ),d ue in part to g rea te r d ilu tion and ex ch ange o f labe l in the p a th -w ay from fruc tose to lo ng-cha in fa tty ac ids than in tha t to g lyc-e ro l-3 -pho spha tc (F ig 1). W hen [U -4C lfruc to se w as in fused tom ain ta in a concen tra tion of 1 .5 mm ol/L in the perfusa te o f liv e rsp repared from fed ra ts, 12% w as ox id ized to carbon d iox ide and2 .4% w as conv er ted to ke tone b od ies; 4 .1% w as in live r lip ids,1 .6% w as inco rpora ted in to V LD LS, an d on ly 0 .4% w as in to ta lcho les tero l (13) . A s the fruc tose load w as increased , p ro portion -a lly less o f the labe led fruc to se en te red lip id produ c ts excep t fo rk eton e bod ies , w h ich rem ained the sam e. T hus , ke tonc bod iesand lac tate ac t as overflow s o f excess ca rbon as fru c to se sa tu ra testh e m etabo lic p athw ays . H ence , ke tone bod ies fu lfill a s im ila rro le in the live r w ith respec t to ca rb ohyd ra te as they do w henfa tty ac ids a re p resen t in excess .Long-term effects of a high fructose intake

Enzym e adap ta tion is a lso resp ons ib le fo r m any of the long -te rm effec ts o f a h ig h-fruc tose d ie t o n lip id m etabo lism . as w ellas fo r the long -term effec ts on carb ohyd ra te m etabo lism . In thelive r, fru ctok inase ac tiv ity in creased in ra ts on a fru ctose -rich d ie t(106) . F ru c to se or sucro se feed ing also increased the ac tiv ity o fg lycero l-3 -ph osp ha te dehy drogen ase , w hich is necessa ry fo r theco nvers io n of fruc tose to g ly cero l-3 -pho sph ate v ia the g lyco ly ticin te rm ed ia te d ihydro xyace to ne phosp ha te (10 7 , 10 8). A fte r 50 don a fruc tose d ie t, bu t n o t o n a su crose d ie t, p y ruva te k inase inra ts inc reased sub stan tia lly (109). S im ilar ly fruc tose d iets in -creased live r PDH activ ity in ra ts (1 10 ). In the pa thw ay of lipo -genesis and trig lycer id e fo rm atio n , A TP -c itra tc ly ase (108 , 1 11 ,11 2), ace ty l-C oA carboxy lase (11 1-113 ), fa tty acid syn thase


7/12

760S MAYES(1 1 i-i 14 ), an d p hospha tid a te pho sphohydro lase (1 15) a re re-po rted to b e increased in ac tiv ity in an im als on fruc tose -co n tain -ing d ie ts . A lso , th e enzym es respon sib le fo r g en eration of red uc-ing pow er fo r lipo gencsis -g lucose-6 -pho sph atc dehy drog en ase(10 7-10 9 , iii, 112 , 116 ), 6 -p hosphog lu co na te d ehydro gcnase(10 7 , 108 , 1 1 1 , 1 1 2), and NAD P m ala te dehydro genase (m alicenzym e) (10 7 , 1 1 1, 1 12 , 1 16)-a re a ll inc reased in ac tiv ity .M any o f these adap tive changes in live r enzym e ac tiv ity arc no tun ique fo r fru ctose because g lucose feed ing w ill a lso inc reasethe ir ac tiv itie s (10 7), illu stra tin g th at th is is a m o re genera l ef fec to f so lu b le ca rbohydra tes . O f co nside rab le in te res t is tha t sucroseor fruc tose feed ing redu ces the activ itie s o f hexok inase , pyruv atek inase , PDH , ATP -c itrate ly ase , ace ty l-C oA carboxy lase , fa ttyacid syn th ase , g lu cose -6 -phospha tc dehy drogen ase , and NAD Pm ala te dehyd rogenase in ad ipo se tis su e , w h ereas feed ing g lucoseor sta rch enhances th eir ac tiv itie s (5 2). It w ou ld appear from arev iew of these enzym e ac tiv itie s tha t lipogenes is is e lev a ted inthe live rs bu t d ep ressed in ad ipose tissue o f sucro se - o r fruc tose -fed an im als. In keep ing w ith th is conc lus io n the co ncen tra tion sof th e fo llow ing in term ed ia tes in the live r a re e lev ated : pyruva te,m ala te , acc ty l-C oA (1 17 , 1 1 8), ace toace ty l-C oA , an d long-ch a inacy l-C oA (1 17). H ow ever, g lycero l-3 -pho spha te con cen tra tionsapparen tly d o no t inc rease (11 9).

