Lippincott 6th 5 (1) Biochemistry PDF

The Fe e d–Fas t Cyc le 24 I. OVERVIEW OF THE ABS ORPTIVE S TATE Availability o f...

The Fe e d–Fas t Cyc le 24 I. OVERVIEW OF THE ABS ORPTIVE S TATE Availability o f s ubs trate s The a bs orptive (we ll-fe d) s ta te is the 2- to 4-hour pe riod a fte r inge s tion of a norma l me a l. During this inte rva l, tra ns ie nt incre a s e s in pla s ma glu- 0 cos e , a mino a cids , a nd tria cylglyce rols (TAG) occur, the la tte r prima rily 50 10 a s compone nts of chylomicrons s ynthe s ize d by the inte s tina l mucos a l minute s20 ce lls (s e e p. 228). Is le t tis s ue of the pa ncre a s re s ponds to the e le va te d 40 30 le ve ls of glucos e with a n incre a s e d s e cre tion of ins ulin a nd a de cre a s e d Allo s te ric ac tivato rs re le a s e of gluca gon. The e le va te d ins ulin-to-gluca gon ra tio a nd the and inhibito rs re a dy a va ila bility of circula ting s ubs tra te s ma ke the a bs orptive s ta te a n a na bolic pe riod cha ra cte rize d by incre a s e d s ynthe s is of TAG a nd 0 glycoge n to re ple nis h fue l s tore s a nd e nha nce d s ynthe s is of prote in. 50 10 During this a bs orptive pe riod, virtua lly a ll tis s ue s us e glucos e a s a fue l, minute 40 s 20 a nd the me ta bolic re s pons e of the body is domina te d by a lte ra tions in 30 the me ta bolis m of live r, a dipos e tis s ue , s ke le ta l mus cle , a nd bra in. In Covalent modification this cha pte r, a n “orga n ma p” is introduce d tha t trace s the move me nt of o f e nzyme s me ta bolite s be twe e n tis s ue s. The goa l is to cre a te a n e xpa nde d a nd 12 1 11 clinica lly us e ful vis ion of whole -body me ta bolis m. 10 2 9 3 8 4 II. ENZYMIC CHANGES IN THE ABS ORPTIVE S TATE minute 7 6 s5 to ho urs S ynthe s is o f ne w The flow of inte rme dia te s through me ta bolic pa thwa ys is controlle d by e nzyme mo le c ule s four me cha nis ms : 1) the a va ila bility of s ubs tra te s ; 2) a llos te ric re gula - tion of e nzyme s ; 3) cova le nt modifica tion of e nzymes ; a nd 4) induction- re pre s s ion of e nzyme s ynthe s is , prima rily through re gula tion of tra ns crip- tion. Although this s che me ma y a t firs t s e e m re dunda nt, e a ch me cha - nis m ope ra te s on a diffe re nt time s ca le (Figure 24.1) a nd a llows the body ho urs to days to a da pt to a wide va rie ty of phys iologic s itua tions. In the we ll-fe d s ta te , the s e re gula tory me cha nis ms e ns ure tha t a va ila ble nutrie nts a re ca p- ture d a s glycoge n, TAG, a nd prote in. Fig ure 24.1 allosteric-change in the shape/activity in Control me cha nis ms of me ta bolis m ↑ A. Allo s te ric e ffe c to rs the enzyme a nd s ome typica l re s pons e time s. Allos te ric cha nge s us ua lly involve ra te -de te rmining re a ctions. For [Note : Re s pons e time s ma y va ry e xa mple , glycolys is in the live r is s timula te d following a me a l by a ccording to the na ture of the s timulus a nd from tis s ue to tis s ue.] a n incre a s e in fructos e 2,6-bis phos pha te , a n a llos te ric a ctiva tor of phos phofructokina s e -1 ([P FK-1] s e e p. 99). In contra s t, gluco- ne oge ne s is is inhibite d by fructos e 2,6-bis phos pha te , a n a llos te ric inhibitor of fructos e 1,6-bis phos pha ta s e (s e e p. 121). 321 322 24. The Fe e d–Fa s t Cycle B. Co vale nt mo dific atio n The activity of many enzymes is regulated by the addition (via kinases, Enzyme s that are s uch a s cyclic a de nos ine monophos pha te [cAMP ]-a ctiva te d prote in ac tive in the ir de pho s pho rylate d s tate kina s e A [P KA] a nd a de nos ine monophos pha te -a ctiva te d prote in kina s e [AMPK]) or re mova l (via phos pha ta s e s ) of phos pha te groups from specific serine, threonine, or tyrosine residues of the protein. In the Enzyme s that are inac tive in the ir absorptive state, most of the covalently regulated enzymes are in the de pho s pho rylate d s tate dephosphorylated form and are active (Figure 24.2). Three exceptions are glycogen phosphorylase kinase (see p. 132), glycogen phosphory- lase (see p. 132), and hormone-sensitive lipase (HSL) of adipose tissue Glyc o g e n Glyc o g e n (see p. 190), which are inactive in their dephosphorylated form. [Note: Glyc o g e n p h o s p h o ryla s e s yn th a s e In liver, the phosphatase domain of bifunctional phosphofructokinase-2 kin a s e UDP-Gluc o s e (PFK-2) is inactive when the protein is dephosphorylated (see p. 100).] Glyc o g e n p h o s p h o ryla s e Gluc o s e 1-P C. Induc tio n and re pre s s io n o f e nzyme s ynthe s is Incre a s e d (induction of) or de cre a s e d (re pre s s ion of) Gluc o s e 6-P Gluc o s e P h o s p h o fru c to kin a s e -2 e nzyme s ynthe s is le a ds to cha nge s in the numbe r of do main (he patic ) e nzyme mole cule s , ra the r tha n influe ncing the a ctivity of Fruc to s e 6-P Fruc to s e 2,6-P Fru c to s e e xis ting e nzyme mole cule s. Enzyme s s ubje ct to re gula tion b is p h o s p h a te p h o s p h a ta s e -2 do main (he patic ) of s ynthe s is a re ofte n thos e tha t a re ne e de d unde r s pe - Fruc to s e 1,6-bis -P cific phys iologic conditions. For e xa mple , in the fe d s ta te , e le va te d ins ulin le ve ls re s ult in a n incre a s e in the s ynthe - Glyc e ralde hyde 3-P Dihydro xyac e to ne -P s is of ke y e nzyme s , s uch a s a ce tyl coe nzyme A (CoA) 1,3-bis -Pho s pho g lyc e rate Glyc e ro l-P Glyc e ro l ca rboxyla s e ([ACC] s e e p. 184) a nd fa tty a cid s yntha s e (s e e p.184), involve d in a na bolic me ta bolis m. In the fa s te d 3-Pho s pho g lyc e rate s ta te , gluca gon induce s e xpre s s ion of phos phoe nolpyru- Triac yl- Ho rm o n e - g lyc e ro l s e n s itive va te ca rboxykina s e (P EP CK) of glucone oge ne s is (s e e lip a s e 2-Pho s pho g lyc e rate p.120). Both hormone s a ffe ct tra ns cription fa ctors. Fatty ac yl Co A Fatty ac ids Pho s pho e no lpyruvate III. LIVER: NUTRIENT DIS TRIBUTION CENTER P yru va te (he patic ) kin a s e Lac tate Pyruvate The live r is unique ly s itua te d to proce s s a nd dis tribute CO2 Malo nyl Co A die ta ry nutrie nts be ca us e the ve nous dra ina ge of the gut CO2 P yru va te a nd pa ncre a s pa s s e s through the he pa tic porta l ve in be fore d e h yd ro g - Ac e tyl Co A c a rb o xyla s e e ntry into the ge ne ra l circula tion. Thus , a fte r a me a l, the live r enas e is ba the d in blood conta ining a bs orbe d nutrie nts a nd e le - Ac e tyl-Co A va te d le ve ls of ins ulin s e cre te d by the pa ncre a s. During the a bs orptive