Метаболизм жирных кислот: катаболизм и анаболизм

Set of biological processes
Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds. In catabolism, fatty acids are metabolized to produce energy, mainly in the form of adenosine triphosphate (ATP). When compared to other macronutrient classes (carbohydrates and protein), fatty acids yield the most ATP on an energy per gram basis, when they are completely oxidized to CO2 and water by beta oxidation and the citric acid cycle. Fatty acids (mainly in the form of triglycerides) are therefore the foremost storage form of fuel in most animals, and to a lesser extent in plants. In anabolism, intact fatty acids are important precursors to triglycerides, phospholipids, second messengers, hormones and ketone bodies. For example, phospholipids form the phospholipid bilayers out of which all the membranes of the cell are constructed from fatty acids. Phospholipids comprise the plasma membrane and other membranes that enclose all the organelles within the cells, such as the nucleus, the mitochondria, endoplasmic reticulum, and the Golgi apparatus. In another type of anabolism, fatty acids are modified to form other compounds such as second messengers and local hormones. The prostaglandins made from arachidonic acid stored in the cell membrane are probably the best known of these local hormones.

One product of fatty acid metabolism are the prostaglandins, compounds having diverse hormone like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are enzymatically derived from arachidonic acid, a 20 carbon polyunsaturated fatty acid. Every prostaglandin therefore contains 20 carbon atoms, including a 5 carbon ring. They are a subclass of eicosanoids and form the prostanoid class of fatty acid derivatives. The prostaglandins are synthesized in the cell membrane by the cleavage of arachidonate from the phospholipids that make up the membrane. This is catalyzed either by phospholipase A acting directly on a membrane phospholipid, or by a lipase acting on DAG (diacyl glycerol). The arachidonate is then acted upon by the cyclooxygenase component of prostaglandin synthase. This forms a cyclopentane ring roughly in the middle of the fatty acid chain. The reaction also adds 4 oxygen atoms derived from two molecules of O. The resulting molecule is prostaglandin G, which is converted by the hydroperoxidase component of the enzyme complex into prostaglandin H. This highly unstable compound is rapidly transformed into other prostaglandins, prostacyclin and thromboxanes. Conversely, thromboxanes (produced by platelet cells) are vasoconstrictors and facilitate platelet aggregation. Their name comes from their role in clot formation (thrombosis).

