Harpers

BIOSYNTHESIS OF FATTY ACIDS / 177the principal site of fatty acid synthesis. Citrate, formedafter condensation of acetyl-CoA with oxaloacetate inthe citric acid cycle within mitochondria, is translocatedinto the extramitochondrial compartment via thetricarboxylate transporter, where in the presence ofCoA and ATP it undergoes cleavage to acetyl-CoA andoxaloacetate catalyzed by ATP-citrate lyase, which increasesin activity in the well-fed state. The acetyl-CoAis then available for malonyl-CoA formation and synthesisto palmitate (Figure 21–4). The resulting oxaloacetatecan form malate via NADH-linked malatedehydrogenase, followed by the generation of NADPHvia the malic enzyme. The NADPH becomes availablefor lipogenesis, and the pyruvate can be used to regenerateacetyl-CoA after transport into the mitochondrion.This pathway is a means of transferring reducingequivalents from extramitochondrial NADH to NADP.Alternatively, malate itself can be transported into themitochondrion, where it is able to re-form oxaloacetate.Note that the citrate (tricarboxylate) transporter in themitochondrial membrane requires malate to exchangewith citrate (see Figure 12-10). There is little ATPcitratelyase or malic enzyme in ruminants, probablybecause in these species acetate (derived from therumen and activated to acetyl CoA extramitochondrially)is the main source of acetyl-CoA.RCH 2OCSAcyl-CoACoA3-KETOACYL-CoASYNTHASERROOCH 2 C S CoACOOHMalonyl-CoACoA SH + CO 2OCH 2 C CH 2 C S3-Ketoacyl-CoA3-KETOACYL-CoAREDUCTASEOHONADP +CH 2 CH CH 2 C S3-Hydroxyacyl-CoA+CoANADPH + H +CoAElongation of Fatty Acid Chains Occursin the Endoplasmic ReticulumThis pathway (the “microsomal system”) elongates saturatedand unsaturated fatty acyl-CoAs (from C 10 upward)by two carbons, using malonyl-CoA as acetyldonor and NADPH as reductant, and is catalyzed bythe microsomal fatty acid elongase system of enzymes(Figure 21–5). Elongation of stearyl-CoA in brain increasesrapidly during myelination in order to provideC 22 and C 24 fatty acids for sphingolipids.THE NUTRITIONAL STATEREGULATES LIPOGENESISExcess carbohydrate is stored as fat in many animals inanticipation of periods of caloric deficiency such as starvation,hibernation, etc, and to provide energy for usebetween meals in animals, including humans, that taketheir food at spaced intervals. Lipogenesis converts surplusglucose and intermediates such as pyruvate, lactate,and acetyl-CoA to fat, assisting the anabolic phase ofthis feeding cycle. The nutritional state of the organismis the main factor regulating the rate of lipogenesis.Thus, the rate is high in the well-fed animal whose dietcontains a high proportion of carbohydrate. It is depressedunder conditions of restricted caloric intake, on3-HYDROXYACYL-CoADEHYDRASEOR CH 2 CH CH C S2-trans-Enoyl-CoA2-trans-ENOYL-CoAREDUCTASEOR CH 2 CH 2 CH 2 CAcyl-CoAH 2 ONADP +SCoANADPH + H +CoAFigure 21–5. Microsomal elongase system for fattyacid chain elongation. NADH is also used by the reductases,but NADPH is preferred.a fat diet, or when there is a deficiency of insulin, as indiabetes mellitus. These latter conditions are associatedwith increased concentrations of plasma free fatty acids,and an inverse relationship has been demonstrated betweenhepatic lipogenesis and the concentration ofserum-free fatty acids. Lipogenesis is increased when su-