pe riod, the live r ta ke s up ca rbohydra te s , lipids , Oxalo ac e tate Citrate a nd mos t a mino a cids. The s e nutrie nts a re the n me ta bo- lize d, s tore d, or route d to othe r tis s ue s. In this wa y, the live r Malate Is o c itrate s mooths out pote ntia lly broa d fluctua tions in the a va ila bility CO2 of nutrie nts for the pe riphe ra l tis s ue s. Fumarate α -Ke to g lutarate CO2 A. Carbo hydrate me tabo lis m S uc c inate S uc c inyl Co A Live r is norma lly a glucos e -producing ra the r tha n a glucos e -us ing tis s ue. Howe ve r, a fte r a me a l conta ining ca rbohydra te , the live r be come s a ne t cons ume r, re ta ining roughly 60 of e ve ry 100 g of Fig ure 24.2 glucos e pre s e nte d by the porta l s ys te m. This incre a s e d us e re fle cts Importa nt re a ctions of inte rme dia ry incre a s e d glucos e upta ke by the he pa tocyte s. The ir ins ulin-inde pe n- me ta bolis m re gula te d by e nzyme de nt glucos e tra ns porte r (GLUT-2) ha s a low a ffinity (high Km ) for phos phoryla tion. Blue te xt = inte rme dia te s of ca rbohydra te glucos e a nd, the re fore , ta ke s up glucos e only whe n blood glucos e me ta bolis m; brown text = is high (s e e p. 97). Additiona l me cha nis ms by which he pa tic glucos e inte rme dia te s of lipid me ta bolis m. me ta bolis m is incre a s e d include the following. [Note : The numbe rs in P = phos pha te ; CoA = coe nzyme A. colore d circle s in the te xt re fe r to Figure 24.3.] III. Live r: Nutrie nt Dis tribution Ce nte r 323 1. Inc re as e d pho s pho rylatio n o f g luc o s e : The e le va te d le ve ls of glucos e within the he pa tocyte (a s a re s ult of e le va te d e xtra ce llu- la r le ve ls ) a llow glucokina s e to phos phoryla te glucose to glucose 6-phospha te (Figure 24.3, ). (Recall tha t glucokinase has a high Km for glucose, is not subject to direct product inhibition, and has a sigmoida l rea ction curve ; see p.98.). * High km > - enzyme requires high concentration to achieve half maximal velocity > - glucokinad act as glucose sens becomes 2. Inc re as e d g lyc o g e ne s is : The conve rs ion of glucos e 6-phos pha te or - > active when to glycoge n is fa vore d by the a ctiva tion of glycoge n s yntha s e , blood giorose is high both by de phos phoryla tion a nd by incre a s e d a va ila bility of glucos e 6-phos pha te , its a llos te ric e ffe ctor (s e e Figure 24.3, ). 3. Inc re as e d ac tivity o f the pe nto s e pho s phate pathway: The incre a s e d a va ila bility of glucos e 6-phos pha te , combine d with the active use of nicotinamide adenine dinucleotide phosphate (NADPH) in hepatic lipogene sis, stimulates the pentose phosphate pathway ([PPP] see p. 145). This pathway typically accounts for 5%–10% of the glucose metabolized by the liver (see Figure 24.3, ). 4. Inc re as e d g lyc o lys is : In live r, glycolysis is significa nt only during the a bsorptive period following a carbohydra te-rich meal. The con- version of glucose to pyruvate is stimulated by the eleva ted insulin- to-glucagon ra tio that re sults in increase d amounts of the regulated e nzyme s of glycolys is : glucokina s e , P FK-1, a nd pyruva te kina s e ([PK] see p. 102). Additionally, PFK-1 is allosterically activated by fructos e 2,6-bis phos pha te ge ne ra te d by the a ctive (de phos phory- lated) kinase doma in of bifunctional PFK-2. PK is dephosphorylated and a ctive. Pyruvate dehydroge na se (PDH), which conve rts pyru- vate to ace tyl CoA, is active (de phosphorylated) beca use pyruva te inhibits PDH kinase (se e Figure 24.3, ). The a cetyl CoA e ither is The ris e in g luc o s e allo ws Glyc o g e n s yn th a s e is ac tivate d pho s ph pho rylatio n by g lu c o kin a s e , Gluc o s e uptake by ins ulin- c o vale ntly (de pho s pho rylate d) and whic h has a hig h Km fo r g luc o s e. inde pe nde nt GLUT-2 is drive n allo s te ric ally (by g luc o s e 6-P). by the ris e in blo o d g luc o s e. Glyc o g e n Gluc o s e 6-P availability LIVER s timulate s the PPP, pro viding 2 Glycogen syntose Glucokinal NADPH fo r fatty ac id s ynthe s is. Glucc o s e 6-P Gl Glu 1 Gluc o s e Gluc o s e 3 4 NH3 (fro m g ut) PP P PPP Pyruvate Py Pyr y uv 7 Amino ac ids Amino Ac tivatio n (de pho s pho rylatio n) 4 7 ac ids o f p yru va te d e h yd ro g e n a s e 8 favo rs ac e tyl y Co A p pro duc tio n. (fro m g ut) Ac e tyl Ac tyll C Co A 7 TCA NH3 Pro te in 5 TCA c yc le inhibitio n at is o c itra te d e h yd ro g e n a s e allo ws us e o f Fatty Fatt Fa atttty ac id 6 Chylo mic ro n re mnants BLOOD ac e tyl Co A in fatty ac id s ynthe s is. 6 VLDL V VLD L LDL L 6 T Triac Tr ria ylg lyc e ro l (TAG) Ac e tyl Co A c a rb o xyla s e Glyc o lys is pro vide s the is ac tivate d c o vale ntly g lyc e ro l bac kbo ne fo r (de pho s pho rylate d) and TAG s ynthe s is. allo s te ric ally (by c itrate ). VLDL (to adipo s e tis s ue ) Fig ure 24.3 Ma jor me ta bolic pa thwa ys in live r in the a bs orptive s ta te. [Note : The a ce tyl CoA is a ls o us e d for chole s te rol s ynthe s is.] The numbe rs in circle s , which a ppe a r both in the figure a nd in the te xt, indica te importa nt pa thwa ys for ca rbohydra te , fa t, or prote in me ta bolis m. Blue te xt = inte rme dia te s of ca rbohydra te me ta bolis m; brown text = inte rme dia te s of lipid me ta bolis m; green text = inte rme dia te s of prote in me ta bolis m. P = phos pha te ; P P P = pe ntos e phos pha te pa thwa y; TCA = trica rboxylic a cid (cycle ); CoA = coe nzyme A; VLDL = ve ry-low-de ns ity lipoprote in; GLUT = glucos e tra ns porte r; NADP H = nicotina mide a de nine dinucle otide phos pha te. 324 24. The Fe e d–Fa s t Cycle Gluc o s e used as a substrate for fatty acid (FA) synthesis or is oxidized for energy in the tricarboxylic acid (TCA) cycle. (See Figure 24.4 for the Glucone oge ne s is Glycoge nolys is central role of glucose 6-phospha te.) Gluc o s e 6-P P e ntos e 5. De c re as e d pro duc tio n o f g luc o s e : Although glycolysis a nd glyco- phos pha te pa thwa y ge ne s is (pa thwa ys tha t promote glucos e s tora ge ) a re s timula te d in live r in the a bs orptive s ta te , glucone oge ne s is a nd glycoge nolys is Ribulos e 5-P NADP H Glycolys is (pa thwa ys tha t ge ne ra te glucos e ) a re de cre a s e d. P yruva te ca rbox- yla s e (P C), which ca ta lyze s the firs t s te p in glucone oge ne s is, is P yruva te Glycoge ne s is la rge ly ina ctive due to low le ve ls of a ce tyl CoA, its a llos te ric a ctiva - (la cta te ) tor (s e e p. 119). [Note : The a ce tyl CoA is be ing us e d