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Home , Beta oxidation, Ketosis

ch22.qxd 3/16/04 10:57 AM Page 180

Oxidation of Fatty Acids: Ketogenesis 22

Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc

BIOMEDICAL IMPORTANCE more -soluble and exist as the un-ionized acid or as a anion. Although fatty acids are both oxidized to acetyl-CoA and synthesized from acetyl-CoA, fatty acid oxidation is not the simple reverse of fatty acid biosynthesis but an Fatty Acids Are Activated Before entirely different process taking place in a separate com- Being Catabolized partment of the cell. The separation of fatty acid oxida- Fatty acids must first be converted to an active interme- tion in mitochondria from biosynthesis in the diate before they can be catabolized. This is the only allows each process to be individually controlled and step in the complete degradation of a fatty acid that re- integrated with tissue requirements. Each step in fatty quires energy from ATP. In the presence of ATP and acid oxidation involves acyl-CoA derivatives catalyzed , the acyl-CoA synthetase (thioki- by separate , utilizes NAD+ and FAD as coen- nase) catalyzes the conversion of a fatty acid (or free zymes, and generates ATP. It is an aerobic process, re- fatty acid) to an “active fatty acid” or acyl-CoA, which quiring the presence of . uses one high-energy phosphate with the formation of Increased fatty acid oxidation is a characteristic of AMP and PPi (Figure 22–1). The PPi is hydrolyzed by starvation and of diabetes mellitus, leading to inorganic pyrophosphatase with the loss of a further body production by the (). high-energy phosphate, ensuring that the overall reac- are acidic and when produced in excess over long peri- tion goes to completion. Acyl-CoA synthetases are ods, as in diabetes, cause , which is ulti- found in the endoplasmic reticulum, , and mately fatal. Because is dependent inside and on the outer membrane of mitochondria. upon fatty acid oxidation, any impairment in fatty acid oxidation leads to . This occurs in vari- ous states of deficiency or deficiency of es- Long-Chain Fatty Acids Penetrate the sential enzymes in fatty acid oxidation, eg, carnitine Inner Mitochondrial Membrane as palmitoyltransferase, or inhibition of fatty acid oxida- Carnitine Derivatives tion by poisons, eg, hypoglycin. Carnitine (β-hydroxy-γ-trimethylammonium buty- +    − rate), (CH3)3N CH2 CH(OH) CH2 COO , is widely distributed and is particularly abundant in mus- OXIDATION OF FATTY ACIDS OCCURS cle. Long-chain acyl-CoA (or FFA) will not penetrate IN MITOCHONDRIA the inner membrane of mitochondria. However, car- Fatty Acids Are Transported in the nitine palmitoyltransferase-I, present in the outer Blood as Free Fatty Acids (FFA) mitochondrial membrane, converts long-chain acyl- CoA to acylcarnitine, which is able to penetrate the Free fatty acids—also called unesterified (UFA) or non- inner membrane and gain access to the β-oxidation esterified (NEFA) fatty acids—are fatty acids that are in system of enzymes (Figure 22–1). Carnitine-acylcar- the unesterified state. In plasma, longer-chain FFA are nitine acts as an inner membrane ex- combined with albumin, and in the cell they are at- change transporter. Acylcarnitine is transported in, tached to a fatty acid-binding , so that in fact coupled with the transport out of one molecule of car- they are never really “free.” Shorter-chain fatty acids are nitine. The acylcarnitine then reacts with CoA, cat- 180 ch22.qxd 3/16/04 10:57 AM Page 181

