Fatty acid oxidation is the utilization or catabolism of fatty acids for the purpose of energy in the form of ATP. There are various types of fatty acid oxidation but the most important type is the beta-oxidation of fatty acids which takes place in the mitochondrial matrix. Fatty acid oxidation, also known as beta-oxidation, is the process by which fatty acids are broken down and converted into usable energy in the form of adenosine triphosphate (ATP). It is a key metabolic pathway that occurs primarily in the mitochondria of cells, particularly in tissues such as the liver, muscle, and adipose tissue. Please watch the below-embedded video in order to understand an overview or introduction of the utilization of fatty acids.
There are many steps involved in fatty acids oxidation or utilization of fatty acids like:
- Hydrolysis of fatty acids from triacylglycerol in the adipose tissue by a process called lipolysis
- Mobilization or transport of these fatty acids to target tissue through blood by binding to albumin
- Activation of these fatty acids in the cytoplasm of the cell by acyl-CoA synthetase or thiokinase enzyme
- Transport of these activated fatty acids or acyl-CoA across the inner mitochondrial membrane into the mitochondrial matrix by carnitine shuttle transport system
- Final oxidation or beta-oxidation proper pathway in the mitochondrial matrix
Lipolysis is the process by which triglycerides, which are the primary storage form of fatty acids in adipose tissue, are broken down into glycerol and free fatty acids. It is a key metabolic process that occurs when the body needs to utilize stored fat as an energy source.
Here is an overview of the lipolysis process:
- Hormonal Stimulation: Lipolysis is primarily regulated by hormones, particularly epinephrine (adrenaline), norepinephrine, and glucagon. These hormones are released in response to various stimuli, such as exercise, fasting, or stress.
- Activation of Lipase: Hormonal stimulation leads to the activation of an enzyme called hormone-sensitive lipase (HSL), which is located within the adipose tissue. HSL is responsible for initiating the breakdown of triglycerides.
- Triglyceride Breakdown: HSL acts on the triglyceride molecules stored within adipocytes (fat cells) and breaks them down into their components—glycerol and free fatty acids. This process occurs through a series of enzymatic steps.
- Release of Glycerol and Free Fatty Acids: Once released, glycerol and free fatty acids enter the bloodstream. Glycerol can be transported to the liver, where it can be converted into glucose through a process called gluconeogenesis, to be used as an energy source. Free fatty acids can be taken up by various tissues, such as muscle cells, to be used as a fuel for energy production.
- Energy Utilization: Free fatty acids that are taken up by tissues can undergo beta-oxidation, as mentioned earlier, to produce ATP and provide energy for cellular processes.
Lipolysis is a dynamic process that is influenced by multiple factors, including hormonal regulation, nutritional status, and energy demands of the body. It is an essential mechanism for maintaining energy balance and fueling the body during periods of energy deficiency or increased energy requirements.
It’s important to note that lipolysis is a normal physiological process, but excessive or prolonged lipolysis can occur in certain conditions, such as obesity or metabolic disorders like diabetes. In these cases, there can be an imbalance between lipolysis and fat storage, leading to an abnormal accumulation of fatty acids in tissues and potential health complications.
Lipolysis is often targeted in weight loss strategies, where individuals aim to enhance fat breakdown and utilize stored fat for energy expenditure. However, it’s crucial to approach weight loss and fat metabolism in a balanced and sustainable manner, considering overall health and individual needs. I have explained in the below embedded my youtube video, the process of lipolysis in detail. Please have a look at it.
Transport of fatty acids to target tissue and activation of fatty acid in the cytoplasm
Once fatty acids are hydrolyzed from triacylglycerol by hormone-sensitive lipase, they are transported to target tissue or cells through circulation by binding with albumin. A small number of fatty acids are also exiting in the blood which we call as free fatty acids. Now, in the cytosol, these fatty acids must be activated before being oxidized in the mitochondrial matrix. Activation of fatty acids is an energy-dependent process and energy is provided by hydrolysis of ATP to AMP and pyrophosphate. Acyl-CoA synthetase or thiokinase helps in the activation of fatty acid to acyl-CoA with the help of coenzyme A. You must remember this step requires 2 ATP as the activation step is 2 step process. Initially, ATP hydrolyzed to AMP and pyrophosphate and this AMP combines with fatty acid to form adenylate fatty acid. later in the second step coenzyme A breaks the bond between AMP and fatty acid forms acyl-CoA. Meanwhile, pyrophosphate undergoes hydrolysis by pyrophosphatase to form 2 inorganic phosphate ions. So, the requirement of ATP for the entire activation step amounts to 2. Here is a video where I have explained the process of activation of fatty acid to acyl-CoA.