for fa tty a cid Glycoge n s ynthe s is.] The high ins ulin-to-gluca gon ra tio a ls o fa vors ina ctiva - tion of othe r glucone oge nic e nzymes s uch a s fructos e 1,6-bis phos- pha ta s e (se e Figure 8.17, p. 100). Glycoge nolys is is inhibite d by Fig ure 24.4 de phos phoryla tion of glycoge n phos phoryla s e a nd phos phoryla s e Ce ntra l role of glucos e 6-phos pha te in me ta bolis m. [Note : The pre s e nce kina s e. of glucos e 6-phos pha ta s e in live r a llows B. Fat me tabo lis m the production of fre e glucos e from glycoge nolys is a nd glucone oge ne s is.] 1. Inc re as e d fatty ac id s ynthe s is : Live r is the prima ry tis s ue for de NADP H = nicotina mide a de nine novo s ynthe s is of FAs (s e e Figure 24.3, ). FA s ynthe s is , a cyto- dinucle otide phos pha te ; P = phos pha te. s olic proce s s , is fa vore d in the a bs orptive pe riod by a va ila bility of the s ubs tra te s a ce tyl CoA (from glucos e a nd a mino a cid me ta bo- lis m) a nd NADP H (from glucos e me ta bolis m) a nd by the a ctiva - tion of ACC, both by de phos phoryla tion a nd by the pre s e nce of its a llos te ric a ctiva tor, citra te. [Note : Ina ctivity of AMPK fa vors de phos - phoryla tion.] ACC ca ta lyze s the forma tion of ma lonyl CoA from a ce tyl CoA, the ra te -limiting re a ction for FA s ynthe s is (s e e p. 183). [Note : Ma lonyl CoA inhibits ca rnitine pa lmitoyltra ns fe ra s e -I (CP T-I) of FA oxida tion (s e e p.191). Citra te , the re by, dire ctly a ctiva te s FA s ynthe s is a nd indire ctly inhibits FA de gra da tion.] a. S o urc e o f c yto s o lic ac e tyl c o e nzyme A: P yruva te from a e robic glycolys is e nte rs mitochondria a nd is de ca rboxyla te d by P DH. The a ce tyl CoA product is combine d with oxa loa ce tate (OAA) to form citra te via citra te s yntha s e. Citra te le a ve s the mitochondria (a s a re s ult of the inhibition of is ocitra te de hydro- Nuc le us ge na s e by a de nosine triphospha te [ATP]) a nd e nte rs the cyto- A g iant lipid dro ple t flatte ns the nuc le us and c yto plas m s ol. Citra te is cle a ve d by ATP-citra te lya se (induce d by ins ulin), at o ne e nd o f the c e ll. producing the a ce tyl CoA s ubs tra te of ACC a nd OAA. The OAA is re duce d to ma la te , which is oxida tive ly de ca rboxyla te d to pyruva te by ma lic e nzyme a s NADPH is forme d (s e e p. 187). Lipid dro ple t 2. Inc re as e d triac ylg lyc e ro l s ynthe s is : TAG s ynthe s is is fa vore d be ca us e fa tty a cyl CoAs a re a va ila ble both from de novo s ynthe - s is from a ce tyl CoA a nd from hydrolys is of the TAG compone nt of chylomicron re mna nts re move d from the blood by he pa tocyte s (s e e p. 178). Glyce rol 3-phos pha te , the ba ckbone for TAG s yn- the s is , is provide d by glycolys is (s e e p. 189). The live r pa cka ge s TAG into ve ry-low-de ns ity lipoprote in (VLDL) pa rticle s tha t a re s e cre te d into the blood for us e by e xtra he pa tic tis s ue s , pa rticu- Fig ure 24.5 la rly a dipos e a nd mus cle tis s ue s (s e e Figure 24.3, ). Colorize d tra ns mis s ion e le ctron microgra ph of a dipocyte s. C. Amino ac id me tabo lis m 1. Inc re as e d amino ac id de g radatio n: In the a bs orptive pe riod, more a mino a cids a re pre s e nt tha n the live r ca n us e in the s ynthe s is IV. Adipos e Tis s ue : Ene rgy S tora ge De pot 325 of prote ins a nd othe r nitroge n-conta ining mole cule s. The s urplus Adipo c yte s c o ntain the a mino a cids a re not s tore d but a re e ithe r re le a s e d into the blood Gluc o s e ins ulin-s e ns itive GLUT-4. for othe r tis s ue s to us e in prote in s ynthe s is or de amina te d, with the 1 re s ulting ca rbon s ke le tons be ing de gra de d by the liver to pyruva te , a ce tyl CoA, or TCA cycle inte rme dia te s. The s e me ta bolite s ca n be ADIP OCYTE oxidize d for e ne rgy or us e d in FA s ynthe s is (s e e Figure 24.3, ). Gluc o s e Gluc o s e 6-P The live r ha s limite d ca pa city to de gra de the bra nche d-cha in a mino 3 2 a cids (BCAAs ) le ucine , is ole ucine , a nd va line. The y pa ss through PPP Pyruvate the live r e s s e ntia lly uncha nge d a nd a re pre fe re ntia lly me ta bolize d 2 in mus cle (s e e p. 266). Ac e tyl Co A TCA 2. Inc re as e d pro te in s ynthe s is : The body doe s not s tore prote in in 4 c yc le the s a me wa y tha t it ma inta ins glycoge n or TAG re s e rve s (s e e Fatty ac id p. 327). Howe ve r, a tra ns ie nt incre a s e in the s ynthe s is of he pa tic 6 5 prote ins doe s occur in the a bs orptive s ta te , re s ulting in re pla ce - 5 Triac ylg lyc y e ro l me nt of a ny prote ins tha t ma y ha ve be e n de gra de d during the pre vious pos ta bs orptive pe riod (s e e Figure 24.3, ). Chylo mic ro ns (fro m g ut) VLDL IV. ADIPOS E TIS S UE: ENERGY S TORAGE DEPOT (fro m live r) Chylo mic ro n re mnants Adipos e tis s ue is s e cond only to the live r in its a bility to dis tribute (to live r) fue l mole cule s. In a 70-kg ma n, white a dipos e tis s ue (WAT) we ighs Fat s to re d in adipo s e tis s ue is de rive d fro m die tary fatty ac ids pac kag e d as a pproxima te ly 14 kg, or a bout ha lf a s much a s the tota l mus cle ma s s. TAG in c hylo mic ro ns and e ndo g e no us Ne a rly the e ntire volume of e a ch a dipocyte in WAT ca n be occupie d fatty ac ids made in the live r and by a drople t of TAG (Figure 24.5). pac kag e d as TAG in VLDL. LP L in the c apillarie s de g rade s the TAG, re le as ing fatty ac ids. A. Carbo hydrate me tabo lis m 1. Inc re as e d g luc o s e trans po rt: Circula ting ins ulin le ve ls a re e le - Fig ure 24.6 va te d in the a bs orptive s ta te , re s ulting in a n influx of glucos e into Ma jor me ta bolic pa thwa ys in a dipos e a dipocyte s via ins ulin-s e ns itive GLUT-4 re cruite d to the ce ll s ur- tis s ue in the a bs orptive s ta te. [Note : fa ce from intra ce llula r ve s icle s (Figure 24.6, ). The glucos e is The numbe rs in the circle s , which phos phoryla te d by he xokina s e. a ppe a r both in the figure a nd in the corre s ponding te xt, indica te 2. Inc re as e d g lyc o lys is : The incre a s e d intra ce llula r a va ila bility of importa nt pa thwa ys for a dipos e glucos e re s ults in a n e nha nce d ra te of glycolys is (s e e Figure tis s ue me ta bolis m.] GLUT = glucos e tra ns porte r; P = phos pha te ; 24.6, ). In a dipos e tis s ue , glycolys is s e rve s a s ynthe tic func- P P P = pe ntos e phos pha te pa thwa y; tion by s upplying glyce rol 3-phos pha te for TAG s ynthe s is (s e e CoA = coe nzyme A; TCA = p. 189). Re ca ll tha t a dipos e tis s ue la cks glyce rol kina s e. trica rboxylic a cid; TAG = tria cylglyce rol; VLDL = ve ry-low-de ns ity lipoprote in; 3. Inc re as e d ac tivity o f the pe nto s e pho s phate pathway: Adipos e LP L = lipoprote in lipa s e. tis s ue ca n me ta bolize glucos e by me a ns of the P P P , the re by producing NADP H, which is e s s e ntia l for fa t s ynthe s is (s e e p. 186 a nd Figure 24.6, ). Howe ve r, in huma ns , de novo s ynthe s is is not a ma jor s ource of FA in a dipos e tis s ue , e xce pt whe n re fe e d- ing a pre vious ly fa s te d individua l (s e e Figure 24.6, ). B. Fat me tabo lis m Mos t of the FAs a dde d to the TAG s tore s of a dipocytes a fte r con- s umption of a lipid-conta ining me a l a re provide d by the de gra da tion of e xoge nous (die ta ry) TAG in chylomicrons s e nt out by the inte stine a nd e ndoge nous TAG in VLDL s e nt out by the live r (s e e Figure 24.6, ). The FAs a re re le a s e d from the lipoprote ins by the a ction of lipo- prote in lipa s e (LP L), a n e xtra ce llula r e nzyme a tta che d to the ca pilla ry wa lls in ma ny tis s ue s , pa rticula rly a dipos e a nd mus cle. In a dipos e 326 24. The Fe e d–Fa s t Cycle tiss ue , LPL is upre gula te d by ins ulin. Thus , in the fe d s ta te , e le va te d Any tis s ue pro te ins le ve ls of glucos e a nd ins ulin fa vor s tora ge of TAG (se e Figure 24.6, de g rade d during the ), a ll the ca rbons of which a re s upplie d by glucos e. [Note : Ele va te d Aminoino po s tabs o rptive ac ids ds ins ulin fa vors the de phos phoryla te d (ina ctive ) form of HS L (s e e p. (incc luding pe rio d are re s ynthe s ize d. 190), the re by inhibiting lipolys is in the fe d s ta te.] BCAAsAAs ) V. RES TING S KELETAL MUS CLE 3 Acc e tty tyl yll Co Co A In the fe d s ta te , mus cle ta ke s up glucos e via GLUT-4 (for e ne rgy a nd TCA TCACA Amino ino ino in no c yycc le glycoge n s ynthe s is ) a nd a mino a cids (for e ne rgy a nd prote in s ynthe - ac ids ds ds Pyruvate P yruvate Pyr y ruvat uvate vate ate te s is ). [Note : The e ne rgy me ta bolis m of s ke le ta l mus cle is unique in be ing a ble to re s pond to s ubs ta ntia l cha nge s in the de ma nd for ATP Pro te in Glyc o g e n 2 Gluc o s e 6-P tha t a ccompa nie s mus cle contra ction. At re s t, mus cle a ccounts for a pproxima te ly 30% of the O 2 cons umption of the body, whe re a s dur- MUS MUS CLE C LE Gluc o s e ing vigorous e xe rcis e , it is re s pons ible for up to 90% of the tota l O 2 cons umption. This gra phica lly illus tra te s the fa ct tha t s ke le ta l mus cle , de s pite its pote ntia l for tra ns ie nt pe riods of a na e robic glycolys is , is a n Mus c le c o ntains 1 oxida tive tis s ue. In contra s t to live r, the re is no cova le nt re gula tion of ins ulin-s e ns itive P FK-2 in s ke le ta l mus cle. In the ca rdia c is ozyme , howe ve r, the kina s e GLUT-4. Gluc o s e doma in is a ctiva te d by e pine phrine -me dia te d phos phoryla tion.] A. Carbo hydrate me tabo lis m Fig ure 24.7 Ma jor me ta bolic pa thwa ys in s ke le ta l 1. Inc re as e d g luc o s e trans po rt: The tra ns ie nt incre a s e in pla s ma mus cle in the a bs orptive s ta te. glucos e a nd ins ulin a fte r a ca rbohydra te -rich me a l le a ds to a n [Note : The numbe rs in circle s , which incre a s e in glucos e tra ns port into mus cle ce lls by GLUT-4 (s e e a ppe a r both in the figure a nd in the te xt, indica te importa nt pa thwa ys p. 97 a nd Figure 24.7, ), the re by re ducing blood glucos e. for ca rbohydra te or prote in Glucos e is phos phoryla te d to glucos e 6-phos pha te by he xokina s e me ta bolis m.] CoA = coe nzyme A; a nd me ta bolize d to provide the e ne rgy ne e ds of the ce lls. P = phos pha te ; GLUT = glucos e tra ns porte r; BCAAs = bra nche d-cha in 2. Inc re as e d g lyc o g e n s ynthe s is : The incre a s e d ins ulin-to-gluca - a mino a cids ; TCA = trica rboxylic a cid. gon ra tio a nd the a va ila bility of glucos e 6-phos pha te fa vor glyco- ge n s ynthe s is , pa rticula rly if glycoge n s tore s ha ve be e n de ple te d a s a re s ult of e xe rcis e (s e e p. 126, a nd Figure 24.7, ). B. Fat me tabo lis m FAs a re re le a s e d from chylomicrons a nd VLDL by the a ction of LP L (s e e pp. 228 a nd 231). Howe ve r, fa tty a cids a re of s e conda ry impor- ta nce a s a fue l for re s ting mus cle during the fe d s ta te , in which glu- cos e is the prima ry s ource of e ne rgy. C. Amino ac id me tabo lis m 1. Inc re as e d pro te in s ynthe s is : An incre a s e in a mino a cid upta ke a nd prote in s ynthe s is occurs in the a bs orptive pe riod a fte r inge s - tion of a me a l conta ining prote in (s e e Figure 24.7, a nd ). This s ynthe s is re pla ce s prote in de gra de d s ince the pre vious me a l. 2. Inc re as e d uptake o f branc he d-c hain amino ac ids : Mus cle is the principa l s ite for de gra da tion of the BCAAs (le ucine , is ole ucine , a nd va line ) be ca us e it conta ins the re quire d tra ns a mina s e (s e e p. 266). The BCAAs e s ca pe me ta bolis m by the live r a nd a re ta ke n up by mus cle , whe re the y a re us e d for prote in s ynthe s is (s e e Figure 24.7, ) a nd a s s ource s of e ne rgy. VII. Ove rvie w of Fa s ting 327 VI. BRAIN Brain c o mple te ly o xidize s g luc o s e Although contributing only 2% of the a dult we ight, the bra in a ccounts to CO2 and wate r. for a cons is te nt 20% of the ba s a l O 2 cons umption of the body a t re s t. BLOOD B Be ca us e the bra in is vita l to the prope r functioning of a ll orga ns of the body, s pe cia l priority is give n to its fue l ne e ds. To provide e ne rgy, s ub- Ac e ty tyl Co A s tra te s mus t be a ble to cros s the e ndothe lia l ce lls tha t line the blood ve s s e ls in the bra in (the blood–bra in ba rrie r [BBB]). In the fe d s ta te , the 1 Pyruvate bra in e xclus ive ly us e s glucos e a s a fue l (GLUT-1 of the BBB is ins ulin TCA 1 inde pe nde nt), comple te ly oxidizing a pproxima te ly 140 g/da y to CO 2 a nd c yc le 1 H2 O. The bra in conta ins no s ignifica nt s tore s of glycoge n a nd is , the re - Gluc o s e 6-P BRAIN fore , comple te ly de pe nde nt on the a va ila bility of blood glucos e (Figure 1 24.8, ). [Note : If blood glucos e le ve ls fa ll be low 40 mg/100 ml (norma l Gluc o s e fa s te d blood glucos e is 70–99 mg/100 ml), ce re bra l function is impa ire d (s e e p. 315).] The bra in a ls o la cks s ignifica nt s tore s of TAG, a nd the FAs circula ting in the blood ma ke little contribution to e ne rgy