2 Acetyl-CoA

FIGURE 17-19 D-ß-Hydroxybutyrate as a fuel. D-ß-Hydroxybutyrate, synthesized in the liver, passes into the blood and thus to other tissues, where it is converted in three steps to acetyl-CoA. It is first oxidized to acetoacetate, which is activated with coenzyme A donated from succinyl-CoA, then split by thiolase. The acetyl-CoA thus formed is used for energy production.

thiolase synthesis by gluconeogenesis, for example, oxidation of cycle intermediates slows—and so does acetyl-CoA oxidation. Moreover, the liver contains only a limited amount of coenzyme A, and when most of it is tied up in acetyl-CoA, ¡3 oxidation slows for want of the free coenzyme. The production and export of ketone bodies free coen-zyme A, allowing continued fatty acid oxidation.

Ketone Bodies Are Overproduced in Diabetes and during Starvation

Starvation and untreated diabetes mellitus lead to overproduction of ketone bodies, with several associated medical problems. During starvation, gluco-neogenesis depletes citric acid cycle intermediates, diverting acetyl-CoA to ketone body production (Fig. 17-20). In untreated diabetes, when the insulin level is insufficient, extrahepatic tissues cannot take up glucose efficiently from the blood, either for fuel or for conversion to fat. Under these conditions, levels of malonyl-CoA (the starting material for fatty acid synthesis) fall, inhibition of carnitine acyltransferase I is relieved, and fatty acids enter mitochondria to be degraded to acetyl-CoA—which cannot pass through the citric acid cycle because cycle intermediates have been drawn off for use as substrates in gluconeogenesis. The resulting accumulation of acetyl-CoA accelerates the formation of ke-tone bodies beyond the capacity of extrahepatic tissues to oxidize them. The increased blood levels of acetoac-etate and d-3-hydroxybutyrate lower the blood pH, causing the condition known as acidosis. Extreme acidosis can lead to coma and in some cases death. Ketone bodies in the blood and urine of untreated diabetics can reach extraordinary levels—a blood concentration of 90 mg/100 mL (compared with a normal level of <3 mg/100 mL) and urinary excretion of 5,000 mg/24 hr (compared with a normal rate of <125 mg/ 24 hr). This condition is called ketosis.

Individuals on very low-calorie diets, using the fats stored in adipose tissue as their major energy source, also have increased levels of ketone bodies in their blood and urine. These levels must be monitored to avoid the dangers of acidosis and ketosis (ketoacidosis). ■

Lipid droplets


Acetoacetate, D-ß-hydroxybutyrate, acetone


Acetoacetate, D-ß-hydroxybutyrate, acetone

Fatty acids ketone body formation

Acetoacetate and D-/3-hydroxybutyrate exported as energy source for heart, skeletal muscle, kidney, and brain

ate citric acid cycle

ß oxidation Oxaloacetate

1\cycle gluconeogenesis


Glucose exported as fuel for brain and other tissues

FIGURE 17-20 Ketone body formation and export from the liver.

Conditions that promote gluconeogenesis (untreated diabetes, severely reduced food intake) slow the citric acid cycle (by drawing off ox-aloacetate) and enhance the conversion of acetyl-CoA to acetoacetate. The released coenzyme A allows continued 3 oxidation of fatty acids.

SUMMARY 17.3 Ketone Bodies

The ketone bodies—acetone, acetoacetate, and d-3-hydroxybutyrate—are formed in the liver. The latter two compounds serve as fuel molecules in extrahepatic tissues, through oxidation to acetyl-CoA and entry into the citric acid cycle.

Overproduction of ketone bodies in uncontrolled diabetes or severely reduced calorie intake can lead to acidosis or ketosis.

Key Terms

Terms in bold are defined P oxidation XXX chylomicron XXX apolipoprotein XXX lipoprotein XXX perilipins XXX hormone-sensitive lipase XXX free fatty acids XXX serum albumin XXX

in the glossary.

carnitine shuttle XXX

carnitine acyltransferase

I XXX acyl-carnitine/carnitine transporter XXX carnitine acyltransferase

II XXX trifunctional protein


mutase XXX coenzyme B12 XXX

pernicious anemia XXX intrinsic factor XXX malonyl-CoA XXX medium-chain acyl-CoA dehydrogenase (MCAD) XXX

multifunctional protein

(MFP) XXX m oxidation XXX mixed-function oxidases XXX a oxidation XXX acidosis XXX ketosis XXX

Chapter 17 Problems 653


Boyer, P.D. (1983) The Enzymes, 3rd edn, Vol. 16: Lipid Enzymology, Academic Press, Inc., San Diego, CA.

Ferry, G. (1998) Dorothy Hodgkin: A Life, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

Fascinating biography of an amazing woman.

Gurr, M.I., Harwood, J.L., & Frayn; K.N. (2002) Lipid Biochemistry: An Introduction, 5th edn, Blackwell Science, Oxford, UK.

Langin, D., Holm, C., & Lafontan, M. (1996) Adipocyte hormone-sensitive lipase: a major regulator of lipid metabolism. Proc. Nutr. Soc. 55, 93-109.

Ramsay, T.G. (1996) Fat cells. Endocrinol. Metab. Clin. N. Am. 25, 847-870.

A review of all aspects of fat storage and mobilization in adipocytes.

Scheffler, I.E. (1999) Mitochondria, Wiley-Liss, New York. An excellent book on mitochondrial structure and function.

Wang, C.S., Hartsuck, J., & McConathy, W.J. (1992) Structure and functional properties of lipoprotein lipase. Biochim. Biophys. Acta 1123, 1-17.