B iosyn thesis o f long -cha in fa tty ac ids (lipog enesis) has b eensh own to increase in live r slices from ra ts fed e ith e r fruc tose(120) o r su crose (121 , 122), as m easured d irec tly by u sing la -be led ace ta te o r tritiated w ate r. Inc reased incorporation o f lab eledfruc tose has a lso been show n (11 8 , i23 ). In the whole an im al,incorpora tion of tritia ted w ate r in to live r fa tty ac ids w as e lev atedin ra ts fed fruc tose com pared w ith those fed g lucose (12 4). A lso ,F4C ]fruc tosc w as incorpo ra ted m o re rap id ly in to fa tty ac id s andacy lg ly cero l g lycero l in p lasm a and live r in ra ts on a fruc tosed iet than in ra ts on a g lucose d ie t (12 5).

In iso la ted live rs perfused w ith w hole b lood , w e s tud ied li-pogenes is in ra ts tha t h ad b een fed the s tan dard lab ora to ry d ieto r a sucrose -su pp lem en ted d ie t (13 , 1 26). H a lf the perfu sionsw ere in fu sed w ith fruc tose to m ain ta in a p hys io lo g ical pe rfusatecon cen tra tion of 1 .4 mm olfL . Incorporation of 3H 2O in to live racy lg lycero l fa tty acids in c reased sign ifican tly on ly in the grou po f p e rf us io n s in w hich fruc to se w as in fu sed in to sucrose -fed ra ts.Th us, lipog en es is is inc reased on sucrose d ie ts bu t on ly w henfruc tose spec ifica lly ac ts as th e subs trate . T h is find in g is sim ilarto tho se found in live r s lices f rom ra ts on a g lu co se d ie t, w h ichenh an ced se lective ly the convers ion of [4C ]g lucose to fa tty ac-id s, bu t no t 4C jf ruc tose , a nd w he re slices from rats o n a f ruc tosed ie t se lec tive ly incorpo ra ted [ 4C jfru ctose in to fatty ac ids bu t no t[4C ]g lucose. T hey dem ons tra te th e h igh ly specific and se lec tivena tu re o f the lipogen ic adap ta tio ns to d iffe ren t sug ars in the d ie t,c lea rly b ased on th e enzym e ad ap ta tions prev io usly d iscu ssed .

P lasm a trig lycerides inc rease in b o th hum ans and ra ts w hend ie ts a re en rich ed w ith carbohydra te , esp ec ia lly sucrose and fruc-tose (12 7). T h is has been , and s till is , o f cons id e rab le in te rest inv iew o f the fac t tha t ra ised co ncen tra tion s of p lasm a trig ly ceridem ay be an independen t fac to r assoc ia ted w ith coronary hear t d is-case (128). T he adap tive changes in en zym e ac tiv ity , ev idenceof inc rease in lipog en ic po ten tia l, p lus the d irec t ac tions of fruc -tose prev ious ly d esc ribed , a ll lead to inc reased ou tp u t o f V LDLtrig lyceride from the live r, inc reasing the am oun t in the circu la -tio n . T he resu ltan t concen tra tion of trig lyceride a lso depen ds onthe ra te o f hy dro lys is by lipopro tein lipase and any im pairm en to f th is en zym e w ould a lso lead to inc reased concen tra tions of