production be ca us e FAs bound to a lbumin do not e fficie ntly cros s the BBB. The Gluc o s e inte rtis s ue e xcha nge s cha ra cte ris tic of the a bs orptive pe riod a re s um- ma rize d in Figure 24.9. Of the fue ls c irc ulating in the blo o d, o nly g luc o s e c an pe ne trate the blo o d– VII. OVERVIEW OF FAS TING brain barrie r. GLUT-1 o f the blo o d–brain barrie r is ins ulin ins e ns itive. Fa s ting be gins if no food is inge s te d a fte r the a bs orptive pe riod. It ma y re s ult from a n ina bility to obta in food, the de s ire to los e we ight ra pidly, or clinica l s itua tions in which a n individua l ca nnot e a t (for Fig ure 24.8 e xa m p le , b e c a u s e o f tra u m a , s u rg e ry, c a n c e r, o r b u rn s ). In th e Ma jor me ta bolic pa thwa ys in bra in a bs e nce of food, pla s ma le ve ls of glucos e , a mino a cids , a nd TAG fa ll, in the a bs orptive s ta te. [Note : The trigge ring a de cline in ins ulin s e cre tion a nd a n incre a s e in gluca gon numbe rs in circle s , which a ppe a r a nd e pine phrine re le a s e. The de cre a s e d ins ulin/counte rre gula tory both in the figure a nd in the te xt, hormone ra tio a nd the de cre a s e d a va ila bility of circula ting s ubs tra te s indica te importa nt pa thwa ys for ma ke the pe riod of nutrie nt de priva tion a ca ta bolic pe riod cha ra cte r- ca rbohydra te me ta bolis m.] CoA = coe nzyme A; TCA = trica rboxylic ize d by de gra da tion of TAG, glycoge n, a nd prote in. This s e ts into a cid; P = phos pha te ; GLUT = motion a n e xcha nge of s ubs tra te s a mong live r, a dipos e tis s ue , s ke l- glucos e tra ns porte r. e ta l mus cle , a nd bra in tha t is guide d by two prioritie s : 1) the ne e d to ma inta in a de qua te pla s ma le ve ls of glucos e to s us ta in e ne rgy me ta b- olis m in the bra in, re d blood ce lls , a nd othe r glucos e -re quiring tis s ue s a nd 2) the ne e d to mobilize fa tty a cids from a dipos e tis s ue a nd the s ynthe s is a nd re le a s e of ke tone bodie s from the live r to s upply e ne rgy to othe r tis s ue s. [Note : Ma inta ining glucos e re quire s tha t the s ub- s tra te s for glucone oge ne s is (s uch a s pyruva te , a la nine , a nd glyce rol) be a va ila ble.] A. Fue l s to re s The me ta bolic fue ls a va ila ble in a norma l 70-kg ma n at the be gin- ning of a fa s t a re s hown in Figure 24.10. Note the e normous ca loric s tore s a va ila ble in the form of TAG compa re d with thos e conta ine d in glycoge n. [Note : Although prote in is lis te d a s a n e ne rgy s ource , e a ch prote in a ls o ha s a function (for e xa mple , a s a s tructura l com- pone nt of the body, a n e nzyme , a nd s o forth). The re fore , only a bout one third of the body’s prote in ca n be us e d for e ne rgy production without fa ta lly compromis ing vita l functions.] 328 24. The Fe e d–Fa s t Cycle DIETARY CARBOHYDRATE AND DIETARY DIETARY FAT CAN BE CONVERTED PROTEIN CAN BE CONVERTED TO BODY FAT TO BODY FAT Whe n c alo ric intake e xc e e ds e ne rg y INTES TINE Whe n c alo ric intake e xc e e ds e ne rg y e xpe nditure , die tary c arbo hydrate and e xpe nditure , die tary fat c an be pro te in c an be c o nve rte d to triac ylg lyc e ro l c o nve rte d to triac ylg lyc e ro l in the in the live r fo r ultimate de po s itio n in the adipo s e tis s ue. adipo s e tis s ue. BLOOD Glyc o g e n LIVER ADIP OCYTE Gluc uc o s e 6-P Gluc Gluc o s e Gluc o s e Gluc o s e Gluc o s e 6-P NH3 PPP Pyruvate Py y ruv ruva ruva uvvate uvate uvat A i Amino ac id ids PPP Pyruvate A m Amino ac ids Ac e tyl Co A TCA NADPH NH3 Pro te in TCA c yc le c yc le Fatty ac id Chylo mic ro n re mnants To all Triac ylg lyc e ro l VLDL Triac ylg lyc e ro l tis s ue s Chylo mic ro n re mnants VLDL VLDL (fro m live r) Pancreas Ins ulin is an anabo lic s ig nal that pro mo te s s ynthe s is o f g lyc o g e n, pro te in, and triac ylg lyc e ro l. Ac e tyl Co A Gluc ag o n Ins ulin lin TCA c yc le Pyruvate Amino ac ids Ac e tyl Co A Gluc o s e 6-P BRAIN TCA MUS CLE Amino c yc le ac ids Pyruvate Pro te in Glyc o g e n Gluc o s e 6-P Gluc o s e Gluc o s e Gluc o s e Fig ure 24.9 Inte rtis s ue re la tions hips in the a bs orptive s ta te a nd the hormona l s igna ls tha t promote the m. [Note : S ma ll circle s on the pe rime te r of mus cle a nd the a dipocyte indica te ins ulin-de pe nde nt glucos e tra ns porte rs.] P = phos pha te ; P P P = pe ntos e phos pha te pa thwa y; CoA = coe nzyme A; NADP H = nicotina mide a de nine dinucle otide phos pha te ; TCA = trica rboxylic a cid; VLDL = ve ry-low-de ns ity lipoprote in. B. Enzymic c hang e s in fas ting In fa s ting (a s in the fe d s ta te ), the flow of inte rme dia te s through the pa thwa ys of e ne rgy me ta bolis m is controlle d by four me cha nis ms : 1) the a va ila bility of s ubs tra te s , 2) a llos te ric re gula tion of e nzyme s , 3) cova le nt modifica tion of e nzyme s , a nd 4) induction–re pre s s ion of e nzyme s ynthe s is. The me ta bolic cha nge s obs e rve d in fa s ting a re ge ne ra lly oppos ite to thos e de s cribe d for the a bs orptive s ta te (s e e Figure 24.9). For e xa mple , a lthough mos t of the e nzyme s re gula te d by cova le nt modifica tion a re de phos phoryla te d a nd a ctive in the fed VIII. Live r in Fa s ting 329 s ta te , the y a re phos phoryla te d a nd ina ctive in the fa s te d s ta te. Thre e e xce ptions a re glycoge n phos phoryla s e (s e e p. 132), glycoge n phos - Fat: 15 kg = 135,000 kc al phoryla s e kina s e (s e e p. 132), a nd HS L of a dipos e tis s ue (s e e p. 190), which a re a ctive in the ir phos phoryla te d s ta te s. In fa s ting, s ub- s tra te s a re not provide d by the die t but a re a va ila ble from the bre a k- Pro te in: 6 kg = 24,000 kc al down of s tore s a nd/or tis s ue s , s uch a s glycoge nolys is with re le a s e of glucos e from live r, lipolys is with re le a s e of FAs a nd glyce rol from TAG in a dipos e tis s ue , a nd prote olys is with re le a s e of amino a cids from Glyc o g e n: 0.2 kg = 800 kc al mus cle. Re cognition tha t the cha nge s in fa s ting a re the re ciproca l of thos e in the fe d s ta te is he lpful in unde rs ta nding the e bb a nd flow of me ta bolis m. Fig ure 24.10 VIII. LIVER IN FAS TING Me ta bolic fue ls pre s e nt in a 70-kg ma n a t the be ginning of a fa s t. The fa t s tore s a re s ufficie nt to me e t The prima ry role of live r in e ne rgy me ta bolis m during fa s ting is ma in- e ne rgy ne e ds for a bout 80 da ys. te na nce of blood glucos e through the production