Harpers

186 / CHAPTER 22In extrahepatic tissues, acetoacetate is activated toacetoacetyl-CoA by succinyl-CoA-acetoacetate CoAtransferase. CoA is transferred from succinyl-CoA toform acetoacetyl-CoA (Figure 22–8). The acetoacetyl-CoA is split to acetyl-CoA by thiolase and oxidized inthe citric acid cycle. If the blood level is raised, oxidationof ketone bodies increases until, at a concentrationof approximately 12 mmol/L, they saturate the oxidativemachinery. When this occurs, a large proportion ofthe oxygen consumption may be accounted for by theoxidation of ketone bodies.In most cases, ketonemia is due to increased productionof ketone bodies by the liver rather than to adeficiency in their utilization by extrahepatic tissues.While acetoacetate and D(−)-3-hydroxybutyrate arereadily oxidized by extrahepatic tissues, acetone is difficultto oxidize in vivo and to a large extent is volatilizedin the lungs.In moderate ketonemia, the loss of ketone bodies viathe urine is only a few percent of the total ketone bodyproduction and utilization. Since there are renal threshold-likeeffects (there is not a true threshold) that varybetween species and individuals, measurement of theketonemia, not the ketonuria, is the preferred methodof assessing the severity of ketosis.KETOGENESIS IS REGULATEDAT THREE CRUCIAL STEPS(1) Ketosis does not occur in vivo unless there is anincrease in the level of circulating free fatty acids thatarise from lipolysis of triacylglycerol in adipose tissue.Free fatty acids are the precursors of ketone bodiesin the liver. The liver, both in fed and in fasting conditions,extracts about 30% of the free fatty acids passingthrough it, so that at high concentrations the flux passinginto the liver is substantial. Therefore, the factorsregulating mobilization of free fatty acids from adiposetissue are important in controlling ketogenesis(Figures 22–9 and 25–8).(2) After uptake by the liver, free fatty acids are either-oxidized to CO 2 or ketone bodies or esterifiedto triacylglycerol and phospholipid. There is regulationof entry of fatty acids into the oxidative pathway by carnitinepalmitoyltransferase-I (CPT-I), and the remainderof the fatty acid uptake is esterified. CPT-I activity isEXTRAHEPATIC TISSUESeg, MUSCLEFFAAcyl-CoAβ-OxidationAcetyl-CoAHMG-CoAAcetoacetateNADH + H +3-HydroxybutyrateNAD +LIVERAcetyl-CoATHIOLASEAcetoacetyl-CoASuccinateCoATRANSFERASECitric acid cycleSuccinyl- CitrateCoAAcetoacetate2CO 2NADH + H +NAD +3-HydroxybutyrateOAATransport of ketone bodies from the liver and pathways of utilization and oxidation in extrahe-Figure 22–8.patic tissues.