OXIDATION OF FATTY ACIDS: KETOGENESIS /181

CoA SH ATP AMP + PP i α + H3C CoA FFA Acyl-CoA β CO S CoA Palmitoyl-CoA

CARNITINE OUTER Acyl-CoA PALMITOYL- H C α SYNTHETASE TRANSFERASE MITOCHONDRIAL 3 I MEMBRANE β CO S CoA +

CH3 CO S CoA

Acyl-CoA CoA Acetyl-CoA

Successive removal of acetyl-CoA (C2) units Carnitine Acylcarnitine

8 CH3 CO S CoA Acetyl-CoA CARNITINE INNER ACYLCAR- CARNITINE MITOCHONDRIAL β PALMITOYL- NITINE Figure 22–2. Overview of -oxidation of fatty acids. TRANSFERASE TRANSLOCASE MEMBRANE II The Cyclic Reaction Sequence Generates CoA Carnitine Acylcarnitine FADH2 & NADH Several enzymes, known collectively as “fatty acid oxi- Acylcarnitine Acyl-CoA β-Oxidation dase,” are found in the or inner membrane adjacent to the respiratory chain. These cat- alyze the oxidation of acyl-CoA to acetyl-CoA, the sys- tem being coupled with the phosphorylation of ADP to Figure 22–1. Role of carnitine in the transport of ATP (Figure 22–3). long-chain fatty acids through the inner mitochondrial The first step is the removal of two hydrogen atoms membrane. Long-chain acyl-CoA cannot pass through from the 2(α)- and 3(β)- atoms, catalyzed by the inner mitochondrial membrane, but its metabolic acyl-CoA dehydrogenase and requiring FAD. This re- product, acylcarnitine, can. sults in the formation of ∆2-trans-enoyl-CoA and FADH2. The reoxidation of FADH2 by the respiratory chain requires the mediation of another flavoprotein, alyzed by carnitine palmitoyltransferase-II, located termed electron-transferring flavoprotein (Chapter on the inside of the inner membrane. Acyl-CoA is re- 11). Water is added to saturate the double bond and formed in the mitochondrial matrix, and carnitine is form 3-hydroxyacyl-CoA, catalyzed by 2-enoyl-CoA liberated. hydratase. The 3-hydroxy derivative undergoes further dehydrogenation on the 3-carbon catalyzed by L(+)-3- hydroxyacyl-CoA dehydrogenase to form the corre- -OXIDATION OF FATTY ACIDS sponding 3-ketoacyl-CoA compound. In this case, INVOLVES SUCCESSIVE CLEAVAGE NAD+ is the coenzyme involved. Finally, 3-ketoacyl- WITH RELEASE OF ACETYL-CoA CoA is split at the 2,3- position by (3-keto- acyl-CoA-thiolase), forming acetyl-CoA and a new acyl- In β-oxidation (Figure 22–2), two at a time are CoA two carbons shorter than the original acyl-CoA cleaved from acyl-CoA molecules, starting at the car- molecule. The acyl-CoA formed in the cleavage reac- boxyl end. The chain is broken between the α(2)- and tion reenters the oxidative pathway at reaction 2 (Fig- β(3)-carbon atoms—hence the name β-oxidation. The ure 22–3). In this way, a long-chain fatty acid may be two-carbon units formed are acetyl-CoA; thus, palmi- degraded completely to acetyl-CoA (C2 units). Since toyl-CoA forms eight acetyl-CoA molecules. acetyl-CoA can be oxidized to CO2 and water via the ch22.qxd 3/16/04 10:57 AM Page 182

182 / CHAPTER 22

O Figure 22–3. β-Oxidation of fatty acids. Long-chain 3 2 Ð R CH2 CH2 C O acyl-CoA is cycled through reactions 2–5, acetyl-CoA Fatty acid being split off, each cycle, by thiolase (reaction 5). CoA SH ATP When the acyl radical is only four carbon atoms in

ACYL-CoA Mg2+ length, two acetyl-CoA molecules are formed in reac- 1 SYNTHETASE tion 5. AMP + PP i O

3 2 R CH2 CH2 C S CoA cycle (which is also found within the mito- Acyl-CoA chondria), the complete oxidation of fatty acids is achieved.