p lasm a trig lyceride (129) . H ow ever, long -term fru ctose or su -c ro se feed in g resu lts in hyp er in su linem ia (55-58) a nd in cre ase sp ost hepan in lipo ly tic ac tiv ity , in d ica ting an enh an cem ent o f li-p opro tc in lip ase ac tiv ity (5 2). T here fo re , ra ised p lasm a concen-tra tions of trig lycerid e in fruc to se - o r sucrose- fed an im als, in -c lud in g hum ans , re flec ts an in creased ra te o f V LDL secre tion bythe live r to ge ther w ith an increased ra te o f VLD L ca tabo lism .

F ruc tose feed in g en hances the re lease of N EFA s from ad iposetissu e (60 ), inc rea sin g its p lasm a con cen tra tio n (6 0 , 6 1), be cau seof a decreased rate o f re -es te rifica tion o f N EFA s w ith in ad iposetissue (69). E s ter ifica tion of N EFA s in ad ipose tis sue depend s ong lu co se u tiliza tion , w hich is d ep ressed u nder cond itions of fruc -tose feed ing . N EFA s are th e m ajo r p recu rso rs o f V LDL tr ig ly c-e ride in th e live r (71). T here fo re , th ey w ill augm en t V LDL for-m atio n in an im als on h ig h-fruc tose or -sucro se d ie ts . M indfu l o fthe fac t th at NEFA s arc a lw ays presen t in p lasm a , w e s tud ied theeffec ts on VLDL secre tion o f a phys io log ica l in fus ion of fruc -tose , and o f sucrose su pp lem en tation o f the d ie t, in iso la ted per-fu sed live rs in fused w ith [1 - 4C ]o lea te N EFA (126). V LDL tn-g lyceride pro duc tio n increased in bo th the liv ers in fu sed w ithfruc tose a lo ne an d in those d er iv ed from sucrose- fed rats . W henliv ers from sucro se -fed an im als w ere in fused w ith fru c to se , thera te o f sec re tio n m ore than doub led . B ecau se sh if ts in b alancebe tw een ox ida tion and esten ifica tio n of N EFA s in the d irec tio nof esten ifica tion h av e been show n to increase sec re tio n of V LDLtrig lycer id e (89) , w e also m easured these indexes. O xida tion of[ 4C ]o lea tc to 4C 0 w as h ig hest and esten ifica tion w as low es t incon tro l p erfus io ns when liv e rs from norm al an im als w ere used .F ru ctose in fu sion or sucro se feed in g sh ifted th e b alance in favoro f es ten ifica tio n and in creased ou tpu t o f [4C ]V LDL . T he corn -b ina tion of fruc to se in fusion p lus sucrose feed in g show ed thelow es t ra te o f o x ida tio n and the h igh est ra te o f es ten ifica tion andou tpu t o f [ 4C ]V LDL . T he m arked ex tra inc rease in V LD L ou tp u tin th e com bined group w as prob ab ly due to in creased lipogenes isfrom fruc tose in th is g roup (13 , 126) .

T he po ten tia l adverse e ffec ts o f f ruc tose on lip id m etabo lismin hum an s has b een rev iew ed (13 0 , 131 ). It w as co nc lu ded froma rev iew of a la rge num ber of s tu d ies th at n orm al ind iv idua lsconsum ing d ie ts con ta in ing average q uan titie s o f f ruc tose havenorm al fasting trig lyceride concen tra tio ns. H ow ever, th is is on lya m easure of tr ig ly ceride c lea rance and do es no t g ive in fo rm ationon prand ia l and p ostp ran d ial con cen tra tions of tr ig ly cerides ,wh ich m igh t be ra ised o n these d ie ts . T he cond ition w as exac-erba ted in ind iv idu als hav ing d efec ts in ca rbo hydra te m etabo lismlead ing to hypertn ig lycen idem ia , even w ith low in takes of fru c-tose . S im ila r co nc lusion s app ly to p lasm a cho les tero l, w h ich m ayincrease if h ig her than norm al am oun ts o f V LDLS arc presen t. Inadd ition , th e com bina tio n of sa tu ra ted fa t an d fruc tose in the d ie tw ou ld appear to favor e leva ted ch o les te ro l concen tra tio ns.

