Ketogenesis Occurs When There Is A High Rate Of Fatty Acid Oxidation In The Liver

Under metabolic conditions associated with a high rate of fatty acid oxidation, the liver produces considerable quantities of acetoacetate and d(—)-3-hydroxybutyrate

(P-hydroxybutyrate). Acetoacetate continually undergoes spontaneous decarboxylation to yield acetone. These three substances are collectively known as the ke-tone bodies (also called acetone bodies or [incorrectly*] "ketones") (Figure 22-5). Acetoacetate and 3-hydroxybu-

* 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.

CIS CIS

Linoleyl-CoA

3 Cycles of ß-oxidation

3 Acetyl-CoA

CIS CIS

A3-ci's-A6-cis-Dienoyl-CoA

A3-cIs (or trans) ^ A2-trans-ENOYL-CoA

ISOMERASE

A2-trans-A6-cis-Dienoyl-CoA

(A2-trans-Enoyl-CoA stage of ß-oxidation)

1 Cycle of ß-oxidation

Acetyl-CoA

C S CoA

ACYL-CoA DEHYDROGENASE

A2-trans-A4-cis-Dienoyl-CoA

A4--cis-Enoyl-CoA

NADP+

A2-frans-A4-c/s-DIENOYL-CoA REDUCTASE

A/VW

A3-trans-Enoyl-CoA

A3-cis (or trans) ^ A2-trans-ENOYL-CoA

ISOMERASE

A2-trans-Enoyl-CoA

Acetone

D(-)-3-HYDROXYBUTYRATE DEHYDROGENASE

Acetone

D(-)-3-HYDROXYBUTYRATE DEHYDROGENASE

Figure 22-5. Interrelationships of the ketone bodies. D(-)-3-hydroxybutyrate dehydrogenase is a mitochondrial enzyme.

tyrate are interconverted by the mitochondrial enzyme d(—)-3-hydroxybutyrate dehydrogenase; the equilibrium is controlled by the mitochondrial [NAD+]/ [NADH] ratio, ie, the redox state. The concentration of total ketone bodies in the blood of well-fed mammals does not normally exceed 0.2 mmol/L except in ruminants, where 3-hydroxybutyrate is formed continuously from butyric acid (a product of ruminal fermentation) in the rumen wall. In vivo, the liver appears to be the only organ in nonruminants to add significant quantities of ketone bodies to the blood. Extrahepatic tissues utilize them as respiratory substrates. The net flow of ketone bodies from the liver to the extrahepatic tissues results from active hepatic synthesis coupled with very low utilization. The reverse situation occurs in extrahepatic tissues (Figure 22-6).

3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) Is an Intermediate in the Pathway of Ketogenesis

Enzymes responsible for ketone body formation are associated mainly with the mitochondria. Two acetyl-CoA molecules formed in P-oxidation condense with one another to form acetoacetyl-CoA by a reversal of the thiolase reaction. Acetoacetyl-CoA, which is the

LIVER

BLOOD

EXTRAHEPATIC TISSUES

Acyl-CoA

Glucose /

__Acetyl-CoA

Ketone bodies

Ketone bodies I

Ketone bodies I

Glucose s

Acyl-CoA /

Acetyl-CoA

Ketone bodies

Acetyl-CoA

Ketone bodies

2CO2

2CO2

Figure 22-6. Formation, utilization, and excretion of ketone bodies. (The main pathway is indicated by the solid arrows.)

starting material for ketogenesis, also arises directly from the terminal four carbons of a fatty acid during P-oxidation (Figure 22-7). Condensation of ace-toacetyl-CoA with another molecule of acetyl-CoA by 3-hydroxy-3-methylglutaryl-CoA synthase forms HMG-CoA. 3-Hydroxy-3-methylglutaryl-CoA lyase then causes acetyl-CoA to split off from the HMG-CoA, leaving free acetoacetate. The carbon atoms split off in the acetyl-CoA molecule are derived from the original acetoacetyl-CoA molecule. Both enzymes must be present in mitochondria for ketogenesis to take place. This occurs solely in liver and rumen epithelium. d(-)-3-Hydroxybutyrate is quantitatively the predominant ketone body present in the blood and urine in ketosis.

Ketone Bodies Serve as a Fuel for Extrahepatic Tissues

While an active enzymatic mechanism produces acetoacetate from acetoacetyl-CoA in the liver, acetoac-etate once formed cannot be reactivated directly except in the cytosol, where it is used in a much less active pathway as a precursor in cholesterol synthesis. This accounts for the net production of ketone bodies by the liver.

ATP CoA

ACYL-CoA SYNTHETASE

Esterification

(Acetyl-CoA)n

Triacylglycerol Phospholipid

ß-Oxidation

HMG-CoA SYNTHASE

OH O

I II

Acetyl-CoA

3-Hydroxy-3-methyl-glutaryl-CoA (HMG-CoA)

Acetyl-CoA

CH3 CO S CoA

Acetyl-CoA

2CO2

CH3 CO S CoA

Acetyl-CoA

HMG-CoA LYASE

CH3 C

Acetoacetate

2CO2

D(-)-3-HYDROXYBUTYRATE DEHYDROGENASE

Figure 22-7. Pathways of ketogenesis in the liver. (FFA, free fatty acids; HMG, 3-hy-droxy-3-methylglutaryl.)

THIOLASE

In extrahepatic tissues, acetoacetate is activated to acetoacetyl-CoA by succinyl-CoA-acetoacetate CoA transferase. CoA is transferred from succinyl-CoA to form acetoacetyl-CoA (Figure 22-8). The acetoacetyl-CoA is split to acetyl-CoA by thiolase and oxidized in the citric acid cycle. If the blood level is raised, oxidation of ketone bodies increases until, at a concentration of approximately 12 mmol/L, they saturate the oxidative machinery. When this occurs, a large proportion of the oxygen consumption may be accounted for by the oxidation of ketone bodies.

In most cases, ketonemia is due to increased production of ketone bodies by the liver rather than to a deficiency in their utilization by extrahepatic tissues. While acetoacetate and d(-)-3-hydroxybutyrate are readily oxidized by extrahepatic tissues, acetone is difficult to oxidize in vivo and to a large extent is volatilized in the lungs.

In moderate ketonemia, the loss of ketone bodies via the urine is only a few percent of the total ketone body production and utilization. Since there are renal threshold-like effects (there is not a true threshold) that vary between species and individuals, measurement of the ketonemia, not the ketonuria, is the preferred method of assessing the severity of ketosis.

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Diabetes 2

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