Ketogenesis

Hi :) In this lecture we'll be discussing the process of ketogenesis, that is the conversion of non esterified fatty acids (NEFAs) to ketone bodies. We'll have a look at a few of the major ketone bodies as well as how the ketogenesis pathway works, including the function, regulation and location of the pathway.

Ketone Bodies

Ketone bodies are the end products of ketogenesis. They are molecules which are fatty acids that contain 4 carbons but are not volatile. They are also highly soluble in water, this allows them to be transported in the blood easily. They major ketone bodies found in animals are beta-hydroxybutyric acid and acetoacetate. 

Beta-Hydroxybutyric Acid

Acetoacetate

Ketogenesis

NEFAs, which are produced by lipolysis, are bound to albumin in the blood and are used by the body as a source of energy through β-oxidation. However, the maximum concentration of NEFAs in the blood is 2mM, any higher than this and damage to membranes in the body occurs.
 

This is where ketogenesis comes into play. The body is able to convert NEFAs into ketone bodies which are converted to acetylCoA and can be used to generate energy. This allows more NEFAs to be used by the body for energy in times of stress. Ketone body concentrations in the blood rise during exercise and are high during fasting. Thus, ketogenesis acts as a good back up pathway that is used when lots of fat is needed to be mobilised.  

In an extreme situation such as when a person has been fasting for 1 week or a twin pregnant sheep has been fasted half the body's NEFAs are used by the tissues. The other half are fed to the liver to be converted to ketone bodies to be used by the tissues. In situations such as these, acetone can be smelled in the breath of the individual. This is because acetoacetate is spontaneously broken down into acetone.

Ketogenesis occurs in the mitochondrial matrix of liver cells according to the following pathway:

The Ketogenesis Pathway

Two AcetylCoA molecules are converted to AcetoacetylCoA which is then converted to HMG-CoA (beta-hydroxy-methylglutaryl-CoA). This molecule is then converted to acetoacetate which is converted to D-beta-hydroxybutyrate, this involves the release of NAD+. D-beta-hydroxybutyrate molecule then breaks down to form acetone which is released in the lungs. Please note that for our unit we aren't required to know the structure of these molecules or all the enzymes, only the general process.

Regulation

The amount of substrate (AcetylCoA) available is the main regulator of ketogenesis, several factors affect this:

• high rates of fat metabolism: in other words, the factors controlling the balance between lipolysis and esterification in adipose tissue.
• high activity of CPT1: this allows fat to enter the mitochondrion for β-oxidation to produce acetylCoA
• The relative shortage of glucose for tissues: this causes a change in the endocrine system which impacts on fat metabolism.

That's it for this post, if you have any questions please feel free to ask :)