E ffec ts o f fruc to se o n pu rin e m etabo lism

The hyperu ric em ic e ffe c t o f fru c to seIt w as fir st reported (13 2) th a t w hen fru c to se w as adm in is te red

in travenous ly to b o th norm al ch ild ren and those w ith h ered ita ryfru ctose in to le rance , the re w as an increase in serum and urina ryuric ac id . T he hyperu n icem ic effec t ap pears to b e d ose depen den tand the fruc tose in fusio n needs to be > 0 .5 gkg body w t to cause d etec tib le hyperun icem ia . A lso , the e ffec t is fruc tosesp ec ific becau se com parab le in fus io ns of e ithe r g lucose o r ga lac-


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METABOL ISM OF FRUCTO SE

FRUCTOSEIC T 1

FR U C T O S E 1 Pto se do not rais e the p lasm a uric acid con cen tra tion (133) . Pa-tien ts su ffe ring from gou t a rc m o re sensitive to fruc tose adm in-is tra t ion th an a re n orm al sub jec ts, a s a re d iabet ics (1 30) . The seresu lts app ly to fru ctose adm in is te red paren te ra lly , bu t is it p os-s ib le to inc rease b lood u ric ac id concen tra tion s w hen fru c to se isconsum ed o ra lly? T he effec t o f feed ing fruc tose a t a do se of 1 g!kg body w t w as stud ied in hea lth y su b jec ts , in pa tien ts w ith g ou t,and in ch ild ren of paren ts w ith gou t (78). H yperu n icem ia oc-curred in a ll g roup s bu t it w as m ore m arked and p ro long ed inth ose su b je cts , o r o ffsprin g of p aren ts, w ith go ut. Sub jec ts co n-sum ing h igher th an 18% of the ir energ y in take as sucrose (ic ,9% as fruc tose ) show ed s ign ifican t inc reases in se rum u ric ac id(13 0). T hese resu lts sug gest tha t the average in take of fruc toseor sucro se in a m ixed d ie t is on th e b orderline fo r p ro vok inghyp erun icem ia in no rm al in d iv idua ls. N o te tha t g ou ty pa tien ts dohave low er se rum ur ic ac id conccn tra tion s w hen fed low er-fruc -to se d ie ts; e ven h ealthy in d iv idu als m ay be a t risk of h ype run i-c em ia w hen co nsum ing a die t h igh in f ruc tose .

P athways o f a den in e nuc le o tid e ca tabo lism and b ios yn th es isTo understand the m echan ism of the hyp erun icem ic ef fect o f