Advanced-level discussion of the enzyme that releases fatty acids from lipoproteins in the capillaries of muscle and adipose tissue.

Mitochondrial p Oxidation

Bannerjee, R. (1997) The yin-yang of cobalamin biochemistry. Chem. Biol. 4, 175-186.

A review of the biochemistry of coenzyme B12 reactions, including the methylmalonyl-CoA mutase reaction.

Eaton, S., Bartlett, K., & Pourfarzam, M. (1996) Mammalian mitochondrial ¡-oxidation. Biochem. J. 320, 345-357.

A review of the enzymology of 3 oxidation, inherited defects in this pathway, and regulation of the process in mitochondria.

Eaton, S., Bursby, T., Middleton, B., Pourfarzam, M., Mills, K., Johnson, A.W., & Bartlett, K. (2000) The mitochondrial trifunctional protein: centre of a 3-oxidation metabolon? Biochem. Soc. Trans. 28, 177-182.

Short, intermediate-level review.

Harwood, J.L. (1988) Fatty acid metabolism. Annu. Rev. Plant Physiol. Plaint Mol. Biol. 39, 101-138.

Jeukendrup, A.E., Saris, W.H., & Wagenmakers, A.J. (1998) Fat metabolism during exercise: a review. Part III: effects of nutritional interventions. Int. J. Sports Med. 19, 371-379.

This paper is one of a series that reviews the factors that influence fat mobilization and utilization during exercise.

Kerner, J. & Hoppel, C. (1998) Genetic disorders of carnitine metabolism and their nutritional management. Annu. Rev. Nutr. 18, 179-206.

Kerner, J. & Hoppel, C. (2000) Fatty acid import into mitochondria. Biochim. Biophys. Acta 1486, 1-17.

Kunau, W.H., Dommes, V., & Schulz, H. (1995) 3-Oxidation of fatty acids in mitochondria, peroxisomes, and bacteria: a century of continued progress. Prog. Lipid Res. 34, 267-342.

A good historical account and a useful comparison of 3 oxidation in different systems.

Rinaldo, P., Matern, D., & Bennett, M.J. (2002) Fatty acid oxidation disorders. Annu. Rev. Physiol. 64, 477-502.

Advanced review of metabolic defects in fat oxidation, including MCAD mutations.

Sherratt, H.S. (1994) Introduction: the regulation of fatty acid oxidation in cells. Biochem. Soc. Trans. 22, 421-422.

Introduction to reviews (in this journal issue) of various aspects of fatty acid oxidation and its regulation.

Thorpe, C. & Kim, J.J. (1995) Structure and mechanism of action of the acyl-CoA dehydrogenases. FASEB J. 9, 718-725. Short, clear description of the three-dimensional structure and catalytic mechanism of these enzymes.

Peroxisomal p Oxidation

Graham, I.A. & Eastmond, P.J. (2002) Pathways of straight and branched chain fatty acid catabolism in higher plants. Prog. Lipid Res. 41, 156-181.

Hashimoto, T. (1996) Peroxisomal 3-oxidation: enzymology and molecular biology. Ann. N Y. Acad. Sci. 804, 86-98.

Mannaerts, G.P. & van Veldhoven, P.P. (1996) Functions and organization of peroxisomal 3-oxidation. Ann. N. Y. Acad. Sci. 804, 99-115.

Wanders, R.J.A., van Grunsven, E.G., & Jansen, G.A. (2000) Lipid metabolism in peroxisomes: enzymology, functions and dysfunctions of the fatty acid a- and 3-oxidation systems in humans. Biochem. Soc. Trans. 28, 141-148.

Ketone Bodies

Foster, D.W. & McGarry, J.D. (1983) The metabolic derangements and treatment of diabetic ketoacidosis. N. Engl. J. Med. 309, 159-169.

McGarry, J.D. & Foster, D.W. (1980) Regulation of hepatic fatty acid oxidation and ketone body production. Annu. Rev. Biochem. 49, 395-420.

Robinson, A.M. & Williamson, D.H. (1980) Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol. Rev. 60, 143-187.


1. Energy in Triacylglycerols On a per-carbon basis, where does the largest amount of biologically available energy in triacylglycerols reside: in the fatty acid portions or the glycerol portion? Indicate how knowledge of the chemical structure of triacylglycerols provides the answer.

2. Fuel Reserves in Adipose Tissue Triacylglycerols, with their hydrocarbon-like fatty acids, have the highest energy content of the major nutrients.

(a) If 15% of the body mass of a 70.0 kg adult consists of triacylglycerols, what is the total available fuel reserve, in both kilojoules and kilocalories, in the form of triacylglyc-erols? Recall that 1.00 kcal = 4.18 kJ.

(b) If the basal energy requirement is approximately 8,400 kJ/day (2,000 kcal/day), how long could this person survive if the oxidation of fatty acids stored as triacylglycerols were the only source of energy?

(c) What would be the weight loss in pounds per day under such starvation conditions (1 lb = 0.454 kg)?

3. Common Reaction Steps in the Fatty Acid Oxidation Cycle and Citric Acid Cycle Cells often use the same enzyme reaction pattern for analogous metabolic conversions. For example, the steps in the oxidation of pyruvate to acetyl-CoA and of a-ketoglutarate to succinyl-CoA, although catalyzed by different enzymes, are very similar. The first stage of fatty acid oxidation follows a reaction sequence closely resembling a sequence in the citric acid cycle. Use equations to show the analogous reaction sequences in the two pathways.

4. Chemistry of the Acyl-CoA Synthetase Reaction

Fatty acids are converted to their coenzyme A esters in a reversible reaction catalyzed by acyl-CoA synthetase:

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