Fatty Acid Metabolism - Transport and Oxidation

Transport and Oxidation

The neutral lipids stored in adipocytes (and in steroid synthesizing cells of the adrenal cortex, ovary, and testes) in the form of lipid droplets, with a core of sterol esters and triacylglycerols surrounded by a monolayer of phospholipids, are coated with perilipin, a protein that acts as a protective coating from the body’s natural lipases, such as hormone-sensitive lipase,. However, when hormones such as epinepherine or glucagon are secreted in response to low levels of glucose, this triggers an intracellular secondary messenger cascade that phosphorylates hormone-sensitive lipase to break triglycerides into glycerol and free fatty acids for use in metabolism, a process called lipolysis.

The free fatty acids move into the blood stream where they are bound by serum albumin and transported to the tissue needing fuel. Once the fatty acids reach the target tissue, they are released by serum albumin and cross into the cytosol. The enzymes used in fatty acid oxidation in animal cells are located in the mitochondrial matrix (as was demonstrated by Eugene P. Kennedy and Albert Lehninger in 1948). Free fatty acid chains of more than 12 carbons require the help of membrane transporters to cross into the membrane into the mitochondria, where they undergo Fatty acid degradation.

Fatty acid degradation is the process in which fatty acids are broken down, resulting in release of energy. It includes three major steps:

• Activation and transport into the mitochondria
• β-Oxidation
• Electron transport chain

Fatty acids are transported across the outer mitochondrial membrane by carnitine-palmitoyl transferase I (CPT-I), and then couriered across the inner mitochondrial membrane by carnitine. Once inside the mitochondrial matrix, the fatty acyl-carnitine (such as palmitoylcarnitine) reacts with coenzyme A to release the fatty acid and produce acetyl-CoA. CPT-I is believed to be the rate-limiting step in fatty acid oxidation.

Once inside the mitochondrial matrix, fatty acids undergo β-oxidation. During this process, two-carbon molecules acetyl-CoA are repeatedly cleaved from the fatty acid. Acetyl-CoA can then enter the citric acid cycle, which produces NADH and FADH₂. NADH and FADH₂ are subsequently used in the electron transport chain to produce ATP, the energy currency of the cell.

Besides β-oxidation, other oxidative pathways are sometimes employed. α-Oxidation is used for branched fatty acids that cannot directly undergo β-oxidation. The smooth ER of the liver can perform ω-oxidation, which is primarily for detoxification but can become much more prevalent in cases of defective β-oxidation. Fatty acids with very long chains (20 or more carbons) are first broken down to a manageable size in peroxisomes.