(outside) C side Oxidation of a Fatty Acid With an Odd INNER MITOCHONDRIAL MEMBRANEC CARNITINE TRANSPORTER Number of Carbon Atoms Yields Acetyl- M side (inside) CoA Plus a Molecule of Propionyl-CoA Fatty acids with an odd number of carbon atoms are oxi- O dized by the pathway of β-oxidation, producing acetyl- 3 2 R CH2 CH2 C S CoA CoA, until a three-carbon (propionyl-CoA) residue re- Acyl-CoA mains. This compound is converted to succinyl-CoA, a constituent of the (Figure 19–2). Hence, FAD the propionyl residue from an odd-chain fatty acid is 2 ACYL-CoA the only part of a fatty acid that is glucogenic. DEHYDROGENASE 2 P

FADH2 H2O O Respiratory chain 3 2 Oxidation of Fatty Acids Produces R CH CH C S CoA ∆2-trans-Enoyl-CoA a Large Quantity of ATP

H2O Transport in the respiratory chain of electrons from ∆2 3 -ENOYL-CoA FADH2 and NADH will lead to the synthesis of five HYDRATASE high-energy phosphates (Chapter 12) for each of the first seven acetyl-CoA molecules formed by β-oxidation OH O × 3 2 of palmitate (7 5 = 35). A total of 8 mol of acetyl- R CH CH2 C S CoA CoA is formed, and each will give rise to 12 mol of L(+)-3-Hydroxy- acyl-CoA ATP on oxidation in the citric acid cycle, making 8 ×

NAD+ 12 = 96 mol. Two must be subtracted for the initial ac- tivation of the fatty acid, yielding a net gain of 129 mol 4 L(+)-3-HYDROXYACYL- × CoA DEHYDROGENASE 3 P of ATP per mole of palmitate, or 129 51.6* = 6656 + kJ. This represents 68% of the free energy of combus- NADH + H H2O Respiratory O O tion of . chain 3 2 R C CH2 C S CoA

3-Ketoacyl-CoA Peroxisomes Oxidize Very Long

CoA SH Chain Fatty Acids 5 THIOLASE A modified form of β-oxidation is found in peroxi- somes and leads to the formation of acetyl-CoA and O O H2O2 (from the flavoprotein-linked dehydrogenase

R C S CoA + CH3 C S CoA step), which is broken down by . Thus, this de- Acyl-CoA Acetyl-CoA hydrogenation in peroxisomes is not linked directly to phosphorylation and the generation of ATP. The sys-

Citric tem facilitates the oxidation of very long chain fatty acid acids (eg, C20, C22). These enzymes are induced by cycle

* ∆G for the ATP reaction, as explained in Chapter 17. 2CO2 ch22.qxd 3/16/04 10:57 AM Page 183

OXIDATION OF FATTY ACIDS: KETOGENESIS /183

Figure 22–4. Sequence of reactions in the oxidation O cis cis of unsaturated fatty acids, eg, . ∆4-cis-fatty 12 9 C S CoA acids or fatty acids forming ∆4-cis-enoyl-CoA enter the pathway at the position shown. NADPH for the dienoyl- Linoleyl-CoA CoA reductase step is supplied by intramitochondrial sources such as glutamate dehydrogenase, isocitrate 3 Cycles of β-oxidation 3 Acetyl-CoA dehydrogenase, and NAD(P)H transhydrogenase. O cis cis high-fat diets and in some species by hypolipidemic 6 3 C S CoA drugs such as clofibrate. The enzymes in peroxisomes do not attack shorter- ∆3-cis-∆6-cis-Dienoyl-CoA chain fatty acids; the β-oxidation sequence ends at oc- ∆3-cis (or trans) → ∆2-trans-ENOYL-CoA tanoyl-CoA. Octanoyl and acetyl groups are both further ISOMERASE oxidized in mitochondria. Another role of peroxisomal β cis -oxidation is to shorten the side chain of in 62 formation (Chapter 26). Peroxisomes also take part in the synthesis of ether glycerolipids (Chapter 24), C S CoA trans cholesterol, and dolichol (Figure 26–2). O

