How We Make Ketones | MWM Energy Metabolism Cliff Notes #32

In conditions of glucose deprivation, such as fasting or carbohydrate restriction, ketogenesis serves to reduce our needs for glucose. This reduces the need to engage in the energetically wasteful process of gluconeogenesis, which would otherwise be extremely taxing on our skeletal muscle if dietary protein were inadequate. Ketogenesis mainly occurs in the liver. The biochemical event that leads to ketogenesis is an accumulation of acetyl CoA that cannot enter the citric acid cycle because it exceeds the supply of oxaloacetate. The set of physiological conditions that provoke this biochemical event are as follows: free fatty acids from adipose tissue reach the liver, providing the energy needed for gluconeogenesis as well as a large excess of acetyl CoA. Oxaloacetate, with the help of the energy provided by free fatty acids, leaves the citric acid cycle for gluconeogenesis. These events increase the ratio of acetyl CoA to oxaloacetate, which leads to the accumulation of acetyl CoA that cannot enter the citric acid cycle and therefore enter the ketogenic pathway. This pathway results in the production of acetoacetate, a ketoacid. Acetoacetate can then be reduced to beta-hydroxybutyrate, a hydroxyacid, in a manner analogous to the reduction of pyruvate, a ketoacid, to lactate, a hydroxyacid. Acetoacetate is an unstable beta-ketoacid just like oxalosuccinate (covered in lesson 6) and can also spontaneously decarboxylate to form acetone, a simple ketone that is extremely volatile and can evaporate through the lungs, causing ketone breath. This lesson covers the basic mechanisms of ketogenesis and sets the ground for the forthcoming lesson on the benefits and drawbacks of ketogenesis in various contexts.

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Chris Masterjohn, PhD, is the Founder and Scientific Director of the mitochondria test Mitome.