Skip to main content
Biology LibreTexts

5.8 Fatty Acid Breakdown

  • Page ID
    16956
  • Hormone-sensitive lipase in adipose tissue hydrolyzes the stored fat in those cells into glycerol and fatty acids. Glycerol can enter the glycolytic cycle via conversion to dihydroxyacetone phosphate (a two-step conversion using glycerol kinase and glycerol-3-phosphate dehydrogenase). The fatty acids are secreted from the adipose cells into the bloodstream where they bind to a carrier protein, albumin. This complex can then be brought inside of other cells by endocytosis, where they can be broken down as an energy source.

    The breakdown of fatty acids occurs by β-oxidation inside the mitochondrial matrix (Figure 14).

    Screen Shot 2018-12-23 at 1.58.33 PM.png
    Figure 14. b oxidation of fatty acids happens in the mitochondrial matrix.

    Since the inner mitochondrial membrane is impermeable to long-chain free fatty acids, they must first be activated to fatty acyl-CoA and linked to carnitine, an amino acid derivative synthesized from methionine and lysine (see Figure 15). The first step is performed by one of a family of enzymes known as acyl-CoA synthetases or thiokinases, and requires Coenzyme A and ATP hydrolysis. These reactions occur either on the cy- toplasmic surface of the mitochondrial outer membrane or the endoplasmic reticulum, where acyl-CoA synthetases are embedded. In the second reaction, carnitine palmitoyl- transferase I on the outside of the inner mitochondrial membrane links the acyl chain to carnitine, releasing CoA. The acyl-carnitine is transported into the mitochondrial matrix where carnitine palmitoyltransferase II releases the fatty acyl chain from the carnitine and reattaches it to an molecule of CoA.

    Screen Shot 2018-12-23 at 1.58.41 PM.png
    Figure 15. Fatty acid breakdown by Carnitine Palmitoyl Transferases.

    Carnitine deficiency syndromes can occur when there is either a dysfunctional mutation of carnitine palmitoyltransferase or a severe deficiency of intracellular carnitine. Since most of the carnitine in the body is found in cardiac and voluntary muscle, the usual symptoms are muscle weakness and cardiac arrhythmias, as well as hypoketosis. In neonates, the arrythmias can lead to death. Carnitine supplementation is a successful treatment in systemic carnitine deficiency due to either low carnitine intake or defects in the carnitine transporter embedded in the cell membranes. However, if the defect is in the palmitoyltransferase, supplementation will be unsuccessful.

    Carnitine is widely sold as a dietary supplement for increasing weight loss by enhancing fat catabolism. The basic idea is obvious: carnitine is needed for long-chain fatty acid breakdown, so more carnitine = more fat burned. However, that only holds true if carnitine levels are below saturation levels for the palmitoyltransferases. Because 75% of the carnitine in the body must be ingested (only 25% is synthesized), this is a mild possibility, depending on diet. Currently, the biomedical community has not reached a consensus on the efficacy of carnitine supplementation on fatty acid oxidation in carnitine-sufficient persons.

    In the mitochondrial matrix, β-oxidation occurs in four steps to yield an acyl-CoA chain that is shortened by two carbons, and an acetyl-CoA that can then enter the TCA. . The β refers to the second closest carbon to the one attached to CoA. The bond that will be broken is the bond between the α and β carbons. All even-numbered, fully saturated, fatty acids can thus be completely oxidized. The presence of double bonds in un- saturated fatty acids introduces complications to this process that must be addressed using additional enzymes that either move the double bond or remove it.

    Most animals and plants generate even-numbered fatty acids; however, some marine animals (e.g. smelt, mullet) and some plants and bacteria synthesize odd-chain fatty acids as well. The same enzymes responsible for β oxidation of even-numbered fatty acids can handle odd-numbered fatty acids as well, except that the final degradation yields propionyl-CoA instead of acetyl-CoA.

    Screen Shot 2018-12-23 at 1.58.59 PM.png

    Propionyl-CoA is converted to succinyl-CoA through a series of three enzymes: propionyl-CoA carboxylase, methylmalonyl-CoA racemase, and methylmalonyl-CoA mutase. The succinyl-CoA could theoretically enter the TCA cycle, but recall that the succinyl-CoA is simply recycled and never actually consumed by the TCA cycle. Thus, in order for the succinyl-CoA to contribute to the energy needs of the cell, it must first be converted to malate (steps 6-8 of TCA cycle), which is then converted to pyruvate by malic enzyme, also known as decarboxylating malate dehydrogenase. Pyruvate can then enter and be consumed by the TCA cycle.

    Vitamin B12, or 5’-deoxyadenosylcobalamin, is a coenzyme component of methylmalonyl-CoA mutase, but it is not made by either plants or animals. It is only made by certain bacteria, some of which live in the intestinal tracts of herbivores. Herbivores thus absorb the B12 for their use, and carnivores obtain their B12 from eating herbivores. Defects in methylmalonyl-CoA mutase or severe deficiency in vitamin B12 (most often in vegetarians) can lead to methymalonyl aciduria/acidemia, that can be fatal in untreated infants due to acidosis. However, depending on the cause, it can be treated with high doses of B12 and/or by avoiding dietary odd-chain fats and proteins rich in isoleucine, leucine, or methionine, which also catabolize to propionyl-CoA. Pernicious anemia, in which usually elderly patients have very low levels of red blood cells and hemoglobin, as well as neurodegeneration, is also related to B12. However, it is usually not due to a vitamin deficiency, but rather to the insufficient secretion of intrinsic factor, which binds B12 in the stomach and then is taken into intestinal cells by receptor-mediated endocytosis.

    In addition to oxidation in the mitochondria, fatty acids also undergo β-oxidation in peroxisomes. However, generally, the oxidation in peroxisomes is limited, and the purpose is to shorten long fatty acids in preparation for final degradation in the mitochondria.

    In addition to the more common single-chain fatty acids, cells will also encounter branched fatty acids, which block β-oxidation is alkyl group is on the β carbon. In these cases, phytanic acid for example, a oxidation is necessary to generate an intermediate with the alkyl group on the a carbon. This is then followed by β-oxidation to completion.

    Finally (with respect to fatty acid catabolism), it must be noted that in liver especially, a large part of the acetyl-CoA generated by oxidation of fatty acids does not enter the TCA cycle. Instead, it is converted into acetoacetate or D-β-hydroxybutyrate, which along with acetone, are known, somewhat bizarrely, as ketone bodies. These molecules are water soluble, and transported through the bloodstream as energy sources for a variety of tissues, even including brain, which typically only uses glucose as fuel since fatty acids cannot pass through the blood-brain barrier. However, ketone bodies can penetrate and are used by brain cells under starvation conditions.

    Ketoacidosis is a condition in which ketone bodies are being produced much faster than they are used. This leads to a buildup of the molecules in the bloodstream, which lowers the pH, since the molecules are acidic. An easy diagnostic of ketoacidosis is a sweet somewhat fruity smell (of acetone) on the breath. This condition can be an indication of diabetes, but may also occur when a person is consuming a high-fat/low-carb diet. When the body’s metabolism is not using glucose/carbohydrates as the primary food source for either reason, fat is used instead, increasing production of ketone bodies. Left untreated, severe ketoacidosis can lead to cell damage as the blood acidifies, and compensation by increased exhalation of carbon dioxide and lead to respiratory failure in susceptible individuals.