∆2 ∆6 OXIDATION OF UNSATURATED FATTY -trans- -cis-Dienoyl-CoA ∆2 β ACIDS OCCURS BY A MODIFIED ( -trans-Enoyl-CoA stage of -oxidation) -OXIDATION PATHWAY 1 Cycle of β-oxidation Acetyl-CoA The CoA esters of these acids are degraded by the en- cis zymes normally responsible for β-oxidation until either 42 a ∆3-cis-acyl-CoA compound or a ∆4-cis-acyl-CoA com- C S CoA pound is formed, depending upon the position of the trans ACYL-CoA DEHYDROGENASE double bonds (Figure 22–4). The former compound is O 3 v 2 isomerized ( cis -trans-enoyl-CoA isomerase) ∆2 ∆4 ∆4 ∆2 β -trans- -cis-Dienoyl-CoA -cis-Enoyl-CoA to the corresponding -trans-CoA stage of -oxidation + 4 H + NADPH for subsequent hydration and oxidation. Any ∆ -cis-acyl- ∆2-trans-∆4-cis-DIENOYL-CoA REDUCTASE CoA either remaining, as in the case of linoleic acid, or NADP+ entering the pathway at this point after conversion by ∆2 ∆4 acyl-CoA dehydrogenase to -trans- -cis-dienoyl- O CoA, is then metabolized as indicated in Figure 22–4. 3 C S CoA KETOGENESIS OCCURS WHEN THERE trans IS A HIGH RATE OF FATTY ACID ∆3 OXIDATION IN THE LIVER -trans-Enoyl-CoA ∆3-cis (or trans) → ∆2-trans-ENOYL-CoA Under metabolic conditions associated with a high rate ISOMERASE of fatty acid oxidation, the liver produces considerable quantities of acetoacetate and D()-3-hydroxybutyrate (β-hydroxybutyrate). Acetoacetate continually under- O goes spontaneous decarboxylation to yield . C S CoA These three substances are collectively known as the ke- trans 2 tone bodies (also called acetone bodies or [incorrectly*] “”) (Figure 22–5). Acetoacetate and 3-hydroxybu- ∆2-trans-Enoyl-CoA

4 Cycles of β-oxidation * The term “ketones” should not be used because 3-hydroxybu- tyrate is not a ketone and there are ketones in blood that are not ketone bodies, eg, pyruvate, fructose. 5 Acetyl-CoA ch22.qxd 3/16/04 10:57 AM Page 184

184 / CHAPTER 22

O tyrate are interconverted by the mitochondrial enzyme D CH C CH ( )-3-hydroxybutyrate dehydrogenase; the equi- 3 3 librium is controlled by the mitochondrial [NAD+]/ Acetone CO2 [NADH] ratio, ie, the state. The concentration of total ketone bodies in the blood of well-fed mam- mals does not normally exceed 0.2 mmol/L except in ruminants, where 3-hydroxybutyrate is formed contin- O Spontaneous uously from butyric acid (a product of ruminal fermen- Ð tation) in the wall. In vivo, the liver appears to CH3 C CH2 COO be the only organ in nonruminants to add significant Acetoacetate quantities of ketone bodies to the blood. Extrahepatic D(Ð)-3-HYDROXYBUTYRATE tissues utilize them as respiratory substrates. The net DEHYDROGENASE NADH + H+ flow of ketone bodies from the liver to the extrahepatic tissues results from active hepatic synthesis coupled OH with very low utilization. The reverse situation occurs NAD+ in extrahepatic tissues (Figure 22–6). Ð CH3 CH CH2 COO

D(Ð)-3-Hydroxybutyrate 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) Is an Intermediate Figure 22–5. Interrelationships of the ketone bod- in the Pathway of Ketogenesis ies. D(−)-3-hydroxybutyrate dehydrogenase is a mito- chondrial enzyme. Enzymes responsible for ketone body formation are as- sociated mainly with the mitochondria. Two acetyl- CoA molecules formed in β-oxidation condense with one another to form acetoacetyl-CoA by a reversal of the thiolase reaction. Acetoacetyl-CoA, which is the

