Ketone Bodies: An Alternate Fuel For Cells

KETONE BODIES: AN ALTERNATE FUEL FOR CELLS

Liver mitochondria have the capacity to convert acetyl CoA derived from fatty acid oxidation into ketone bodies. The compounds categorized as ketone bodies are acetoacetate, 3-hydroxybutyrate (also called β-hydroxybutyrate), and acetone (a nonmetabolized side product, Figure 16.22). [Note: The two functional ketone bodies are actually organic acids.] Acetoacetate and 3-hydroxybutyrate are transported in the blood to the peripheral tissues. There they can be reconverted to acetyl CoA, which can be oxidized by the TCA cycle. Ketone bodies are important sources of energy for the peripheral tissues because 1) they are soluble in aqueous solution and, therefore, do not need to be incorporated into lipoproteins or carried by albumin as do the other lipids; 2) they are produced in the liver during periods when the amount of acetyl CoA present exceeds the oxidative capacity of the liver; and 3) they are used in proportion to their concentration in the blood by extrahepatic tissues, such as the skeletal and cardiac muscle, intestinal mucosa, and renal cortex. Even the brain can use ketone bodies to help meet its energy needs if the blood levels rise sufficiently. Thus, ketone bodies spare glucose, which is particularly important during prolonged periods of fasting. [Note: Disorders of fatty acid oxidation present with the general picture of hypoketosis (due to decreased availability of acetyl CoA) and hypoglycemia (due to increased reliance on glucose for energy.]

Figure 16.22 Synthesis of ketone bodies. [Note: The release of CoA in ketogenesis supports continued fatty acid oxidation.] CoA = coenzyme A; HMG = hydroxymethylglutarate; NAD(H) = nicotinamide adenine dinucleotide.

A. Synthesis of ketone bodies by the liver: ketogenesis

During a fast, the liver is flooded with fatty acids mobilized from adipose tissue. The resulting elevated hepatic acetyl CoA produced by fatty acid oxidation inhibits pyruvate dehydrogenase, and activates pyruvate carboxylase. The OAA produced is used by the liver for gluconeogenesis rather than for the TCA cycle. Therefore, acetyl CoA is channeled into ketone body synthesis. Additionally, fatty acid oxidation decreases the NAD⁺ to NADH ratio, and the rise in NADH shifts OAA to malate. This also pushes acetyl CoA into ketogenesis (Figure 16.24).] [Note: Acetyl CoA for ketogenesis is also generated by the catabolism of ketogenic amino acids.]

1. Synthesis of 3-hydroxy-3-methylglutaryl coenzyme A: The first step, formation of acetoacetyl CoA, occurs by reversal of the thiolase reaction of fatty acid oxidation (see Figure 16.17). Mitochondrial 3-hydroxy-3-methylglutaryl (HMG) CoA synthase combines a third molecule of acetyl CoA with acetoacetyl CoA to produce HMG CoA. HMG CoA synthase is the rate-limiting step in the synthesis of ketone bodies and is present in significant quantities only in the liver. [Note: HMG CoA is also an intermediate in cytosolic cholesterol synthesis. The two pathways are separated by location in, and conditions of, the cell.]

Figure 16.17 Enzymes involved in the β-oxidation of fatty acyl coenzyme A (CoA). [Note: 2,3-Enoyl CoA hydratase requires a trans double bond between carbon 2 and carbon 3.] FAD(H2) = flavin adenine dinucleotide; NAD(H) = nicotinamide adenine dinucleotide.

2. Synthesis of the ketone bodies: HMG CoA is cleaved by HMG CoA lyase to produce acetoacetate and acetyl CoA, as shown in Figure 16.22. Acetoacetate can be reduced to form 3-hydroxybutyrate with NADH as the hydrogen donor. Acetoacetate can also spontaneously decarboxylate in the blood to form acetone, a volatile, biologically nonmetabolized compound that can be released in the breath. The equilibrium between acetoacetate and 3-hydroxybutyrate is determined by the NAD⁺/NADH ratio. Because this ratio is low during fatty acid oxidation, 3-hydroxybutyrate synthesis is favored. [Note: The generation of free CoA during ketogenesis allows fatty acid oxidation to continue.]

B. Use of ketone bodies by the peripheral tissues: ketolysis

Although the liver constantly synthesizes low levels of ketone bodies, their production becomes much more significant during fasting when ketone bodies are needed to provide energy to the peripheral tissues. 3-Hydroxybutyrate is oxidized to acetoacetate by 3-hydroxybutyrate dehydrogenase, producing NADH (Figure 16.23). Acetoacetate is then provided with a CoA molecule taken from succinyl CoA by succinyl CoA:acetoacetate CoA transferase (thiophorase). This reaction is reversible, but the product, acetoacetyl CoA, is actively removed by its conversion to two acetyl CoAs. This pulls the reaction forward. Extrahepatic tissues, including the brain but excluding cells lacking mitochondria (for example, RBCs), efficiently oxidize acetoacetate and 3-hydroxybutyrate in this manner. In contrast, although the liver actively produces ketone bodies, it lacks thiophorase and, therefore, is unable to use ketone bodies as fuel.

Figure 16.23 Ketone body synthesis in the liver and use in peripheral tissues. Liver and red blood cells cannot use ketone bodies. [Note: Thiophorase is also known as succinyl CoA:acetoacetate CoA transferase.] CoA = coenzyme A; NAD(H) = nicotinamide adenine dinucleotide; TCA = tricarboxylic acid.

C. Excessive production of ketone bodies in diabetes mellitus

When the rate of formation of ketone bodies is greater than the rate of their use, their levels begin to rise in the blood (ketonemia) and, eventually, in the urine (ketonuria). This is seen most often in cases of uncontrolled type 1 diabetes mellitus. In diabetic individuals with severe ketosis, urinary excretion of the ketone bodies may be as high as 5,000 mg/24 hr, and the blood concentration may reach 90 mg/dl (versus less than 3 mg/dl in normal individuals). A frequent symptom of diabetic ketoacidosis (DKA) is a fruity odor on the breath, which results from increased production of acetone. An elevation of the ketone body concentration in the blood results in acidemia. [Note: The carboxyl group of a ketone body has a pK_a of about 4. Therefore, each ketone body loses a proton (H+) as it circulates in the blood, which lowers the pH. Also, in DKA, urinary loss of glucose and ketone bodies results in dehydration. Therefore, the increased number of H+ circulating in a decreased volume of plasma can cause severe acidosis (ketoacidosis).] Ketoacidosis may also be seen in cases of prolonged fasting and excessive ethanol consumption.

Figure 16.24 Mechanism of diabetic ketoacidosis seen in type 1 diabetes.