The synthesis of 3-hydroxy-3-methylglutaryl CoA begins with the formation of acetoacetyl CoA, which is achieved by reversing the final thiolase reaction in fatty acid oxidation. In the mitochondria, 3-hydroxy-3-methylglutaryl (HMG) CoA synthase combines acetyl CoA with acetoacetyl CoA to produce HMG CoA, marking the rate-limiting step in ketone body synthesis. It's important to note that HMG CoA is also involved in cytosolic cholesterol synthesis but the two pathways are separate due to their location and cellular conditions.

Moving on to ketone body synthesis, HMG CoA is cleaved by HMG CoA lyase, resulting in the production of acetoacetate and acetyl CoA. Acetoacetate can be reduced with the help of NADH to form 3-hydroxybutyrate. Acetoacetate can also spontaneously decarboxylate in the bloodstream to form acetone, which is a biologically nonmetabolized compound detectable in breath. The ratio of NAD+/NADH determines the equilibrium between acetoacetate and 3-hydroxybutyrate, favoring the synthesis of the latter during fatty acid oxidation.

In peripheral tissues, a process called ketolysis occurs, where 3-hydroxybutyrate is oxidized to acetoacetate by 3-hydroxybutyrate dehydrogenase, generating NADH. Succinyl CoA:acetoacetate CoA transferase (thiophorase) then transfers a CoA molecule from succinyl CoA to acetoacetate. While this reaction is reversible, thiolase actively removes the product, acetoacetyl CoA, by cleaving it into two acetyl CoA, driving the reaction forward. This mechanism is efficient in extrahepatic tissues, including the brain, except for cells lacking mitochondria like red blood cells. The liver, on the other hand, cannot use ketone bodies as fuel because it lacks thiophorase.

In cases of uncontrolled type 1 diabetes mellitus (T1D), excessive production of ketone bodies occurs when their formation rate surpasses their utilization rate. This leads to an increase in their levels in the blood (ketonemia) and eventually in the urine (ketonuria). Individuals with uncontrolled T1D may experience blood concentrations of ketone bodies as high as 90 mg/dl (compared to less than 3 mg/dl in normal individuals), with urinary excretion reaching up to 5,000 mg/24 hours. Elevated levels of ketone bodies in the blood can result in acidemia.
3-Hydroxy-3-methylglutaryl CoA synthesis: The first step, formation of acetoacetyl CoA, occurs by reversal of the final thiolase reaction of fatty acid oxidation (see Fig. 16.17). Mitochondrial 3-hydroxy-3methylglutaryl (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 (see p. 220). The two pathways are separated by location in, and conditions of, the cell.] 2.
Ketone body synthesis: 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 electron donor. [Note: Because ketone bodies are not linked to CoA, they can cross the inner mitochondrial membrane.] Acetoacetate can also spontaneously decarboxylate in the blood to form acetone, a volatile, biologically nonmetabolized compound that can be detected 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.
B. Ketone body use by the peripheral tissues: Ketolysis
Although the liver constantly synthesizes low levels of ketone bodies, their production increases 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 (Fig. 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 cleavage to two acetyl CoA by thiolase. This pulls the reaction forward. Extrahepatic tissues, including the brain but excluding cells lacking mitochondria (for example, RBC), 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.
C. Excessive ketone body production 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 (T1D), where the blood concentration of ketone bodies may reach 90 mg/dl (versus <3 mg/dl in normal individuals), and urinary excretion of ketone bodies may be as high as 5,000 mg/24 hour. The elevation of the ketone body concentration in the blood can result in acidemia. [Note: The carboxyl group of a ketone body has a pKa of ~4.