EXTRAHEPATIC LIVER BLOOD TISSUES

Acyl-CoA FFA

Glucose Acyl-CoA

Acetyl-CoA URINE Acetyl-CoA

Ketone Ketone Ketone bodies bodies bodies

Acetone Citric Citric acid acid cycle cycle LUNGS

2CO2 2CO2

Figure 22–6. Formation, utilization, and excretion of ketone bodies. (The main pathway is indicated by the solid arrows.) ch22.qxd 3/16/04 10:57 AM Page 185

OXIDATION OF FATTY ACIDS: KETOGENESIS /185

starting material for ketogenesis, also arises directly predominant ketone body present in the blood and from the terminal four carbons of a fatty acid during urine in ketosis. β-oxidation (Figure 22–7). Condensation of ace- toacetyl-CoA with another molecule of acetyl-CoA Ketone Bodies Serve as a Fuel by 3-hydroxy-3-methylglutaryl-CoA synthase forms for Extrahepatic Tissues HMG-CoA. 3-Hydroxy-3-methylglutaryl-CoA lyase then causes acetyl-CoA to split off from the HMG- While an active enzymatic mechanism produces ace- CoA, leaving free acetoacetate. The carbon atoms split toacetate from acetoacetyl-CoA in the liver, acetoac- off in the acetyl-CoA molecule are derived from the etate once formed cannot be reactivated directly except original acetoacetyl-CoA molecule. Both enzymes in the cytosol, where it is used in a much less active must be present in mitochondria for ketogenesis to pathway as a precursor in cholesterol synthesis. This ac- take place. This occurs solely in liver and rumen ep- counts for the net production of ketone bodies by the ithelium. D(−)-3-Hydroxybutyrate is quantitatively the liver.

FFA ATP CoA ACYL-CoA SYNTHETASE

Esterification Tr iacylglycerol Acyl-CoA Phospholipid

β-Oxidation (Acetyl-CoA)n

O O

CH3 C CH2 C S CoA Acetoacetyl-CoA HMG-CoA SYNTHASE CoA SH THIOLASE OH O

H2O CH3 C CH2 C S CoA O Ð *CH2 *COO CoA SH *CH3 *C S CoA 3-Hydroxy-3-methyl- Acetyl-CoA glutaryl-CoA (HMG-CoA)

HMG-CoA CH3 CO S CoA LYASE Acetyl-CoA Citric O acid cycle CH3 C Ð *CH2 *COO Acetoacetate 2CO 2 NADH + H+ D(Ð)-3-HYDROXYBUTYRATE DEHYDROGENASE NAD+ OH Ð CH3 CH *CH2 *COO D(Ð)-3-Hydroxybutyrate Figure 22–7. Pathways of ketogenesis in the liver. (FFA, free fatty acids; HMG, 3-hy- droxy-3-methylglutaryl.) ch22.qxd 3/16/04 10:57 AM Page 186