fruc tose a kn ow ledge of pun in c nuc leo tide m etabo lism and itsregu la tion is n ecessa ry . A d eny la te k inase m ain ta ins equ ilib riumbetw een the aden ine n uc leo tides ATP , adenos inc d iph osp ha te(A DP ), an d adenos in e m onopho spha te (AM P) (F ig 2) . T hus , a llth ree aden ine nuc lco tides a re ab le to be degraded and fo rm ed v iaAM P . H owever, as w ith m any o ther comm on m etabo lite s, thepa thw ay o f d egrada tio n of ad en ine nu cleo tid es is n o t th e sim plereverse of the pa thw ay of b io syn the sis. In the deg rad ative p ath -w ay, ino sine m onophosp ha te ( IM P ) is fo rm ed from AM P by theaction of AM P deam inase . P hospha te is then rem oved by 5 -nuc leo tidase to fo rm inos ine . A lte rna tive ly , in osine m ay befo rm ed from AM P via aden osinc b u t ex perim en ts in iso la ted h e-pa tocy tes (31 ) have in d ica ted tha t th is is no t as im po rtan t a ro u tefo r AM P degrad ation as tha t v ia IM P. In add ition , th e reactionca ta ly zed b y AM P deam in ase appears to be the ra te -lim itin g stepin the b reak dow n o f hepa tic aden inc nuc leo tides (13 4-136 ), andP i a t norm al in trace llu la r co ncen tration s is an im po rtan t in h ib ito ro f th is enzym e. Inos in c is b ro ken dow n to uric ac id v ia hy po-xan th ine an d xan th inc . In hum ans an d o ther p rim ates th is is thee nd p ro du ct o f purinc m etabo lism and is excre ted as such , bu to the r m amm als p ossess th e en zym e un icase , w hich a llow s fu rthe rox id a tion to the m uch m ore so lub le a llan to in . A consequ en ce ofthe absence o f u n icase in h um ans is the o ccu rrence of go u t, w h ichis asso cia ted w ith hypcru n iccm ia .

IM P is a lso the firs t fo rm ed pun ine nuc leo tid e in the p athw ayof de novo syn thes is from nibose 5-ph osp ha te . T h is pa thw ay in -vo lv es n o less than 1 1 separa te steps (1 37). O f these, o n ly thefirs t tw o need to b e m ention ed becau se they ca ta lyze the ra te -con tro lling reac tions , bo th o f w hich are he ld in ch eck by a feed -back reg u lation because of h igh concen tra tio ns of pun in c nude-o tides . In add ition , 5 -p hosphon ibo sy l-1 -pyrop hospha tc (PRPP ),the prod uc t o f the firs t reac tio n in the pa thw ay is an allos ten icac tiv a to r o f the seco nd reac tion in the pa thw ay ca talyzed b yPRPP glu tam yl am ido transfe rase (F ig 2 ).

M echan ism unde rly in g the hype ru ricem ic ac tion o f fru c to seThe essen tia l find in g tha t led to the exp lan ation as to why

fru c to se adm in is tra tion cau sed increased uric ac id fo rm ation w asthe ob serva tion th at it w as accom pan ied by a sharp fa ll no t o n ly

76 lS

e 3.f

AM P+ A TP 1 2 A D P

A denosine A denylo- IMP4 9 steps

Inossne 5-P hospho-p ribo sylam ineA T P

MJd IEOS1O#{ 128 } A M P. G M P I4

P RP P G L. UT AM Y I.H y p o x a n t h i n e M4IDO TR4j:ER*.SEA

XANTHINE

(O) D A S E ) P R P PA M P . A DP . A lP

X anthine S_____________ 4X A N T H I N E I P R P P

o&{ DmGB SYN ETASE( O X I D A S E )

U ric acid R ib ose 5-PF IG 2. Th e re la tion sh ip be tw een fruc tose m etabo lism and u ric ac id

fo rm ation in th e liv e r. P . phospha te ; AM P, aden osine m onophospha te:ADP , adenos ine d iph osp hate; A TP , adenos ine tr iph osp hate; P i , o rg an icph ospha te; GM P , gu an osine m onophosp ha te; PRPP , 5 -ph osp honib osy l-1 -pyrophospha te; IM P , inos ine m onopho sp hate .

