Harpers

178 / CHAPTER 21crose is fed instead of glucose because fructose bypassesthe phosphofructokinase control point in glycolysis andfloods the lipogenic pathway (Figure 20–5).P iPROTEINPHOSPHATASEH 2 OSHORT- & LONG-TERM MECHANISMSREGULATE LIPOGENESISLong-chain fatty acid synthesis is controlled in theshort term by allosteric and covalent modification ofenzymes and in the long term by changes in gene expressiongoverning rates of synthesis of enzymes.Acetyl-CoAACETYL-CoACARBOXYLASE(active)PACETYL-CoACARBOXYLASE(inactive)Acetyl-CoA Carboxylase Is the MostImportant Enzyme in the Regulationof LipogenesisAcetyl-CoA carboxylase is an allosteric enzyme and isactivated by citrate, which increases in concentration inthe well-fed state and is an indicator of a plentiful supplyof acetyl-CoA. Citrate converts the enzyme from aninactive dimer to an active polymeric form, having amolecular mass of several million. Inactivation is promotedby phosphorylation of the enzyme and by longchainacyl-CoA molecules, an example of negative feedbackinhibition by a product of a reaction. Thus, ifacyl-CoA accumulates because it is not esterifiedquickly enough or because of increased lipolysis or aninflux of free fatty acids into the tissue, it will automaticallyreduce the synthesis of new fatty acid. Acyl-CoAmay also inhibit the mitochondrial tricarboxylatetransporter, thus preventing activation of the enzymeby egress of citrate from the mitochondria into the cytosol.Acetyl-CoA carboxylase is also regulated by hormonessuch as glucagon, epinephrine, and insulin viachanges in its phosphorylation state (details in Figure21–6).Malonyl-CoAAcyl-CoAGlucagonATPH 2 OP icAMP+ +AMPK(active)PAMPK(inactive)+ATPADPAMPKKcAMP-DEPENDENTPROTEIN KINASEFigure 21–6. Regulation of acetyl-CoA carboxylaseby phosphorylation/dephosphorylation. The enzyme isinactivated by phosphorylation by AMP-activated proteinkinase (AMPK), which in turn is phosphorylatedand activated by AMP-activated protein kinase kinase(AMPKK). Glucagon (and epinephrine), after increasingcAMP, activate this latter enzyme via cAMP-dependentprotein kinase. The kinase kinase enzyme is also believedto be activated by acyl-CoA. Insulin activatesacetyl-CoA carboxylase, probably through an “activator”protein and an insulin-stimulated protein kinase.+Pyruvate Dehydrogenase Is AlsoRegulated by Acyl-CoAAcyl-CoA causes an inhibition of pyruvate dehydrogenaseby inhibiting the ATP-ADP exchange transporter ofthe inner mitochondrial membrane, which leads to increasedintramitochondrial [ATP]/[ADP] ratios andtherefore to conversion of active to inactive pyruvatedehydrogenase (see Figure 17–6), thus regulating theavailability of acetyl-CoA for lipogenesis. Furthermore,oxidation of acyl-CoA due to increased levels of freefatty acids may increase the ratios of [acetyl-CoA]/[CoA] and [NADH]/[NAD + ] in mitochondria, inhibitingpyruvate dehydrogenase.Insulin Also Regulates Lipogenesisby Other MechanismsInsulin stimulates lipogenesis by several other mechanismsas well as by increasing acetyl-CoA carboxylaseactivity. It increases the transport of glucose into thecell (eg, in adipose tissue), increasing the availability ofboth pyruvate for fatty acid synthesis and glycerol3-phosphate for esterification of the newly formed fattyacids, and also converts the inactive form of pyruvatedehydrogenase to the active form in adipose tissue butnot in liver. Insulin also—by its ability to depress thelevel of intracellular cAMP—inhibits lipolysis in adiposetissue and thereby reduces the concentration of