186 / CHAPTER 22

In extrahepatic tissues, acetoacetate is activated to ketonemia, not the , is the preferred method acetoacetyl-CoA by succinyl-CoA-acetoacetate CoA of assessing the severity of ketosis. transferase. CoA is transferred from succinyl-CoA to form acetoacetyl-CoA (Figure 22–8). The acetoacetyl- KETOGENESIS IS REGULATED CoA is split to acetyl-CoA by thiolase and oxidized in AT THREE CRUCIAL STEPS the citric acid cycle. If the blood level is raised, oxida- tion of ketone bodies increases until, at a concentration (1) Ketosis does not occur in vivo unless there is an of approximately 12 mmol/L, they saturate the oxida- increase in the level of circulating free fatty acids that tive machinery. When this occurs, a large proportion of arise from of triacylglycerol in . the oxygen consumption may be accounted for by the Free fatty acids are the precursors of ketone bodies oxidation of ketone bodies. in the liver. The liver, both in fed and in condi- In most cases, ketonemia is due to increased pro- tions, extracts about 30% of the free fatty acids passing duction of ketone bodies by the liver rather than to a through it, so that at high concentrations the flux pass- deficiency in their utilization by extrahepatic tissues. ing into the liver is substantial. Therefore, the factors While acetoacetate and D(−)-3-hydroxybutyrate are regulating mobilization of free fatty acids from adi- readily oxidized by extrahepatic tissues, acetone is diffi- pose tissue are important in controlling ketogenesis cult to oxidize in vivo and to a large extent is volatilized (Figures 22–9 and 25–8). in the lungs. (2) After uptake by the liver, free fatty acids are ei- In moderate ketonemia, the loss of ketone bodies via ther -oxidized to CO2 or ketone bodies or esterified the urine is only a few percent of the total ketone body to triacylglycerol and phospholipid. There is regulation production and utilization. Since there are renal thresh- of entry of fatty acids into the oxidative pathway by car- old-like effects (there is not a true threshold) that vary nitine palmitoyltransferase-I (CPT-I), and the remain- between species and individuals, measurement of the der of the fatty acid uptake is esterified. CPT-I activity is

EXTRAHEPATIC TISSUES eg, MUSCLE

FFA

Acyl-CoA Acetyl-CoA LIVER β-Oxidation THIOLASE

Acetyl-CoA Acetoacetyl-CoA Succinate OAA

CoA Citric acid cycle HMG-CoA TRANSFERASE Succinyl- Citrate CoA 2CO Acetoacetate Acetoacetate 2 + NADH + H NADH + H+ + NAD NAD+ 3-Hydroxybutyrate 3-Hydroxybutyrate

Figure 22–8. Transport of ketone bodies from the liver and pathways of utilization and oxidation in extrahe- patic tissues. ch22.qxd 3/16/04 10:57 AM Page 187

OXIDATION OF FATTY ACIDS: KETOGENESIS /187

Tr iacylglycerol (3) In turn, the acetyl-CoA formed in β-oxidation is oxidized in the citric acid cycle, or it enters the pathway of ketogenesis to form ketone bodies. As the level of ADIPOSE TISSUE 1 serum free fatty acids is raised, proportionately more Lipolysis free fatty acid is converted to ketone bodies and less is oxidized via the citric acid cycle to CO2. The partition FFA of acetyl-CoA between the ketogenic pathway and the pathway of oxidation to CO2 is so regulated that the BLOOD total free energy captured in ATP which results from the oxidation of free fatty acids remains constant. This FFA may be appreciated when it is realized that complete oxidation of 1 mol of palmitate involves a net produc- LIVER β tion of 129 mol of ATP via -oxidation and CO2 pro- duction in the citric acid cycle (see above), whereas only 33 mol of ATP are produced when acetoacetate is the Acyl-CoA CPT-I end product and only 21 mol when 3-hydroxybutyrate gateway 2 Esterification is the end product. Thus, ketogenesis may be regarded β-Oxidation as a mechanism that allows the liver to oxidize increas- ing quantities of fatty acids within the constraints of a Acylglycerols tightly coupled system of oxidative phosphorylation— without increasing its total energy expenditure. Acetyl-CoA Citric acid Theoretically, a fall in concentration of oxaloacetate, 3 cycle particularly within the mitochondria, could impair the Ketogenesis ability of the citric acid cycle to metabolize acetyl-CoA and divert fatty acid oxidation toward ketogenesis.

