Fatty acid oxidation

Our bodies are capable of surviving without food for long periods of time, at least 3-4 weeks with hydration!

The reason we can do that is that we can store our dietary fuels, and then break them down when needed to make energy in the form of adenosine triphosphate, or ATP.

Fat is one of the most important ways we store energy and the term “burning fat”, actually refers to fatty acid oxidation.

In fact, if two individuals were stranded in the Andes mountains with no food, the person with more fat content would survive longer - yet another reason to avoid working out.

What makes fat such a great source of energy are fatty acids, which are the simplest form of fats, composed of long chains of carbon and hydrogens.

The transfer of electrons in the form of hydrogen from these fatty acids to certain molecules, can then be used to generate ATP.

Fatty acid oxidation primarily takes place in the mitochondria of heart, skeletal muscle, and liver cells.

Before we can oxidize fat, it needs to be moved from storage sites to the cells that can use it. Fat is stored in adipocytes or fat cells as triglycerides, which are 3 fatty acids attached to a glycerol molecule.

Triglycerides can be broken down by the enzyme hormone sensitive lipase, into free fatty acids and glycerol. So if you’re starving in the Andes, first your blood glucose level falls.

In response, the pancreas secretes a hormone called glucagon which increases the activity of hormone sensitive lipase, and increases the breakdown of triglycerides.

Now, the free fatty acids can leave the fat cell, and enter the bloodstream, where they bind to a protein called albumin.

Albumin carries the fatty acids to target cells, like liver cells, that are capable of fatty acid oxidation. First, the free fatty acid dissociates from albumin and diffuses into the cell.

Once inside the cell, a cytosolic enzyme called fatty acyl-CoA synthetase adds a coenzyme A molecule to the end of the fatty acid, turning it into a metabolically active fatty acyl-CoA.

This process requires 2 ATP molecules - so it takes a little energy to make energy, but it’s totally worth it in the end.

Now the mitochondria is composed of two membranes - an outer membrane and an inner membrane, with a small space in between - and the mitochondrial matrix at the core.

The enzymes required for beta oxidation are located in the mitochondrial matrix - however, the fatty acid can’t cross the inner mitochondrial membrane when CoA is attached to it. To get around this problem, we need to free the CoA from the fatty acid.

An enzyme within the outer mitochondrial membrane called carnitine palmitoyltransferase 1, or CPT1 replaces the CoA with a carnitine, making fatty acyl-carnitine and a free CoA, both of which can easily cross the inner mitochondrial membrane.

Then, along the inner mitochondrial membrane, another enzyme called carnitine palmitoyltransferase 2, or CPT2, substitutes carnitine and CoA back, therefore regenerating fatty acyl-CoA and free carnitine - which is now within the mitochondrial matrix.

This whole slick process is called the carnitine shuttle. Carnitine can cross the inner mitochondrial membrane by itself, so it can go back to the outer membrane to meet the next incoming fatty acid. We can also get more carnitine from our diet, mainly from meat products.

Finally, the carnitine shuttle can be regulated by a product of fatty acid synthesis called malonyl-CoA, which specifically inhibits CPT1 slowing down fatty acid oxidation. After all, you don’t want to make and break fatty acids at the same time.

Okay, so fatty acid chains can vary in length, from short, medium, long and very long fatty acids, but the process of fatty acid oxidation is the same for any length.

We’ll explain fatty acid oxidation with an example of a long chain fatty acid: the 16-carbon long palmitoyl-CoA.

The enzymatic modifications that take place in fatty acid oxidation happen on the 2nd and 3rd carbon of the chain, also called the alpha and beta carbons, respectively.

Each of those carbons enters fatty acid oxidation with 2 hydrogens bound to it. First, an enzyme called acyl-CoA dehydrogenase removes 1 hydrogen from the 2nd carbon, and one hydrogen from the 3rd.

The same enzyme then gives those 2 hydrogens to a nearby flavin adenine dinucleotide molecule, or FAD, making FADH2, and converting the palmitoyl-CoA to enoyl-CoA in the process.