Textbook - BIOLOGICAL CHEMISTRY - Hubsky Yu.I. - 2000

Section III. METABOLISM OF THE MAIN CLASSES OF BIOMOLECULES

CHAPTER 14. LIPID METABOLISM. I. CATABOLISM OF TRIACYLGLYCEROLS AND FATTY ACIDS

14.4. BIOSYNTHESIS AND CATABOLISM OF KETONE BODIES

Under normal metabolic conditions in a healthy Organism, the primary pathway for utilizing acetyl-CoA produced during β-Oxidation of Fatty acids is The Tricarboxylic Acid Cycle. When METABOLISM shifts toward biosynthetic pathways, cytoplasmic acetyl-CoA is reused for fatty acid synthesis, i.e., The formation of lipid reserves (Chapter 15).

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At the same time, the Liver features a physiologically important pathway for acetyl-CoA utilization that leads to the formation of alternative metabolic fuel molecules used by other Tissues—the so-called ketone (acetone) bodies. Ketone Bodies include acetoacetate, β-hydroxybutyrate, and acetone.

ENZYMATIC REACTIONS OF ketone body formation

The Formation of Ketone bodies occurs in the Cytosol (initial stages) and Cell/35.html">Mitochondria of hepatocytes through the following reactions:

1. Condensation of two acetyl-CoA molecules to form acetoacetyl-CoA. The reaction is catalyzed by the cytosolic enzyme thiolase.

2. Interaction of acetoacetyl-CoA with another acetyl-CoA molecule to yield β-hydroxy-β-methylglutaryl-CoA (β-HMG-CoA). During ketone body formation, this reaction takes place in the mitochondria and is catalyzed by β-HMG-CoA synthase.

3. Cleavage of β-hydroxy-β-methylglutaryl-CoA by the mitochondrial enzyme β-HMG-CoA lyase to form acetoacetate and acetyl-CoA.

It should be noted that the formation of β-HMG-CoA from acetoacetyl-CoA can also occur in the hepatocyte cytosol; in this case, β-HMG-CoA undergoes biochemical transformations that constitute the biosynthetic pathway of Cholesterol (Chapter 15), which takes place in the Cells of the liver, intestine, and Skin. However, in hepatocytes, the majority of acetyl-CoA generated from The oxidation of CARBOHYDRATES, Fatty acids, and Amino Acids that is not utilized in the citrate cycle enters The pathway of ketone body formation.

β-Hydroxybutyrate is formed from acetoacetate via reduction by the NADH-dependent β-hydroxybutyrate dehydrogenase:

The reaction proceeds toward the formation of β-hydroxybutyrate under conditions of a high NADH/NAD⁺ ratio in hepatocytes, which typically occurs during starvation.

Acetone is formed in minor amounts from circulating Blood acetoacetate through its non-enzymatic decarboxylation or the action of the enzyme acetoacetate decarboxylase. Acetone is eliminated from the body via the Lungs; a significant increase in breath acetone levels is observed in decompensated Diabetes Mellitus.

Reactions of ketone body utilization

After being produced in hepatocytes, ketone bodies (primarily acetoacetate) enter the bloodstream and are transported to peripheral tissues, where they serve as important substrates for Biological Oxidation.

The utilization of acetoacetate as a metabolic fuel substrate is preceded by its activation to form acetoacetyl-CoA. There are two enzymatic mechanisms for generating acetoacetyl-CoA in hepatocytes:

a) interaction of acetoacetate with succinyl-CoA:

b) activation of acetoacetate by HS-CoA involving ATP:

Acetoacetyl-CoA formed via one of the aforementioned mechanisms undergoes thiolytic cleavage mediated by thiolase to yield two molecules of acetyl-CoA, which are subsequently oxidized in the tricarboxylic acid cycle:

Acetoacetate serves as a vital energy source for the myocardium, skeletal Muscles, and the renal cortex, where the cellular Catabolism of this compound exceeds glucose utilization. During starvation, acetoacetate also becomes the primary oxidation substrate for the Brain, which under normal conditions relies exclusively on glucose to meet its energy demands.

Pathophysiological Metabolism of Ketone Bodies

Under normal conditions, the concentration of ketone bodies in the blood and most tissues is low (averaging 10–20 mg/L). However, starvation and diabetes mellitus create metabolic conditions that sharply elevate tissue levels of ketone bodies due to a marked upregulation of their synthesis. This leads to a dramatic increase in both blood ketone body concentration (ketonemia) and their urinary excretion (ketonuria).

The biochemical basis for the elevation of ketone bodies in pathological states is the diminished utilization of acetyl-CoA in the tricarboxylic acid cycle resulting from impaired Carbohydrate Metabolism.

The underlying reason is that The entry of acetyl-CoA into the TCA cycle depends on a sufficient cellular supply of oxaloacetate, which is required for citrate formation. In turn, the synthesis of oxaloacetate—essential for the proper functioning of the tricarboxylic cycle—depends on Pyruvate availability (Chapter 10, Section 10.4), primarily supplied by the glycolytic breakdown of glucose. When cellular glucose uptake is impaired (as in starvation or diabetes mellitus), oxaloacetate is diverted into Gluconeogenesis, rendering it unavailable to interact with acetyl-CoA in the citrate synthase reaction. Under these metabolic conditions, acetyl-CoA is largely channeled into the synthesis of ketone bodies, namely acetoacetate and β-hydroxybutyrate. Furthermore, intracellular accumulation of acetyl-CoA is promoted by its enhanced production via fatty acid β-oxidation, driven by The stimulation of lipolysis in adipose tissue during glucose deprivation. These biochemical principles explain the classical adage: "Fats burn in the flame of carbohydrates."

The administration of glucose (during starvation) or glucose combined with Insulin (in diabetes mellitus) elevates intracellular monosaccharide levels and normalizes Glycolysis. This leads to increased utilization of acetyl-CoA in the tricarboxylic acid cycle and a subsequent decline in ketone body production. Nevertheless, in the absence of proper therapy, the concentration of acetoacetate, β-hydroxybutyrate, and acetone in patients with diabetes mellitus can surge tenfold or more, disrupting acid-base balance and triggering metabolic ketoacidosis, which poses a severe threat to normal brain cell function.