Fatty acid metabolism
Fatty acids are a family of molecules classified within the lipid macronutrient class. One role of fatty acids within animal metabolism is energy production in the form of adenosine triphosphate (ATP) synthesis. When compared to other macronutrient classes (carbohydrates and protein), fatty acids yield the most ATP on an energy per gram basis by a pathway called β-oxidation. In addition, fatty acids are important for energy storage, phospholipid membrane formation, and signaling pathways. Fatty acid metabolism consists of catabolic processes that generate energy and primary metabolites from fatty acids, and anabolic processes that create biologically important molecules from fatty acids and other dietary sources.
- Lipolysis is carried out by lipases.
- Once freed from glycerol, free fatty acids can enter blood and muscle fiber by diffusion.
- Beta oxidation splits long carbon chains of the fatty acid into acetyl CoA, which can eventually enter the TCA cycle.
Briefly, the steps in β-oxidation (lipolysis of free fatty acids) are as follows:
- Dehydrogenation by acyl-CoA dehydrogenase, yielding 1 FADH2
- Hydration by enoyl-CoA hydratase
- Dehydrogenation by 3-hydroxyacyl-CoA dehydrogenase, yielding 1 NADH
- Cleavage by thiolase, yielding 1 acetyl-CoA and a fatty acid that has now been shortened by 2 carbons (acyl-CoA)
This cycle repeats until the fatty acid has been completely reduced to acetyl-CoA or, in the case of fatty acids with odd numbers of carbon atoms, acetyl-CoA and 1 molecule of propionyl-CoA per molecule of fatty acid.
The glycerol released by lipase action is phosphorylated by glycerol kinase, and the resulting glycerol 3-phosphate is oxidized to dihydroxyacetone phosphate. The glycolytic enzyme triose phosphate isomerase converts this compound to glyceraldehyde 3-phosphate, which is oxidized via glycolysis.
Fatty acids as an energy source
Fatty acids, stored as triglycerides in an organism, are an important source of energy because they are both reduced and anhydrous. The energy yield from a gram of fatty acids is approximately 9 kcal (37 kJ), compared to 4 kcal (17 kJ) for carbohydrates. Since the hydrocarbon portion of fatty acids is hydrophobic, these molecules can be stored in a relatively anhydrous (water-free) environment. Carbohydrates, on the other hand, are more highly hydrated. For example, 1 g of glycogen can bind approximately 2 g of water, which translates to 1.33 kcal/g (4 kcal/3 g). This means that fatty acids can hold more than six times the amount of energy per unit of storage mass. Put another way, if the human body relied on carbohydrates to store energy, then a person would need to carry 31 kg (67.5 lb) of hydrated glycogen to have the energy equivalent to 4.6 kg (10 lb) of fat.
Hibernating animals provide a good example for utilizing fat reserves as fuel. For example, bears hibernate for about 7 months, and, during this entire period, the energy is derived from degradation of fat stores. Migrating birds similarly build up large fat reserves before embarking on their intercontinental journeys.
Thus the young adult human’s fat stores average between about 10-20 kg, but varies greatly depending on age, gender, and individual disposition. By contrast the human body stores only about 400 g of glycogen, of which 300 g is locked inside the skeletal muscles and is unavailable to the body as a whole. The 100 g or so of glycogen stored in the liver is depleted within one day of starvation. Thereafter the glucose that is released into the blood by the liver for general use by the body tissues, has to be synthesized from the glucogenic amino acids and a few other gluconeogenic substrates, which do not include fatty acids.
Animals cannot synthesize carbohydrates from fatty acids
Fatty acids are broken down to acetyl-CoA by means of beta oxidation inside the mitochondria, whereas fatty acids are synthesized from acetyl-CoA outside the mitochondrion, in the cytosol. The two pathways are distinct, not only in where they occur, but also in the reactions that occur, and the substrates that are used. The two pathways are mutually inhibitory, preventing the acetyl-CoA produced by beta-oxidation from entering the synthetic pathway via the acetyl-CoA carboxylase reaction. It can also not be converted to pyruvate as the pyruvate decarboxylase reaction is irreversible. Instead the acetyl-CoA produced by the beta-oxidation of fatty acids condenses with oxaloacetate, to enter the citric acid cycle. During each turn of the cycle, two carbon atoms leave the cycle as CO2 in the decarboxylation reactions catalyzed by isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase. Thus each turn of the citric acid cycle oxidizes an acetyl-CoA unit while regenerating the oxaloacetate molecule with which the acetyl-CoA had originally combined to form citric acid. The decarboxylation reactions occur before malate is formed in the cycle. This is the only substance that can be removed from the mitochondrion to enter the gluconeogenic pathway to form glucose or glycogen in the liver or any other tissue. There can therefore be no net conversion of fatty acids into glucose.
The energy in the fat stores is therefore extracted directly via the beta-oxidation of their fatty acids, and their combustion in the citric acid cycle, and never via their conversion to carbohydrates.