in hepa tic A lT concen tra tio n bu t a lso in to ta l aden inc n uc leo tides(76) . T he reason fo r th is becam e apparen t w hen it w as show ntha t fru c to sc -1 -p hospha tc accum ula ted an d P i concen tra tio ns fell(27 ) . T hus , th e sequen ce of even ts a fte r fruc tose adm in istra tioninvo lves rap id p hosphory la tion of the su gar to fruc tose-1 -pho s-ph ate becau se of th e h igh ac tiv ity o f fruc tok inase. T h is lead s todep le tion o f A TP due to in h ib ition of ox ida tive ph osp hory la tionof ADP because of a shortage of P i sequeste red in fru ctose -i-ph osph a te . T he low ering o f A lP co ncen tration is a lso assis tedby the ac tiv ity o f tn iok inase in u tilizing A l? in th e p hosphory -lation of g lycera ldehyde to g lyccra ldehyde-3 -phospha tc . Th e de-p le tion of P i and ATP leads to th e rem ova l o f the a llosten ic in -h ib ition on the enzym es tha t d egrade AM P, respec tiv ely , AM Pdeam inase and 5 -nuc lco tidase . T here is a rise in inos inc con-cen tra tio n th at leads to in creased fo rm ation o f u ric ac id w ith d e-p le tion of the to ta l aden in e n uc leo tide p oo l.T he dep le tio n o f aden in e nuc leo tides a lso leads to s tim ula tionof the pa thw ay of pun ine nuc leo tide sy n thesis as a feedback re-ac tio n (F ig 2). T he low ering of th e co ncen tration of aden ine nu-c leo tid es rem oves the a llos ten ic inh ib ition of the firs t tw o stepsin the pa thw ay ca ta ly zed by PR PP syn the tase and PRPP glu tam ylam ido transfe rase . T he p roduc tion of PRPP ac ts as a fu rth e r ac-tiva to r o f PRPP glu tam yl am ido transfe rase , lead ing to IM P syn-thesis . If 5 -nuc leo tid ase is s till ac tive , IM P w ill be d egraded touric ac id ra the r than converted to AM P . In th is w ay the in itia lp ro duc tion of u ric ac id from the aden ine nuc lco tidc poo l is aug-m en ted b y dc n ovo sy n thesis .


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quan titie s o f fruc tose m ay be at inc reased risk .

T he redu ction in con cen tra tion of A TP and o ther h igh en ergyphospha tes has o th er p ro found effec ts on m etab o lism and o th erfunc tions dependen t o n a con tin ua l sup p ly of these v ita l sourceso f f ree energy , eg , inh ib ition of p ro te in (76 ) and nuc le ic ac idsyn th es is (1 38).

S umm ary and co nc lu sionsM any in vestiga tio ns bo th in v ivo an d in v itro have been carried

ou t b y us ing unphysio log ica l co ncen tra tion s of fruc tose. D educ-tions m ad e from such observa tions can be m is lead ing , particu -la rly w h en app lied to hum ans con sum ing norm al quan titie s o fsucrose and fruc tose . T h is aspec t has been tak en in to accoun t incom pilin g th is rev iew .

Spec ific en zym es in the live r- fruc tok inase, a ld o lase B , andtn iok in ase -a llow fru ctose ready access to the tn iose ph osp ha tep oo l and a ll pa thw ay s lead ing from it, af te r bypassing the ph os-p hofruc tok in ase regu la to ry step in g lyco lysis . In the fed s ta te ,th is a llow s a grea te r sa tu ra tion o f th e g ly co ly sis pa thw ay w ithconseq uen t lac ta te p roduc tion , ac tiv ation of PDH , an d dom i-n an ce of the ox ida tive pa thw ays lead ing to carbo n d iox id e fo r-m ation and ke tone body produc tion w hen under fruc tose load .G lucose produc tion , g ly cogenesis , and lipo genesis a re no t en -h an ced bu t th ere is an imm edia te sh if t in the ba lance be tw eenox ida tion and esten ifica tion of N EFA s in favor o f es ten ifica tion .T h is leads to augm ented o u tpu t o f V LDLS from the live r. In thelive r o f sta rved an im als , the enzym es of g lu coneogenes is a re ac -tive an d fruc tose w ill fo rm m uch m ore g lucose un der th ese con-d i t ions .

