From the Guidelines
Yes, HMG-CoA is directly involved in ketone formation. HMG-CoA serves as a critical intermediate in the metabolic pathway that produces ketone bodies in the liver during periods of low glucose availability, such as during fasting, prolonged exercise, or carbohydrate restriction 1. When glucose levels are low, fatty acids are broken down through beta-oxidation to produce acetyl-CoA. Two molecules of acetyl-CoA condense to form acetoacetyl-CoA, which then combines with another acetyl-CoA to form HMG-CoA through the action of HMG-CoA synthase. HMG-CoA is subsequently cleaved by HMG-CoA lyase to produce acetoacetate, one of the primary ketone bodies, and acetyl-CoA 1.
The key steps in ketone body formation from HMG-CoA include:
- The condensation of two acetyl CoA leads to the production of an acetoacetylCoA in a reaction catalyzed by the acetoacetyl-CoA thiolase
- The acetoacetyl CoA becomes 3HMGCoA through the addition of a third acetyl-CoA (catalyzed by the mitochondrial HMG-CoA synthetase) 1
- The HMG-CoA lyase catalyzes the passage from HMG-CoA to acetoacetate plus acetyl-CoA 1
- Acetoacetate is the first ketone body which can be reduced by the NADH-dependent β-hydroxybutyrate dehydrogenase into the other ketone body: the β-Hydroxybutyrate and, by a spontaneous decarboxylation, to acetone, the third, volatile ketone 1.
This ketogenesis pathway is particularly important during starvation or diabetic ketoacidosis when the body shifts from glucose to fat metabolism for energy production 1. The levels of ketone bodies, produced from fats by the liver during carbohydrate restriction, varies typically between 0.3 up to 4 mmol/L 1. The involvement of HMG-CoA in ketone formation is a crucial step in the metabolic adaptation to low carbohydrate availability, highlighting the importance of understanding this pathway in the context of ketogenic diets and their applications in various clinical conditions 1.
From the Research
HMG-CoA Involvement in Ketone Formation
- HMG-CoA synthase is a key enzyme in the process of ketogenesis, which is the production of ketone bodies 2.
- The enzyme catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA into 3-hydroxy-3-methylglutaryl CoA, a crucial step in the formation of ketone bodies 3.
- Research has shown that HMG-CoA synthase 2 (HMGCS2), the mitochondrial isoform, is increased in the kidneys of type 2 diabetic mice, leading to excess ketogenic activity and the production of ketone bodies 2.
- The formation of ketone bodies is an important physiological process that occurs in response to low glucose levels, and HMG-CoA synthase plays a critical role in this process 4.
- Studies have also investigated the structural basis of HMG-CoA synthase and its isoforms, providing insights into the development of isoform-specific inhibitors and the understanding of inherited ketogenesis disorders 3.
Ketone Body Formation and Diabetes
- Ketone bodies are produced by the liver and used as an energy source when glucose is not readily available, and their levels increase in diabetic patients 4.
- Diabetic ketoacidosis (DKA) is a complication of diabetes characterized by high levels of ketone bodies, and the ketone body ratio (3HB:AcAc) is an important indicator of ketone body levels 4.
- Research has focused on the development of predictive models for elevated ketone bodies in patients with type 1 diabetes, using continuous glucose monitoring and insulin data 5.
- The understanding of ketone body formation and its relationship to diabetes is crucial for the development of effective therapeutic strategies and the prevention of complications associated with diabetes 6.