CO2 Such a fall may occur because of an increase in the + β Ketone bodies [NADH]/[NAD ] ratio caused by increased -oxida- tion affecting the equilibrium between oxaloacetate and Figure 22–9. Regulation of ketogenesis. 1 –3 show malate and decreasing the concentration of oxaloac- three crucial steps in the pathway of of free etate. However, , which catalyzes fatty acids (FFA) that determine the magnitude of keto- the conversion of pyruvate to oxaloacetate, is activated genesis. (CPT-I, carnitine palmitoyltransferase-I.) by acetyl-CoA. Consequently, when there are signifi- cant amounts of acetyl-CoA, there should be sufficient oxaloacetate to initiate the condensing reaction of the citric acid cycle. low in the fed state, leading to depression of fatty acid oxidation, and high in starvation, allowing fatty acid ox- idation to increase. Malonyl-CoA, the initial intermedi- CLINICAL ASPECTS ate in fatty acid biosynthesis (Figure 21–1), formed by Impaired Oxidation of Fatty Acids acetyl-CoA carboxylase in the fed state, is a potent in- Gives Rise to Diseases Often hibitor of CPT-I (Figure 22–10). Under these condi- Associated With Hypoglycemia tions, free fatty acids enter the liver cell in low concen- trations and are nearly all esterified to acylglycerols and Carnitine deficiency can occur particularly in the new- transported out of the liver in very low density lipopro- born—and especially in preterm infants—owing to in- teins (VLDL). However, as the concentration of free adequate biosynthesis or renal leakage. Losses can also fatty acids increases with the onset of starvation, acetyl- occur in hemodialysis. This suggests a -like di- CoA carboxylase is inhibited directly by acyl-CoA, and etary requirement for carnitine in some individuals. [malonyl-CoA] decreases, releasing the inhibition of Symptoms of deficiency include hypoglycemia, which CPT-I and allowing more acyl-CoA to be β-oxidized. is a consequence of impaired fatty acid oxidation and These events are reinforced in starvation by decrease in accumulation with muscular weakness. Treatment the []/[] ratio. Thus, β-oxidation from is by oral supplementation with carnitine. free fatty acids is controlled by the CPT-I gateway into Inherited CPT-I deficiency affects only the liver, the mitochondria, and the balance of the free fatty acid resulting in reduced fatty acid oxidation and ketogene- uptake not oxidized is esterified. sis, with hypoglycemia. CPT-II deficiency affects pri- ch22.qxd 3/16/04 10:57 AM Page 188

188 / CHAPTER 22

Glucose FFA VLDL BLOOD

LIVER Acetyl-CoA Acylglycerols

Insulin − + Acyl-CoA Esterification

Lipogenesis ACETYL-CoA CARBOXYLASE Cytosol − Glucagon

Malonyl-CoA − CARNITINE PALMITOYL- M TRANSFERASE I ito ch m on Palmitate em d b ria ra l ne Figure 22–10. Regulation of Acyl-CoA long-chain fatty acid oxidation in the β -Oxidation liver. (FFA, free fatty acids; VLDL, very low density lipoprotein.) Posi- Acetyl-CoA tive (+ ) and negative (− ) regulatory effects are represented by broken Ketogenesis CO2 arrows and substrate flow by solid Ketone bodies arrows.

