Harpers

OXIDATION OF FATTY ACIDS: KETOGENESIS / 183Figure 22–4. Sequence of reactions in the oxidationof unsaturated fatty acids, eg, linoleic acid. ∆ 4 -cis-fattyacids or fatty acids forming ∆ 4 -cis-enoyl-CoA enter thepathway at the position shown. NADPH for the dienoyl-CoA reductase step is supplied by intramitochondrialsources such as glutamate dehydrogenase, isocitratedehydrogenase, and NAD(P)H transhydrogenase.high-fat diets and in some species by hypolipidemicdrugs such as clofibrate.The enzymes in peroxisomes do not attack shorterchainfatty acids; the β-oxidation sequence ends at octanoyl-CoA.Octanoyl and acetyl groups are both furtheroxidized in mitochondria. Another role of peroxisomalβ-oxidation is to shorten the side chain of cholesterol inbile acid formation (Chapter 26). Peroxisomes also takepart in the synthesis of ether glycerolipids (Chapter 24),cholesterol, and dolichol (Figure 26–2).OXIDATION OF UNSATURATED FATTYACIDS OCCURS BY A MODIFIED-OXIDATION PATHWAYThe CoA esters of these acids are degraded by the enzymesnormally responsible for β-oxidation until eithera ∆ 3 -cis-acyl-CoA compound or a ∆ 4 -cis-acyl-CoA compoundis formed, depending upon the position of thedouble bonds (Figure 22–4). The former compound isisomerized ( 3 cis v 2 -trans-enoyl-CoA isomerase)to the corresponding ∆ 2 -trans-CoA stage of β-oxidationfor subsequent hydration and oxidation. Any ∆ 4 -cis-acyl-CoA either remaining, as in the case of linoleic acid, orentering the pathway at this point after conversion byacyl-CoA dehydrogenase to ∆ 2 -trans-∆ 4 -cis-dienoyl-CoA, is then metabolized as indicated in Figure 22–4.KETOGENESIS OCCURS WHEN THEREIS A HIGH RATE OF FATTY ACIDOXIDATION IN THE LIVERUnder metabolic conditions associated with a high rateof fatty acid oxidation, the liver produces considerablequantities of acetoacetate and D()-3-hydroxybutyrate(β-hydroxybutyrate). Acetoacetate continually undergoesspontaneous decarboxylation to yield acetone.These three substances are collectively known as the ketonebodies (also called acetone bodies or [incorrectly*]“ketones”) (Figure 22–5). Acetoacetate and 3-hydroxybu-* The term “ketones” should not be used because 3-hydroxybutyrateis not a ketone and there are ketones in blood that are notketone bodies, eg, pyruvate, fructose.cis 12cis3 Cycles ofβ-oxidationH + + NADPHNADP +Linoleyl-CoAcis 6ciscis6 2CtransOO9 C S CoASOCoA3 Acetyl-CoA3 C S CoA∆ 3 -cis-∆ 6 -cis-Dienoyl-CoAOC∆ 3 -cis (or trans) → ∆ 2 -trans-ENOYL-CoAISOMERASESCoA∆ 2 -trans-∆ 6 -cis-Dienoyl-CoA(∆ 2 -trans-Enoyl-CoA stage of β-oxidation)1 Cycle ofβ-oxidationcis4 2trans∆ 2 -trans-∆ 4 -cis-Dienoyl-CoAtrans3CS∆ 3 -trans-Enoyl-CoAtransC2OOS∆ 2 -trans-Enoyl-CoA4 Cycles ofβ-oxidation5 Acetyl-CoACoAACYL-CoADEHYDROGENASE∆ 4 -cis-Enoyl-CoA∆ 2 -trans-∆ 4 -cis-DIENOYL-CoAREDUCTASE∆ 3 -cis (or trans) → ∆ 2 -trans-ENOYL-CoAISOMERASECoAAcetyl-CoA