Fatty acids are organic carboxylic acids containing an aliphatic hydrocarbon chain. They naturally occur in the form of esters such as phospholipids, triglycerides and cholesterol esters (Berg, Tymoczko, & Stryer, 2007). Fatty acids have different lengths; there are short, medium, long and very long chain fatty acids, depending on the number of carbon atoms on the aliphatic chain. They may also be saturated, meaning they have no carbon-carbon double bonds, or may be unsaturated, giving cis and trans isomers.
Fatty acid metabolism refers to the processes of generation and breakdown of lipids and lipid components. It involves catabolism of fatty acids to generate energy, and anabolism to create fatty acids and more complex fats from other molecules. As a body fuel, fatty acids have the highest yield of energy, in the form of adenosine triphosphate (ATP) molecules, compared to carbohydrates and proteins, and are thus stored in adipose tissue and in smaller amounts in other tissues for periods of sustained energy demand. Fatty acids also have multiple physiological roles, such as in the formation of the plasma membrane in the cell and cellular organelles, intracellular signaling, and prostaglandin formation and effect pathways.
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Digestion, Absorption and Transport of Dietary Fatty Acids
The human body receives a large proportion of its fatty acids from animal and plant dietary sources. Fish and plant fatty acids are polyunsaturated and occur as oils, while other animals provide saturated fatty acids. These fatty acids are ingested in the form of triglycerides, three fatty acid chains bound to a glycerol molecule (Nelson, Cox, & Lehninger, 2017). The small intestine cannot absorb triglycerides as is; they have to be broken down into monoglycerides, diglycerides and free fatty acids. This is done by the enzyme pancreatic lipase, together with its protein cofactor, colipase.
The digestion of fatty acids requires emulsification of the ingested fats by bile salts in order to increase enzyme activity (Hofmann, 1963). As pancreatic lipase is only active at a water-fat interface, bile salts break up large fat globules into small droplets and prevent them from re-associating, allowing the enzyme a much larger surface area to act. Activity of the lipase is further enhanced by colipase, which anchors the enzyme onto the surface of an emulsified droplet.
The monoglycerides, diglycerides and fatty acids produced combine with bile salts and phospholipids into micelles. These micelles are temporary structures and serve to increase the solubility of the digestion products within the watery content of the duodenum. The micelles break up and allow their contents to diffuse across the enterocytes of the small intestine (except the bile salts, which are recycled). Within the enterocyte, the products are reassembled into triglycerides, which are then reorganized into chylomicrons, together with fat-soluble vitamins and cholesterol. These chylomicrons are released into the lacteals of the lymphatic system, and join the blood circulation at the termination of the thoracic duct.
The chylomicrons within the general circulation are hydrolyzed by lipoprotein lipase, an enzyme found on the endothelium of capillaries, and in especially high amounts within adipose tissue. This liberates free fatty acids and monoglycerides, which are absorbed by adipocytes, and converted into triglycerides and stored as fat droplets.
Synthesis of Fatty Acids
The cytoplasm is the site of fatty acid synthesis within the cell, where fatty acid synthase and acetyl-CoA carboxylase act on acetyl-CoA and NADPH to produce fatty acids. Acetyl-CoA carboxylase converts acetyl CoA to malonyl CoA, the main substrate for the biosynthesis of fatty acids. This is the committed step for this process, as the carboxylation is irreversible, and malonyl-CoA only serves as a fatty acid precursor. Fatty acid synthase is a multi-enzyme complex comprised of two subunits, which are identical and have seven different enzyme actions.
The acetyl-CoA necessary for fatty acid synthesis is made within the mitochondrion, while the synthesis itself occurs in the cytosol. This creates the need for a shuttle system to move acetyl-CoA across the mitochondrial membrane. This process begins with the combination of acetyl-CoA with oxaloacetate to form citrate by citric acid synthetase within the Krebs cycle. Citrate is then translocated out of the mitochondrion using the citrate/malate and the citrate/phosphate antiports of the tricarboxylate transporter on the mitochondrial membrane. Once in the cytoplasm, it is broken down by ATP-citrate lyase to liberate acetyl-CoA.
The initial step of fatty acid synthesis is the translocation of the acetyl group of acetyl-CoA to a section of the fatty acid synthase subunit called acyl transfer protein (ACP). This acetyl group is then transferred to a cysteine group on the enzyme, after which ACP receives the malonyl group of malonyl-CoA. The acetyl group reacts with the malonyl group, catalyzed by 3-ketoacyl synthase, generating a ketoacid derivative bound to ACP, and releasing the carboxyl group added by acetyl-CoA carboxylase as CO 2 .
This ketoacid then undergoes reduction, dehydration and reduction once more to form a saturated fatty acid with 4 carbon atoms. These reduction reactions require NADPH. The fatty acid is elongated by addition of malonyl groups, adding two carbon atoms at a time, until the chain gets to 16, when palmitoyl-ACP is formed. The thioesterase activity of the fatty acid synthetase complex then cleaves the fatty acid chain from the ACP group, releasing palmitate into the cytosol of the cell. Palmitate is the fatty acid substrate used in elongation reactions to form longer chain fatty acids, performed by microsomal enzymes.
Fatty Acids Catabolism
Mobilization of fatty acids occurs in periods of energy demand, such as between meals. This becomes the predominant source of fuel for the body in periods of prolonged starvation, when carbohydrate sources have been depleted. Lipolysis breaks the triglyceride molecule into free fatty acids and glycerol in the cytosol of adipocytes. The free fatty acids are released into the circulation and are taken up by various cells via specific transport proteins.