marily skeletal muscle and, when severe, the liver. The syndrome occurs in individuals with a rare inherited drugs (glyburide [glibenclamide] and absence of peroxisomes in all tissues. They accumulate tolbutamide), used in the treatment of C26–C38 polyenoic acids in brain tissue and also exhibit mellitus, reduce fatty acid oxidation and, therefore, hy- a generalized loss of peroxisomal functions, eg, im- perglycemia by inhibiting CPT-I. paired bile acid and ether lipid synthesis. Inherited defects in the enzymes of β-oxidation and ketogenesis also lead to nonketotic hypoglycemia, coma, Ketoacidosis Results From and fatty liver. Defects are known in long- and short- Prolonged Ketosis chain 3-hydroxyacyl-CoA dehydrogenase (deficiency of the long-chain enzyme may be a cause of acute fatty Higher than normal quantities of ketone bodies present liver of pregnancy). 3-Ketoacyl-CoA thiolase and in the blood or urine constitute ketonemia (hyperke- HMG-CoA lyase deficiency also affect the degradation tonemia) or ketonuria, respectively. The overall condi- of leucine, a ketogenic (Chapter 30). tion is called ketosis. Acetoacetic and 3-hydroxybutyric Jamaican vomiting sickness is caused by eating the acids are both moderately strong acids and are buffered unripe fruit of the akee tree, which contains a toxin, when present in blood or other tissues. However, their hypoglycin, that inactivates medium- and short-chain continual excretion in quantity progressively depletes acyl-CoA dehydrogenase, inhibiting β-oxidation and the alkali reserve, causing ketoacidosis. This may be causing hypoglycemia. Dicarboxylic aciduria is char- fatal in uncontrolled diabetes mellitus. ω acterized by the excretion of C6–C10 -dicarboxylic The basic form of ketosis occurs in starvation and acids and by nonketotic hypoglycemia. It is caused by a involves depletion of available coupled lack of mitochondrial medium-chain acyl-CoA dehy- with mobilization of free fatty acids. This general pat- drogenase. Refsum’s disease is a rare neurologic disor- tern of metabolism is exaggerated to produce the patho- der due to a defect that causes the accumulation of phy- logic states found in diabetes mellitus, twin lamb dis- tanic acid, which is found in plant foodstuffs and ease, and ketosis in lactating cattle. Nonpathologic blocks β-oxidation. Zellweger’s (cerebrohepatorenal) forms of ketosis are found under conditions of high-fat ch22.qxd 3/16/04 10:57 AM Page 189

OXIDATION OF FATTY ACIDS: KETOGENESIS /189

feeding and after severe exercise in the postabsorptive • Diseases associated with impairment of fatty acid oxi- state. dation lead to hypoglycemia, fatty infiltration of or- gans, and hypoketonemia. SUMMARY • Ketosis is mild in starvation but severe in diabetes mellitus and ruminant ketosis. • Fatty acid oxidation in mitochondria leads to the gen- eration of large quantities of ATP by a process called β-oxidation that cleaves acetyl-CoA units sequentially from fatty acyl chains. The acetyl-CoA is oxidized in REFERENCES the citric acid cycle, generating further ATP. Eaton S, Bartlett K, Pourfarzam M: Mammalian mitochondrial β- • The ketone bodies (acetoacetate, 3-hydroxybutyrate, oxidation. Biochem J 1996;320:345. and acetone) are formed in hepatic mitochondria Mayes PA, Laker ME: Regulation of ketogenesis in the liver. when there is a high rate of fatty acid oxidation. The Biochem Soc Trans 1981;9:339. pathway of ketogenesis involves synthesis and break- McGarry JD, Foster DW: Regulation of hepatic fatty acid oxida- down of 3-hydroxy-3-methylglutaryl-CoA (HMG- tion and ketone body production. Annu Rev Biochem CoA) by two key enzymes, HMG-CoA synthase and 1980;49:395. HMG-CoA lyase. Osmundsen H, Hovik R: β-Oxidation of polyunsaturated fatty • Ketone bodies are important fuels in extrahepatic tis- acids. Biochem Soc Trans 1988;16:420. sues. Reddy JK, Mannaerts GP: Peroxisomal . Annu Rev Nutr 1994;14:343. • Ketogenesis is regulated at three crucial steps: (1) Scriver CR et al (editors): The Metabolic and Molecular Bases of In- control of free fatty acid mobilization from adipose herited Disease, 8th ed. McGraw-Hill, 2001. tissue; (2) the activity of carnitine palmitoyltrans- Treem WR et al: Acute fatty liver of pregnancy and long-chain 3- ferase-I in liver, which determines the proportion of hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatol- the fatty acid flux that is oxidized rather than esteri- ogy 1994;19:339. fied; and (3) partition of acetyl-CoA between the Wood PA: Defects in mitochondrial beta-oxidation of fatty acids. pathway of ketogenesis and the citric acid cycle. Curr Opin Lipidol 1999;10:107.