A s a resu lt o f en zym e adap ta tio n to th e long-te rm feed ing offruc to se or sucrose d ie ts , the pa tte rn of fruc tose m etabo lism ischang ed . E nh an ced ac tiv ity o f fruc tose-1 ,6 -b isp hospha tase , g ly -cog en syn thase , an d g luco se-6 -p hospha tase a llow m o re fruc to seto fo rm glycogen and g lucose . E nhanced ac tiv ity o f lip ogen icenzym es in the liv e r, bu t no t in ad ipose tissue , stim ula tes lon g-cha in fa tty ac id syn thesis, w h ich au gm ents the imm ed ia te h ep aticac tio ns of fru cto se in p rom oting VLDL trig lyceride o u tpu t. T h islead s to hyp ertn ig ly cen id em ia . F ruc tose m etabo lism in ad iposetissue a lso cau ses im pa ired g lucose u tilization an d im pa ired es-ten ification o f fa tty ac ids, w h ich prom otes release of N EFA s w ithconsequen t ra ised p lasm a NEFA concen tra tion s and increasedV LDL p roduc tion . T he increased trig ly cer id e and N EFA con-cen tra tio ns im pa ir u tiliza tion of g lucose in m uscle , decreas ingg lucose to le rance and in creas ing insu lin res istance w ith conse-qu en t hy pen insu linem ia . T h is , in tu rn , w ill stim ula te the a lread yincreased V LDL p roduc tion by th e live r. B ecause VLDLS con-tam 20% cho leste ro l, the re is a co rrespo nd ing rise in p lasm acho les te ro l, w ith little ch ange in LD L cho leste ro l.

A cu te lo ad ing of th e live r w ith fruc to se is a lso a cau se ofhyp erun icem ia . T h is is due to u tiliza tion of A l? in the phospho -ry la tio n of fruc tose an d seques tra tion of P i in fru ctose -1 -p hos-pha te , p reven ting o x ida tive regenera tion o f A lT from AD P. B e-cause the enzym es o f ad en inc nuc leo tide d eg rada tio n are inh ib -ited b y A lT and P i, rem ova l o f the inh ib ition lead s to des tru c tionof the to ta l aden inc nu cleo tide poo l and g en eration of u ric ac id .

B o th the hyp er lip idem ic an d hyperu ricem ic ef fects o f fruc tosecan b e dem on stra ted in hum an s. A lth ough these effec ts seemm in im al in h ea lthy in d iv idua ls o n no rm al d ie ts , ind iv idua ls o nvery -h igh -fruc tose d ie ts and ind iv idu a ls w ho are ac tua lly o r p0-ten tia lly hyperlip idem ic or h yperun icem ic w ho take in average

It w ill be app aren t th a t a lthough there have been no tew orthycon tribu tions o n fru ctose m etab o lism in hum an s, m os t inves ti-ga tions hav e been car ried ou t in laborato ry an im als, pa rticu la rlyra ts. T h is is inev itab le w hen prec ise in fo rm ation abou t in trace l-lu lar p rocesses is req u ired , invo lv in g in vasive an d critical p ro -cedures . It is c lea r tha t sys tem atic in vestiga tio ns in hum an s areneeded to ascerta in the p recise am oun ts , bo th of fruc tose con -sum ption and of its con cen tra tion in th e b lo od , a t w hich dde-ten ious e ffec ts such as hy perlip id em ia and hyperun icem ia o ccur .N uc lea r m agne tic reso nance spec trosco py is c lea rly o f v alue asa n on invas iv e techn iq ue in m onito ring in trace llu la r ch an ges inthe co ncen tra tion of key m etabo lites . U

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68 . V r#{225}naA , P oledne R , F abry P . K azdov#{225} L . Pa lm ita te and g lucoseox ida tio n by diaph ragm o f ra ts w ith fruc tose indu ced hyper trig ly -cen id em ia. M etabo lism i9 78 ;27 :88 5-8 .

69 . V r#{ 225} na, Fabry P . S labochov #{22 5} Z , K azdov #{22 5}L . E ffec t o f d ieta ryfru cto se on free fatty ac id re lease from ad ipo se tissue and serumfre e fatty ac id con cen tra tio n in the ra t. N u tr M etab l974 ;i7 :74 -8 3 .