Only plants possess the enzymes to convert acetyl-CoA into oxaloacetate from which malate can be formed to ultimately be converted to glucose.
Digestion and transport
Fatty acids are usually ingested as triglycerides, which cannot be absorbed by the intestine. They are broken down into free fatty acids and monoglycerides by pancreatic lipase, which forms a 1:1 complex with a protein called colipase, which is necessary for its activity. The activated complex can work only at a water-fat interface. Therefore, it is essential that fatty acids (FA) be emulsified by bile salts for optimal activity of these enzymes.
The digestion products of triglycerides are absorbed primarily as free fatty acids and 2-monoglycerides, but a small fraction are absorbed as free glycerol and as diglycerides. Once across the intestinal barrier, they are reformed into triglycerides and packaged into chylomicrons or lipoproteins, which are released into the lacteals, the capillaries of the lymph system and then into the blood. Eventually, they bind to the membranes of hepatocytes, adipocytes or muscle fibers, where they are either stored or oxidized for energy. The liver acts as a major organ for fatty acid treatment, processing chylomicron remnants and liposomes into the various lipoprotein forms, in particular VLDL and LDL. Fatty acids synthesized by the liver are converted to triglyceride and transported to the blood as VLDL. In peripheral tissues, lipoprotein lipase digests part of the VLDL into LDL and free fatty acids, which are taken up for metabolism. This is done by the removal of the triglycerides contained in the VLDL. What is left of the VLDL absorbs cholesterol from other circulating lipoproteins, becoming LDLs. LDL is absorbed via LDL receptors. This provides a mechanism for absorption of LDL into the cell, and for its conversion into free fatty acids, cholesterol, and other components of LDL. The liver controls the concentration of cholesterol in the blood by removing LDL. Another type of lipoprotein known as high-density lipoprotein, or HDL collects cholesterol, glycerol and fatty acids from the blood and transports them to the liver. In summary:
- Chylomicrons carry diet-derived lipids to body cells
- VLDLs carry lipids synthesized by the liver to body cells
- LDLs carry cholesterol around the body
- HDLs carry cholesterol from the body back to the liver for breakdown and excretion.
When blood sugar is low, decreasing insulin levels signal the adipocytes to activate hormone-sensitive lipase, and to convert triglycerides into free fatty acids. These have very low solubility in the blood, typically about 1 μM. However, the most abundant protein in blood, serum albumin, binds free fatty acids, increasing their effective solubility to ~ 1 mM. Thus, serum albumin transports fatty acids to organs such as muscle and liver for oxidation when blood sugar is low.
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 epinephrine are secreted, or when insulin levels drop in response to low blood glucose levels, 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:
Fatty acids are transported across the outer mitochondrial membrane by carnitine acyl transferases (for e.g. 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 of 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. Since β-oxidation cleaves two-carbon molecules repeatedly, it works well for even carbon chain length saturated fatty acids. For odd-carbon chain length fatty acids and unsaturated fatty acids, a slightly different pathway is taken.
Besides β-oxidation, other oxidative pathways are sometimes employed. α-Oxidation is used for branched fatty acids that cannot directly undergo β-oxidation such as phytanic acid. 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.
Regulation and control
It has long been held that hormone-sensitive lipase (HSL) is the enzyme that hydrolyses triacylglycerides to free fatty acids from fats (lipolysis). However, more recently it has been shown that at most HSL converts diacylglycerides to monoglycerides and free fatty acids. Monoglycerides are hydrolyzed by monoglyceride lipase; adipose triglyceride lipase may have a special role in converting triacylglycerides to diacylglycerides, while diacylglycerides are the best substrate for HSL. HSL is regulated by the hormones insulin, glucagon, norepinephrine, and epinephrine.
Glucagon is associated with low blood glucose, and epinephrine is associated with increased metabolic demands. In both situations, energy is needed, and the oxidation of fatty acids is increased to meet that need. Glucagon, norepinephrine, and epinephrine bind to G protein-coupled receptors that activate adenylate cyclase to produce cyclic AMP. As a consequence, cAMP activates protein kinase A, which phosphorylates (and activates) hormone-sensitive lipase.
When blood glucose is high, lipolysis is inhibited by insulin. Insulin activates protein phosphatase 2A, which dephosphorylates HSL, thereby inhibiting its activity. Insulin also activates the enzyme phosphodiesterase, which breaks down cAMP and stops the re-phosphorylation effects of protein kinase A.
For the regulation and control of metabolic reactions involving fat synthesis, see lipogenesis.
Disorders of fatty acid metabolism can be described in terms of, for example, hypertriglyceridemia (too high level of triglycerides), or other types of hyperlipidemia. These may be familial or acquired.
Familial types of disorders of fatty acid metabolism are generally classified as inborn errors of lipid metabolism. These disorders may be described as fatty oxidation disorders or as a lipid storage disorders, and are any one of several inborn errors of metabolism that result from enzyme defects affecting the ability of the body to oxidize fatty acids in order to produce energy within muscles, liver, and other cell types.
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