Ketone body synthesis 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 ([PC] ). The OAA produced by PC is used by the liver for gluconeogenesis rather than for the TCA cycle. Additionally, fatty acid oxidation decreases the NAD+/NADH ratio, and the rise in NADH shifts OAA to malate .

The decreased availability of OAA for condensation with acetyl CoA results in the increased use of acetyl CoA for ketone body synthesis. [Note: Acetyl CoA for ketogenesis is also generated by the catabolism of ketogenic amino acids .]
1. 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 . 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.]
2. Ketone body synthesis: HMG CoA is cleaved by HMG CoA lyase to produce acetoacetate and acetyl CoA, as shown in Figure 1. 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.

Figure 1: 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; CO2 = carbon dioxide.

مواضيع ذات صلة

آلية عمل المجموعة الأولى من الهرمونات

الهرمونات وآليات الاستتباب

تدرك (تقويض) الهرمونات وتعطيلها

نقل الهرمونات في البلازما

تغاير خزن الهرمونات وإفرازها

تخليق POMC ومعالجته

The Amino Acids

Absorption & Transport of Transition Metals

Physiologic Roles of The Essential Transition Metals

تخليق الأنجيوتنسين

تخلیق PTH

تخليق الأنسولين