70 . B jo rn to rp P , S j#{246} strOm L . C arbohyd rate s to rage in m an: spe cu-la tio ns an d som e qu an tita tive con sid era tio ns. M etabo lism 1978 ;2 7 : 1 8 5 3 - 6 5 .

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79 . R om so s D R , L ev eille G A . E ffect o f d ieta ry fructose on in v itro an din v ivo fa tty a cid sy n th esis in the rat . B io ch im B iophys A c ta1 9 7 4 ; 3 6 0 : i - i 1 .

80 . Topp ing DL , M ayes PA . E ffects of fruc tose con cen trat ion o n ad -en ine nuc leo tide con cen tra tion s an d py ru vate dehy dro gen ase ac tiv -ity of pe rfu sed rat liver . B iochem Soc T ra ns 1 97 7; 5: 10 01 -2 .

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85. Exton JH , P ark CR . C on tro l o f g lu co neogenes is in live r III . E ffec tso f L - lacta te , p yru va te , fru ctose , g lu cag on , ep inephn ine and ad eno -sine-35 -m onophosp ha te o n g luconeogenic in term ediate s in pe r-fu sed ra t live r. J B io l C hem 1969 ;24 4:1 424 -33 .

86 . M cG a rry JD , Takab aya sh i Y , F oster DW . T he ro le of m alony l-C oAin the coord in atio n o f fat ty acid syn the sis an d ox ida tio n in iso la tedra t h epa tocy te s. J B io l C hem i978 ;25 3:8 29 4-3 00 .

87 . G oodnid ge AG . R egu lat ion ofl ipo gen es is. S tim ulatio n o f fa tty acidsy n th esis in v iv o and in v i tro in th e l ive r of the new ly ha tch edch ick . B iochem J 1970;i18 :25 9-6 3 .

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89 . M ay es PA , Fe lts JM . R egula tio n o f fat m etab o lism in th e l iver .N at ure 1 96 7;2 15 :7 16 -8 .

90 . M cG arn y JD , F oster DW . R egula tion of h epa tic fatty a cid ox idationan d ke to ne body produ ction . A nnu R ev B iochem 1980 :4 9 :395-420 .

91 . Topp ing DL , M ay es PA . T he imm edia te e ffec ts o f insu lin an d fru c-tose on th e m e tab o lism of the p erfu sed liver . C han ges in lip op ro te insecretio n , fa tty acid ox ida tio n and es ten ific ation , lip ogenes is andcarb oh ydrate m etabo lism . B ioch em J 1972:1 26 :29 5-3 11 .

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95. Ba tes E J, Topping D L , S oorann a SP , S ag gerson D , M ay es PA .A cute e ffe cts of in su l in on g lyc ero l ph osp hate acy ltrans fera se ac -tiv ity , k eto genes is an d serum free fatty a cid con cen tra tio n in p er-fused liver . F EB S Le tt 19 77;84 :225 -8 .

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1 02 . M ahuram a Y , M acdona ld I. Inco rpo rat ion o f ora lly adm in isteredg lu co se-U 4C and fruc to se -U 4C in to the trig lyceride of the l iver ,p lasm a and ad ipo se tis su e of ra ts. M etabo lism 1973 ;22 : 1205-15 .

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1 10 . V r#{225}na, R ou lin J, L orie tte C , K azdov#{225}L . B asal pyru va te de-h ydrog enase ac tiv ity in the live r, ad ipose tis su e and bra in of ra ts


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M ETABOL ISM OF FRUCTO SE 765Sw ith fructo se -ind uced hyp en tn ig lyc en idem ia . N utn R ep In t 1 983 ;2 8: i 4 3 7- 4 4 .

1 1 1 . Sh afn ir E , B en chim o l A , O rev i M . H ype rlip idem ia an d

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Am J Clin Nutr 1993 Mayes 754S 65S