of glucos e from gly- coge nolys is a nd glucone oge ne s is for glucos e -de pe nde nt tis s ue s a nd the s ynthe s is a nd dis tribution of ke tone bodie s for us e by othe r tis s ue s. The re fore , “he pa tic” me ta bolis m a nd “e xtra he pa tic” or “pe riphe ra l” me ta bolis m a re dis tinguis he d. A. Carbo hydrate me tabo lis m The live r firs t us e s glycoge n de gra da tion a nd the n glucone oge ne s is to ma inta in blood glucos e le ve ls to s us ta in e ne rgy me ta bolis m of the bra in a nd othe r glucos e -re quiring tis s ue s in the fa s te d (pos ta b- s orptive ) s ta te. [Note : Re ca ll tha t the pre s e nce of glucos e 6-phos - 40 pha ta s e in the live r a llows the production of fre e glucos e both from glycoge nolys is a nd from glucone oge ne s is (s e e Figure 24.4).] Ing e s te d g luc o s e 1. Inc reas e d glyc oge n de gradation: Figure 24.11 shows the source s Gluc o s e us e d, g /hr of blood glucose after ingestion of 100 g of glucose. During the brie f a bs orptive pe riod, inge s te d glucos e is the ma jor s ource of blood glucos e. S e ve ra l hours la te r, blood glucos e le ve ls ha ve de cline d 20 sufficiently to cause increased secretion of glucagon and decrease d release of insulin. The incre ased glucagon-to-insulin ratio cause s a Glyc o g e n rapid mobilization of liver glycoge n stores (which contain about 80 g Gluc o ne o g e ne s is of glycogen in the fed state) due to PKA-mediated phosphorylation (and activation) of glycoge n phosphorylase kinase that phosphory- lates (and activa tes) glycogen phosphorylase (see p. 130). Figure 24.11 s hows tha t live r glycoge n is ne a rly e xha us te d a fte r 10–18 0 hours of fasting, and therefore, hepa tic glycoge nolysis is a transient 0 8 16 24 10 20 40 response to ea rly fa sting. Figure 24.12, , shows glycogen de gra - Ho urs Days dation as pa rt of the overall metabolic response of the liver during fa s ting. [Note : P hos phoryla tion of glycoge n s yntha s e s imulta ne - Fig ure 24.11 ously inhibits glycogenesis.] S ource s of blood glucos e a fte r inge s tion of 100 g of glucos e. 2. Inc re as e d g luc o s e s ynthe s is : The s ynthe s is of glucos e a nd [Note : S e e S e ction B.2. for a n its re le a s e into the circula tion a re vita l he pa tic functions during e xpla na tion a s to why gluco- s hort- a nd long-te rm fa s ting (s e e Figure 24.12, ). The ca rbon ne oge ne s is de cline s.] s ke le tons for glucone oge ne s is a re de rive d prima rily from glu- coge nic a mino a cids a nd la cta te from mus cle a nd glyce rol from a dipos e tis s ue. Glucone oge ne s is , fa vore d by a ctiva tion of fructos e 1,6-bis phos pha ta s e (due to de cre a s e d a va ila bility of its inhibitor fructos e 2,6-bis phos pha te ; s e e p. 121) a nd by induction of P EP CK 330 24. The Fe e d–Fa s t Cycle Glyc o g e n p h o s p h o ryla s e and p h o s p h o ryla s e kin a s e are Glyc yc o g e n Gly Glu c o s e 6-p h o s p h a ta s e pho s pho rylate d and ac tive. 1 BLOOD g e ne rate s fre e g luc o s e. LIVER 2 Ac tivatio n o f fru c to s e Gluc o s e 6-P Gluc o s e Gluc o s e 2,6-b is p h o s p h a ta s e favo rs 2 Live r lac ks th io p h o ra s e , g luc o ne o g e ne s is. Pyruvate P Py Pyruv yr pre ve nting us e o f ke to ne bo die s. oA 4 Ac e tyl Co Ke to ne bo die s Ke to ne TCA bo die s c yc le 3 NADH fro m β-o xidatio n inhibits the TCA c yc le , Fatty ac ids Lo w malo nyl Co A le ve l allo ws pus hing ac e tyl Co A 2 β-o xidatio n. The ac e tyl Co A to ke to g e ne s is. pro duc t ac tivate s p yru va te c a rb o xyla s e and inhibits Fatty ac ids p yru va te d e h yd ro g e n a s e. MUS CLE Amino ac ids , lac tate Glyc e ro l ADIP OS E TIS S UE Fig ure 24.12 Ma jor me ta bolic pa thwa ys in live r during fa s ting. [Note : The numbe rs in circle s , which a ppe a r both in the figure a nd in the corre s ponding cita tion in the te xt, indica te importa nt me ta bolic pa thwa ys for ca rbohydra te or fa t.] P = phos pha te ; CoA = coe nzyme A; TCA = trica rboxylic a cid; NADH = nicotina mide a de nine dinucle otide. by gluca gon (s e e p. 122), be gins 4–6 hours a fte r the la s t me a l a nd be come s fully a ctive a s s tore s of live r glycoge n a re de ple te d (s e e Figure 24.11). [Note : The de cre a s e in fructos e 2,6-bis phos pha te s imulta ne ous ly inhibits glycolys is a t P FK-1 (s e e p. 99).] 6 3-Hydro xybutyrate B. Fat me tabo lis m 1. Inc re as e d fatty ac id o xidatio n: The oxida tion of FAs obta ine d from TAG hydrolys is in a dipos e tis s ue is the ma jor s ource of 4 e ne rgy in he pa tic tis s ue in the pos ta bs orptive s ta te (s e e Figure mmo l/l blo o d 24.12, ). The fa ll in ma lonyl CoA due to phos phoryla tion (ina c- Fatty ac ids tiva tion) of ACC by AMP K re move s the bra ke on CP T-1, a llowing β-oxida tion to occur (s e e p. 191). FA oxida tion ge ne ra te s NADH, 2 FADH2 , a nd a ce tyl CoA. The NADH inhibits the TCA cycle. The a ce tyl CoA is a n a llos te ric a ctiva tor of P C a nd a n a llos te ric inhib- itor of P DH, the re by fa voring us e of pyruva te in glucone oge ne s is (s e e Figure 8.24). [Note : The a ce tyl CoA ca nnot be us e d a s a 0 0 10 20 30 40 s ubs tra te for glucone oge ne s is , in pa rt be ca us e the P DH re a ction Days o f fas ting is irre ve rs ible.] Oxida tion of NADH a nd FADH2 couple d with oxi- da tive phos phoryla tion s upplie s the e ne rgy re quire d by the P C a nd P EP CK re a ctions of glucone oge ne s is. Fig ure 24.13 Conce ntra tions of fa tty a cids a nd 2. Inc re as e d ke to ne bo dy s ynthe s is : The live r is unique in be ing a ble 3-hydroxybutyra te in the blood to s ynthe s ize a nd re le a s e ke tone bodie s , prima rily 3-hydroxybutyr- during fa s ting. [Note : 3-Hydroxy- a te but a ls o a ce toa ce ta te , for us e as fue l by pe riphe ra l tis s ue s (s e e butyra te is ma de from the re duction of a ce toa ce ta te.] p. 195) but not by the live r its e lf be ca us e live r la cks thiophora s e. Ke toge ne s is , which s ta rts during the firs t da ys of fa s ting (Figure 24.13), is fa vore d whe n the concentra tion of a ce tyl CoA from FA oxida tion e xce e ds the oxida tive capa city of the TCA cycle. [Note : X. Re s ting S ke le ta l Mus cle in Fa s ting 331 Ke toge ne s is re le a s e s CoA, e ns uring its a va ila bility for continue d FA oxida tion.] The a va ila bility of circula ting wa te r-s oluble ke tone bodie s is importa nt in fa s ting be ca us e the y ca n be us e d for fue l ADIP OCYTE by mos t tis s ue s , including