Ketosis Part I

Everyone has heard of it, some of you may love it, some of you may hate it.  While most people know the general facts about ketosis, I have been hearing a lot about it lately, and it seems like every time you talk to someone different about it they have a different opinion on it.  Some people think it is the ideal state for our bodies to be in, while some think of it like the plague, and something to be avoided at all costs. Well, I am going to try and clear up some of the confusion on the matter.  This won’t be an easy, or small task, so bear with me as I try and go through all the facts to make sure I get everything right.   As a general game plan I think a good place to start will be what are ketone bodies, how are they made, how are they transported and what tissues can use them.  Then we can move into their metabolism, uses, and long term ketosis.  Other topics will come up along the way, but that is what the information I hope to synthesize here for you.  In order to transmit all of this information we will have to get fairly technical, and I will have some pretty complicated figures presented, but hopefully I can pull out the main points of them for everyone.  Well, let’s get started.

What is a ketone body?

First, we must pick out exactly what we are talking about.  Many people will refer to the ketone bodies our body produces as merely “ketones” but this is incorrect.  In organic chemistry a ketone is simply a molecule that contains two “R” groups with a double bonded oxygen in between. 

A Generic Ketone Group (Photo from Wiki Commons)

An R group is simply any carbon containing compound.  As you can see, a ketone in this general sense can refer to an incredible variety of compounds.  Our body has a huge array of ketones that are used in a variety of processes throughout.  But most of these are not the ones we are interested in.  It is the three “Ketone Bodies” that we are concerned about, because they can be used as energy substrates.  These three are: acetone, acetoacetate, and ß- hydroxybutyrate (BHB).  While acetoacetate and BHB can be interconverted (changed from one to the other and back again) once acetoacetate is turned into acetone it is stuck like that. 

Of these three BHB seems to be the most important, as it accounts for around 75% of all ketone bodies found in the blood (1).  One of the main problems with urinary ketone testing is that these tests usually only measure acetoacetate, and not BHB.  Since BHB is the main type of ketone body used by humans these tests can make it seem like someone is not in ketosis when they actually are. Also, ketone bodies are produced at some rate during normal resting conditions, and <.05 mM concentrations are considered normal (2).

How are Ketone Bodies formed?

Ketone body synthesis is a relatively simple process and can be easily seen in the following diagram

(3)

Hmmm, not so simple I guess!  Lets break this down a bit so we can get a better picture of how we create ketone bodies.  First, lets look at our initial two reactants, the two acetyl-CoA’s.  Acetyl-CoA is an extremely important molecule for our bodies, as it in tons of reactions, and is the basis of all metabolism.  When glucose or fatty acids are oxidized (broken down) to create energy they are broken down so that all the carbons that were once part of the fatty acid of glucose molecule are incorporated into an acetyl-CoA molecule.  Now these Acetyl-CoA’s can have many fates, but one of the most important is that they are put into the TCA cycle, and supply the substrates that will enter the electorn transport chain and provide the energy to create ATP, our bodies energy currency.  However, in order for an acetyl-CoA to enter the TCA cycle, it needs another molecule, oxaloacetate.  Oxaloacetate is one of the main products of glycolysis, or glucose metabolism.  Without the oxaloacetate around the acteyl-CoA just kind of hangs around and can’t enter the TCA cycle.  When the actely-CoA’s are just left to their own devices they just naturally begin to start combining and move down our path to either BHB, acetoacetate, or acetate.  And thus begins ketone body formation!

Where does ketogenesis occur?

Ketogenesis occurs exclusively in the mitochondria of cells.  Ketogenesis must occur here because the enzyme that joins the two acetyl-CoA molecules, HMG-CoA synthase,  also exists outside the mitochondria of the cell.  However, these two enzymes, while performing the same function, work towards different end goals.  The cytosolic enzyme will join two acetyl-CoA’s for the purpose of creating cholesterol, while the mitochondrial enzyme will work towards creating ketone bodies.

So ketones must be produced inside mitochondria because the enzymes to produce them only exist there, but what tissues produce ketones?  Well, most of us know that the liver is the main producer of ketones, and can even create up to 185g of ketone bodies per day (2)!  However, some other tissues are capable of producing ketones.  When conditions are right it appears skeletal muscle is capable of producing some ketones (3).  Although, some studies have found that the ability of muscle tissue to produce ketone bodies to negligible (4).  From my point of view, it looks like muscle probably does produce ketone bodies, but they don’t send them out for circulation so it is much thougher to measure them.

To Summarize:

· ß-hydroxybutyrate, acetoacetate, and acetate are the three types of ketone bodies produced by our bodies, with BHB being the one that appears in the highest concentration

 · A small amount of ketone bodies are produced at rest in all individuals, and this production can be increased several ways.

· All glucose and fatty acid metabolism creates acetyl-CoA molecules that are normally used to create ATP.  However, when no oxaloacetate is around to begin the TCA cycle the natural reaction Acetyl-CoA undergoes is the beginging of ketone body formation.

· The enzymes to synthesize ketone bodies are found only inside mitochondria, thus all ketone body production must occur inside mitchondria.

· Almost all ketone body production is done by the liver, but some may be produced by skeletal muscle tissue in certain conditions.

I think this is a good place to stop for the first article on ketosis.  I hope that now we all understand what we are really talking about when we say ketone bodies, and that we have a general idea of when/how the process of ketosis is started.  In the next article I will go deeper into the regulation of ketone body formation.  After that I think the best place to go will be ketone body uses, then finally a full summary.