Carnitine shuttle transport system
Acyl-CoA or activated fatty acids are transported across the outer mitochondrial membrane to inter mitochondrial space but it is not permeable to the inner mitochondrial membrane. Here we have a shuttle pathway where carnitine combines with acyl-CoA to form acylcarnitine. This reaction is catalyzed by an enzyme carnitine acyl transferase-I [CAT-I]which is located in the inner surface of the outer mitochondrial membrane. Now, this acylcarnitine easily transported across the inner mitochondrial membrane to the mitochondrial matrix by a translocase called carnitine-acylcarnitine translocase. In the mitochondrial matrix, this acylcarnitine converted back to acyl-CoA and carnitine by another enzyme which is an isoenzyme of carnitine acyl transferase-I called carnitine acyl transferase-II [CAT-II]. Carnitine is going back to inter mitochondrial space through carnitine-acylcarnitine translocase to participate in another reaction. Please watch the below embedded video to know more about carnitine shuttle transport system.
An overview of Beta oxidation pathway
Before going to study beta oxidation pathway you should know overview of beta oxidation pathway in order to understand the pathway better. In the below embedded video I have explained overview of beta oxidation pathway by taking a specific example that is palmitic acid. Palmitic acid is a saturated even number fatty acid with 16 carbon atoms. After beta oxidation of palmitic acid or palmitoyl-CoA we will get 8 molecules of acetyl-CoA and reducing equivalents like 7 NADH and 7 FADH2.
Beta oxidation pathway
Beta oxidation is a pathway that takes place in the mitochondrial matrix where every 2 carbon units are releases as acetyl-CoA. There are 4 main steps involved in this pathway inside the mitochondrial matrix.
- Oxidation by FAD dependent acyl-CoA dehydrogenase
- Hydrolysis by enoyl-CoA hydratase
- Oxidation by NAD dependent 3-hydroxyacyl-CoA dehydrogenase
- Thiolysis or cleavage
In one cycle of beta-oxidation, we will get one acetyl-CoA and the remaining acyl-CoA shortened by 2 carbon units. So, if ‘n’ number of even chain acid undergo beta-oxidation, there will be n/2 – 1 cycles and we are going to get n/2 acetyl-CoA. In addition, there will be a lot of reducing equivalents in the form of NADH and FADH2 which will generate ATP after oxidative phosphorylation which we will study in the energetics of beta-oxidation. To know more about the beta-oxidation pathway please watch the below-embedded video.
Energetics of beta oxidation pathway
We will study energy yield from complete oxidation of palmitic acid. Since palmitic acid is a 16 carbon fatty acid there are 7 cycles, 8 acetyl-CoA, 7 NADH and 7 FADH2. One must remember each NADH after oxidative phosphorylation through electron transport chain going to give 2.5 ATP. Similarly, each FADH2 after oxidative phosphorylation through electron transport chain going to give 1.5 ATP. Each acetyl-CoA will generate 10 ATP. Energy expenditure for the activation step is 2ATP which we are going to subtract for the final calculation.
Odd chain fatty acid oxidation
Most fatty acids have an even number of carbon atoms and the beta-oxidation pathway can successfully complete the degradation of these molecules. Fatty acids with an odd number of carbon atoms are oxidized by the pathway of β-oxidation to acetyl CoA until a three-carbon compound propionyl-CoA. This compound is converted to succinyl-CoA, an intermediate of the citric acid cycle . So, the propionyl-CoA from an odd-chain fatty acid is glucogenic. This pathway requires two water soluble vitamins biotin and vitamin b12 as coenzymes. Here is a video where I have explained steps involved in odd chain fatty acid oxidation.