bra in, once the ir le ve l in the blood is s ufficie ntly high. This re duce s the ne e d for glucone oge ne s is from a mino a cid ca rbon s ke le tons , thus pre s e rving e s s e ntia l prote in Ac e tyl Co A (s e e Figure 24.11). Ke toge ne s is a s pa rt of the ove ra ll he pa tic TCA c yc le re s pons e to fa s ting is s hown in Figure 24.12,. [Note : Ke tone bodie s a re orga nic a cids a nd, whe n pre s e nt a t high conce ntra tions , Triac ylg lyc e ro l ca n ca us e ke toa cidos is.] 1 Fatty ac ids Glyc e ro l IX. ADIPOS E TIS S UE IN FAS TING 2 A. Carbo hydrate me tabo lis m Fatty ac ids Glyc e ro l Glucos e tra ns port by ins ulin-s e ns itive GLUT-4 into the a dipocyte BLOOD a nd its s ubs e que nt me ta bolis m a re de pre s s e d due to low le ve ls of circula ting ins ulin. This re s ults in de cre a s e d TAG s ynthe s is. Fig ure 24.14 B. Fat me tabo lis m Ma jor me ta bolic pa thwa ys in a dipos e tis s ue during fa s ting. [Note : The 1. Inc re as e d de g radatio n o f fat: The P KA-me dia te d phos phoryla tion numbe rs in the circle s , which a ppe a r a nd a ctiva tion of HS L (s e e p. 190) a nd s ubs e que nt hydrolys is of both in the figure a nd in the s tore d fa t a re e nha nce d by the e le va te d ca te chola mine s nore pi- corre s ponding cita tion in the te xt, ne phrine a nd e pine phrine. The s e hormone s , which a re re le a s e d indica te importa nt pa thwa ys for fa t from the s ympa the tic ne rve e ndings in a dipos e tis s ue a nd/or from me ta bolis m.] CoA = coe nzyme A; TCA = trica rboxylic a cid. the a dre na l me dulla , a re phys iologica lly importa nt a ctiva tors of HS L (Figure 24.14, ). 2. Inc re as e d re le as e o f fatty ac ids : FAs obta ine d from hydrolysis of BLOOD s tore d TAG a re prima rily re le a s e d into the blood (s e e Figure 24.14, ). Bound to a lbumin, the y a re tra ns porte d to a va rie ty of tis s ue s Gluc o ne o g e nic Fatty ac ids pre c urs o rs for us e a s fue l. The glyce rol produce d from TAG de gra da tion is us e d a s a glucone oge nic pre curs or by the live r, which conta ins Ke to ne glyce rol kina s e. [Note : FA ca n a ls o be oxidize d to a ce tyl CoA, Amino ac ids bo die s which ca n e nte r the TCA cycle , the re by producing e ne rgy for the a dipocyte. The y a ls o ca n be re -e s te rifie d to glyce rol 3-phos pha te Fatty ac ids (from glyce rone oge ne s is , s e e p. 190), ge ne ra ting TAG a nd re duc- Amino 3 Pro te in 1 ac ids ing pla s ma FA conce ntra tion.] Ac e tyl Co A TCA c yc le 3. De c re as e d uptake o f fatty ac ids : In fa s ting, LP L a ctivity of a di- MUS CLE 2 Ke to ne bo die s pos e tis s ue is low. Cons e que ntly, circula ting TAG of lipoprote ins is not a va ila ble to a dipos e tis s ue. X. RES TING S KELETAL MUS CLE IN FAS TING Fig ure 24.15 Ma jor me ta bolic pa thwa ys in s ke le ta l mus cle during fa s ting. [Note : The Re s ting mus cle s witche s from glucos e to FAs a s its ma jor fue l s ource in numbe rs in the circle s , which a ppe a r fa s ting. [Note : By contra s t, e xe rcis ing mus cle initially us e s its glycoge n both in the figure a nd in the s tore s a s a s ource of e ne rgy. During inte ns e e xe rcis e , glucos e 6-phos - corre s ponding cita tion in the te xt, pha te de rive d from glycoge n is conve rte d to la cta te by a na e robic glycol- indica te importa nt pa thwa ys for fa t ys is (s e e p. 103). The la cta te is us e d by live r for glucone oge ne s is (Cori or prote in me ta bolis m.] CoA = coe nzyme A; TCA = trica rboxylic a cid. cycle ; s e e p.118). As the s e glycoge n re s e rve s a re de ple te d, fre e FAs provide d by the mobiliza tion of TAG from a dipos e tis s ue be come the 332 24. The Fe e d–Fa s t Cycle Ke to ne domina nt e ne rgy s ource. The contra ction-ba s e d ris e in AMP a ctiva te s bo die s AMP K tha t phos phoryla te s a nd ina ctiva te s the mus cle is ozyme of ACC, BLOOD 2 de cre a s ing ma lonyl CoA a nd a llowing FA oxida tion (s e e p. 183). Ac e tyl Co A A. Carbo hydrate me tabo lis m 1 Pyruvate Glucos e tra ns port into s ke le ta l mus cle ce lls via ins ulin-s e ns itive TCA 1 GLUT-4 (s e e p. 97) a nd s ubs e que nt glucos e me ta bolis m a re c yc le 1 de pre s s e d be ca us e of low le ve ls of circula ting ins ulin. The re fore , the Gluc o s e 6-P BRAIN glucos e from he pa tic glucone oge ne s is is una va ila ble to mus cle (a nd 1 a dipos e tis s ue ). Gluc o s e B. Lipid me tabo lis m During the firs t 2 we e ks of fa s ting, mus cle us e s FA from a dipos e tis s ue a nd ke tone bodie s from the live r a s fue ls (Figure 24.15, Gluc o s e a nd ). Afte r a bout 3 we e ks of fa s ting, mus cle de cre a s e s its us e of ke tone bodie s (thus s pa ring the m for bra in) a nd oxidize s FA a lmos t e xclus ive ly. [Note : The a ce tyl CoA from FA oxida tion indire ctly inhib- Fig ure 24.16 its P DH (by a ctiva tion of P DH kina s e ) a nd s pa re s pyruva te , which Ma jor me ta bolic pa thwa ys in the is tra ns a mina te d to a la nine a nd us e d by live r for glucone oge ne s is bra in during fa s ting. [Note : The numbe rs in the circle s , which a ppe a r (glucos e –a la nine cycle ; s e e p. 253).] both in the figure a nd in the corre s ponding cita tion in the te xt, C. Pro te in me tabo lis m indica te importa nt pa thwa ys for During the firs t fe w da ys of fa s ting, the re is a ra pid bre a kdown of me ta bolis m of fa t or ca rbohydra te s.] CoA = coe nzyme A; TCA = mus cle prote in, providing a mino a cids tha t a re us e d by the live r for trica rboxylic a cid; P = phos pha te. glucone oge ne s is (s e e Figure 24.15, ). Be ca us e mus cle doe s not ha ve gluca gon re ce ptors , mus cle prote olys is is initia te d by a fa ll in insulin and sustained by a rise in glucocorticoids. [Note: Alanine and glutamine are qua ntita tively the most important gluconeogenic amino acids released from muscle. They are produced by the catabolism of BCAAs (see p. 267).] The gluta mine is used a s a fuel by enterocytes, 100 for exa mple, which send out alanine that is used in hepa tic gluconeo- Amino ac ids genesis. In the se cond week of fasting, the rate of muscle proteolysis Ac e to ac e tate decreases, pa ralleling a decline in the nee d for glucose as a fuel for the brain, which has begun using ketone bodies as a source of energy. XI. BRAIN IN FAS TING Pe rc e ntag e 50 3-Hydro xy- Gluc o s e butyrate During the e a rly da ys of fa s ting, the bra in continue s to us e only glucos e a s a fue l (Figure 24.16, ). Blood glucos e is ma inta