Breakdown of fatty acids is achieved via beta-oxidation. This process begins in the cytoplasm, where fatty acids are activated by addition of a coenzyme A group. The activation is catalyzed by fatty acyl CoA synthetase and occurs in two steps: the fatty acid first reacts with ATP to form an adenylate, which then reacts with free coenzyme A to form a fatty acyl-CoA ester. The activated fatty acid can then be transported into the mitochondrion.
The inner membrane of the mitochondrion is impermeable to long chain fatty acids. The carnitine transport system is thus required to carry these fatty acids across (Houten & Wanders, 2010). The fatty acyl-CoA ester binds to carnitine, catalyzed by carnitine acyltransferase I on the outer mitochondrial membrane. The fatty acid-CoA-carnitine molecule is then carried across the membrane by a translocase, before being cleaved back into the fatty acid ester and carnitine by carnitine acyltransferase II on the inner membrane. Malonyl-CoA offers allosteric inhibition to carnitine acyltransferase I to prevent needless cycling between fatty acid synthesis and breakdown.
Beta-oxidation of fatty acids occurs in a four-step recurring sequence (Mehta, 2013). The fatty acid is oxidized by acyl-CoA dehydrogenase, creating an unsaturated acyl-CoA with a double bond between C2 and C3. This reaction utilizes FAD + as an electron acceptor, which is reduced to FADH 2 . The double bond is then broken by hydration, adding an OH group to C2. This OH group is oxidized to a carbonyl group to form a ketoacyl-CoA, using NAD + as the electron acceptor. Thiolysis then occurs, releasing acetyl-CoA and leaving the fatty acid ester with two less carbons.
This sequence occurs repeatedly until all the carbon atoms in the fatty acid chain are converted to acetyl-CoA, which then joins the Krebs cycle and is used to produce ATP. Breakdown of odd-numbered long chain fatty acids yields a three-carbon propionyl-CoA, which is converted to methylmalonyl-CoA then to succinyl-CoA, a tricarboxylic acid cycle intermediate. Each beta-oxidation cycle yielding an acetyl-CoA molecule generates 5 molecules of ATP. The acetyl-CoA molecules thus produced combine with oxaloacetate to form citrate within the Krebs cycle, as elaborated earlier. This process leads to the generation of 11 ATP molecules and 1 GTP molecule for every acetyl-CoA molecule oxidized.
The beta-oxidation of cis unsaturated fatty acids continues as normal until the area of the double bond is reached, at which point enoyl CoA isomerase and dienoyl CoA reductase enzymes are required, the former for odd-numbered double bonds and the latter for even-numbered ones.
Very long chain fatty acids, prostaglandins and leukotrienes are too long to be processed by the mitochondrion, and are broken down in peroxisomes. This beta-oxidation is not geared toward ATP synthesis, and is mostly a precursor to mitochondrial oxidation. The electron acceptor in this case is oxygen, forming hydrogen peroxide and releasing heat in the process. Catalase within the peroxisome breaks down the H 2 O 2 to give oxygen and water. NADH formed in the third step also cannot be recycled via oxidation within the peroxisome, thus cytosolic NAD + is needed.
Disorders of Fatty Acids Metabolism
With the many roles played by fatty acids in the body, and the complex and tightly regulated processes that are involved in their dietary uptake, synthesis, transport and breakdown, a malfunction of any such process has catastrophic effects on the metabolism of fatty acids. These disorders stem from genetic defects in the production or activation of various enzymes (Houten & Wanders, 2010). Such defects make the body unable to harness fatty acid sources for energy production within the liver and muscles.
The diseases of fatty acid metabolism are broadly grouped into fatty acid oxidation disorders and carnitine/transport system disorders. The fatty acid oxidation disorders cause deficiencies of various acyl-CoA dehydrogenase enzymes as well as mitochondrial trifunctional protein, while the transport disorders include carnitine acyltransferase and translocase deficiencies.
The fatty-acid metabolism disorders are autosomal recessive; if only one defective allele is present the individual becomes an asymptomatic carrier. Symptomatology includes cardiomegaly, muscle weakness, poor appetite, irritable mood and heart failure. These disorders can be treated using dietary modifications to small carbohydrate snack every 2 to 6 hours, and by drugs such as carnitor, an L-carnitine supplement.
Fatty acids are organic compounds that are essential to the body, both as a fuel source and as precursors to other vital molecules such as prostaglandins and phospholipids. A significant proportion of fatty acids is sourced from diet, the rest synthesized by sequential reactions catalyzed by cytosolic enzymes. Catabolism of fatty acids gives acetyl-CoA molecules that are incorporated int the Krebs cycle, and accounts for the highest energy return of all macronutrient molecules. Disorders of fatty acid metabolism arise from genetic enzyme deficiencies, and can render the body incapable of handling fatty acids normally.
References
Berg, J. M., Tymoczko, J. L., & Stryer, L. (2007). Biochemistry: Jeremy M. Berg, John L. Tymoczko, Lubert Stryer . New York: W.H. Freeman & Co Ltd.
Hofmann, A. F. (1963). The function of bile salts in fat absorption. The solvent properties of dilute micellar solutions of conjugated bile salts. Biochemical Journal , 89 (1), 57-68.
Houten, S. M., & Wanders, R. J. (2010). A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation. Journal of Inherited Metabolic Disease , 33 (5), 469-477.
Mehta, S. (2013, October 11). Oxidation of Fatty Acids. Retrieved from https://pharmaxchange.info/2013/10/oxidation-of-fatty-acids/
Nelson, D. L., Cox, M. M., & Lehninger, A. L. (2017). Lehninger principles of biochemistry . New York: W. H. Freeman and Company.