ine d by he pa tic glu- cone oge ne s is from glucoge nic pre curs ors , s uch a s a mino a cids from prote olys is a nd glyce rol from lipolys is. In prolonge d fa s ting (be yond 2–3 we e ks ), pla s ma ke tone bodie s (s e e Figure 24.12) re a ch s ignifica ntly Gluc o s e e le va te d le ve ls a nd re pla ce glucos e a s the prima ry fue l for the bra in 0 (s e e Figure 24.16, , a nd Figure 24.17). This re duce s the ne e d for We ll fe d S tarve d prote in ca ta bolis m for glucone oge ne s is : ke tone bodie s s pa re glucos e (5–6 we e ks ) a nd, thus , mus cle prote in. [Note : As the dura tion of a fa s t e xte nds from ove rnight to da ys to we e ks , blood glucos e le ve ls initia lly drop a nd the n Fig ure 24.17 a re ma inta ine d a t the lowe r le ve l (65–70 mg/dl).] The me ta bolic cha nge s Fue l s ource s us e d by the bra in to tha t occur during fa s ting e ns ure tha t a ll tis s ue s ha ve a n a de qua te s upply me e t e ne rgy ne e ds in the we ll fe d of fue l mole cule s. The re s pons e of the ma jor tis s ue s involve d in e ne rgy a nd s ta rve d s ta te s. me ta bolis m during fa s ting is s umma rize d in Figure 24.19 (s e e be low). XIII. Cha pte r S umma ry 333 XII. KIDNEY IN LONG-TERM FAS TING Branc he d-c hain amino ac ids (BCAAs ) As fa s ting continue s into e a rly s ta rva tion a nd be yond, the kidne y pla ys Glutamine importa nt role s. The kidne y e xpre s s e s the e nzyme s of glucone oge ne s is , including glucos e 6-phos pha ta s e , a nd in la te fa s ting a bout 50% of gluco- Gluta mina s e ne oge ne s is occurs he re. [Note : A portion of this glucos e is us e d by the H+ Glutamate + NH3 → NH+4 kidne y its e lf.] The kidne y a ls o provide s compe ns a tion for the a cidos is Gluta ma te tha t a ccompa nie s the incre a s e d production of ke tone bodie s (orga nic de hydroge na s e a cids ). The gluta mine re le a s e d from the mus cle ’s me ta bolis m of BCAAs H+ is ta ke n up by the kidne y a nd a cte d upon by re na l gluta mina s e a nd gluta - α-Ke to g lutarate + NH3 → NH+4 ma te de hydroge na s e (s e e p. 256), producing α -ke togluta ra te tha t ca n be us e d a s a s ubs tra te for glucone oge ne s is , plus a mmonia (NH3 ). The NH3 picks up protons from ke tone body dis s ocia tion a nd is e xcre te d in the Fig ure 24.18 urine a s a mmonium (NH4 +), the re by de cre a s ing the a cid loa d in the body Us e of gluta mine from BCAA (Figure 24.18). In long-te rm fa s ting, the n, the re is a s witch from nitroge n ca ta bolis m in mus cle to ge ne ra te dis pos a l in the form of ure a to dis pos a l in the form of a mmonia. [Note : a mmonia (NH3 ) us e d for the e xcre tion of protons (H+) a s As ke tone body conce ntration ris e s , e nte rocyte s , typica lly cons ume rs of a mmonium (NH+4 ) in kidne y. gluta mine , be come cons ume rs of ke tone bodie s. This a llows more gluta - mine to be a va ila ble to the kidne y.] XIII. CHAPTER S UMMARY The flow of inte rme dia te s through me ta bolic pa thwa ys is controlle d by four me cha nis ms : 1) the a va ila bility of s ub- s tra te s , 2) a llos te ric a ctiva tion a nd inhibition of e nzyme s , 3) cova le nt modifica tion of e nzyme s , a nd 4) induction- re pre s s ion of e nzyme s ynthe s is. In the a bs orptive s ta te , the 2–4-hour pe riod a fte r inge s tion of a me a l, the s e re gula tory me cha nis ms e ns ure tha t a va ila ble nutrie nts a re ca pture d a s g lyc o g e n , triac ylg lyc e ro l (TAG), a nd pro - te in (Figure 24.20). During this inte rva l, tra ns ie nt incre a s e s in pla s ma glucos e , a mino a cids , a nd TAG occur, the la s t prima rily a s compone nts of chylomicrons s ynthe s ize d by the inte s tina l mucos a l ce lls. The panc re as re s ponds to the e le va te d le ve ls of glucos e with a n inc re as e d s e c re tio n o f ins ulin a nd a de c re as e d s e c re tio n o f g luc ag o n by the panc re as. The e le va te d ins ulin-to-gluca gon ra tio a nd the re a dy a va ila bility of circula ting s ubs tra te s ma ke the a bs orptive s ta te a n anabo lic pe rio d during which virtua lly a ll tis s ue s us e g luc o s e a s a fue l. In a ddition, the live r re ple nis he s its g lyc o g e n s tore s , re pla ce s a ny ne e de d he patic pro te ins , a nd incre a s e s TAG s ynthe s is. The la tte r a re pa cka ge d in ve ry-lo w-de ns ity lipo pro te ins , which a re e xporte d to the pe riphe ra l tis s ue s. Adipo s e tis s ue incre a s e s TAG s ynthe s is a nd s tora ge , whe re a s mus c le incre a s e s pro te in s ynthe s is to re pla ce prote in de gra de d s ince the pre vious me a l. In the fe d s ta te , the brain us e s glucos e e xclus ive ly a s a fue l. In the abs e nc e o f fo o d , pla s ma le ve ls of glucos e , a mino a cids , a nd TAG fa ll, trigge ring a de c line in ins ulin s e c re tio n a nd a n inc re as e in g luc ag o n a nd e pine phrine re le as e. The de cre a s e d ins ulin/counte rre gula tory hormone ra tio a nd the de cre a s e d a va ila bility of circula ting s ubs tra te s ma ke the fa s ting s ta te a c atabo lic pe rio d. This s e ts into motion a n e xc hang e o f s ubs trate s a mong live r, a dipos e tis s ue , s ke le ta l mus cle , a nd bra in tha t is guide d by two prioritie s : 1) the ne e d to ma inta in a de qua te pla s ma le ve ls of glucos e to s us ta in e ne rgy me ta bolis m of the bra in a nd othe r glucos e -re quiring tis s ue s a nd 2) the ne e d to mobilize fa tty a cids (FAs ) from a dipos e tis s ue a nd re le a s e ke tone bodie s from live r to s upply e ne rgy to othe r tis s ue s. To a ccomplis h the s e goa ls , the live r de gra de s g lyc o g e n a nd initia te s g luc o ne o - g e ne s is , us ing inc re as e d fatty ac id o xidatio n a s a s ource of the e ne rgy a nd re ducing e quiva le nts ne e de d for glu- cone oge ne s is a nd to s upply the a ce tyl coe nzyme A building blocks for ke to g e ne s is. The adipo s e tis s ue de gra de s s tore d TAG, thus providing FAs a nd g lyc e ro l to the live r. The mus c le ca n a ls o us e FAs a s fue l a s we ll a s ke to ne bo die s s upplie d by the live r. Mus cle pro te in is de g rade d to s upply amino ac ids for the live r to us e in glucone oge n- e s is , but de ce a s e s a s ke tone bodie s incre a s e. The brain ca n us e both g luc o s e a nd ke to ne bo die s a s fue ls. From la te fa s ting into s ta rva tion, the kidne ys pla y importa nt role s by s ynthe s izing g luc o s e a nd e xc re ting the pro to ns from ke tone body dis s ocia tion a s a mmonium (NH4 +).