A significant proportion of the fatty acids in the body are obtained from the diet, in the form of triglycerides of either animal or plant origin. The fatty acids in the fats obtained from land animals tend to be saturated, whereas the fatty acids in the triglycerides of fish and plants are often polyunsaturated and therefore present as oils. These triglycerides cannot be absorbed by the intestine. They are broken down into mono and di glycerides plus free fatty acids (but no free glycerol) by pancreatic lipase, which forms a 1:1 complex with a protein called colipase (also a constituent of pancreatic juice), which is necessary for its activity. The activated complex can work only at a water fat interface. Therefore, it is essential that fats are first emulsified by bile salts for optimal activity of these enzymes. The digestion products consisting of a mixture of tri , di and monoglycerides and free fatty acids, which, together with the other fat soluble contents of the diet (e. g. the fat soluble vitamins and cholesterol) and bile salts form mixed micelles, in the watery duodenal contents (see diagrams on the right). The contents of these micelles (but not the bile salts) enter the enterocytes (epithelial cells lining the small intestine) where they are resynthesized into triglycerides, and packaged into chylomicrons which are released into the lacteals (the capillaries of the lymph system of the intestines). These lacteals drain into the thoracic duct which empties into the venous blood at the junction of the left jugular and left subclavian veins on the lower left hand side of the neck. This means that the fat soluble products of digestion are discharged directly into the general circulation, without first passing through the liver, unlike all other digestion products. The reason for this peculiarity is unknown. The chylomicrons circulate throughout the body, giving the blood plasma a milky or creamy appearance after a fatty meal. Lipoprotein lipase on the endothelial surfaces of the capillaries, especially in adipose tissue, but to a lesser extent also in other tissues, partially digests the chylomicrons into free fatty acids, glycerol and chylomicron remnants. The fatty acids are absorbed by the adipocytes, but the glycerol and chylomicron remnants remain in the blood plasma, ultimately to be removed from the circulation by the liver. The free fatty acids released by the digestion of the chylomicrons are absorbed by the adipocytes, where they are resynthesized into triglycerides using glycerol derived from glucose in the glycolytic pathway. These triglycerides are stored, until needed for the fuel requirements of other tissues, in the fat droplet of the adipocyte. The liver absorbs a proportion of the glucose from the blood in the portal vein coming from the intestines. After the liver has replenished its glycogen stores (which amount to only about 100 g of glycogen when full) much of the rest of the glucose is converted into fatty acids as described below. These fatty acids are combined with glycerol to form triglycerides which are packaged into droplets very similar to chylomicrons, but known as very low density lipoproteins (VLDL). These VLDL droplets are processed in exactly the same manner as chylomicrons, except that the VLDL remnant is known as an intermediate density lipoprotein (IDL), which is capable of scavenging cholesterol from the blood. This converts IDL into low density lipoprotein (LDL), which is taken up by cells that require cholesterol for incorporation into their cell membranes or for synthetic purposes (e. g. the formation of the steroid hormones). The remainder of the LDLs is removed by the liver. Adipose tissue and lactating mammary glands also take up glucose from the blood for conversion into triglycerides. This occurs in the same way as in the liver, except that these tissues do not release the triglycerides thus produced as VLDL into the blood. Adipose tissue cells store the triglycerides in their fat droplets, ultimately to release them again as free fatty acids and glycerol into the blood (as described above), when the plasma concentration of insulin is low, and that of glucagon and/or epinephrine is high. Mammary glands discharge the fat (as cream fat droplets) into the milk that they produce under the influence of the anterior pituitary hormone prolactin. All cells in the body need to manufacture and maintain their membranes and the membranes of their organelles. Whether they rely entirely on free fatty acids absorbed from the blood, or are able to synthesize their own fatty acids from blood glucose, is not known. The cells of the central nervous system will almost certainly have the capability of manufacturing their own fatty acids, as these molecules cannot reach them through the blood brain barrier. The diagrams presented show how fatty acids are synthesized in microorganisms and list the enzymes found in Escherichia coli. In animals as well as some fungi such as yeast, these same reactions occur on fatty acid synthase I (FASI), a large dimeric protein that has all of the enzymatic activities required to create a fatty acid. FASI is less efficient than FASII; however, it allows for the formation of more molecules, including "medium chain" fatty acids via early chain termination. Once a 16:0 carbon fatty acid has been formed, it can undergo a number of modifications, resulting in desaturation and/or elongation. Elongation, starting with stearate (18:0), is performed mainly in the endoplasmic reticulum by several membrane bound enzymes. The enzymatic steps involved in the elongation process are principally the same as those carried out by fatty acid synthesis, but the four principal successive steps of the elongation are performed by individual proteins, which may be physically associated. Step Enzyme Reaction Description (a) Acetyl CoA:ACP transacylase Activates acetyl CoA for reaction with malonyl ACP (b) Malonyl CoA:ACP transacylase Activates malonyl CoA for reaction with acetyl ACP (c) 3 ketoacyl ACP synthase Reacts ACP bound acyl chain with chain extending malonyl ACP (d) 3 ketoacyl ACP reductase Reduces the carbon 3 ketone to a hydroxyl group (e) 3 Hydroxyacyl ACP dehydrase Eliminates water (f) Enoyl ACP reductase Reduces the C2 C3 double bond. Abbreviations: ACP – Acyl carrier protein, CoA – Coenzyme A, NADP – Nicotinamide adenine dinucleotide phosphate. Note that during fatty synthesis the reducing agent is NADPH, whereas NAD is the oxidizing agent in beta oxidation (the breakdown of fatty acids to acetyl CoA). This difference exemplifies a general principle that NADPH is consumed during biosynthetic reactions, whereas NADH is generated in energy yielding reactions. (Thus NADPH is also required for the synthesis of cholesterol from acetyl CoA; while NADH is generated during glycolysis.) The source of the NADPH is two fold. When malate is oxidatively decarboxylated by “NADP+ linked malic enzyme" pyruvate, CO and NADPH are formed. NADPH is also formed by the pentose phosphate pathway which converts glucose into ribose, which can be used in synthesis of nucleotides and nucleic acids, or it can be catabolized to pyruvate. The cytosolic acetyl CoA is carboxylated by acetyl CoA carboxylase into malonyl CoA, the first committed step in the synthesis of fatty acids.

Acetyl CoA is formed into malonyl CoA by acetyl CoA carboxylase, at which point malonyl CoA is destined to feed into the fatty acid synthesis pathway. Acetyl CoA carboxylase is the point of regulation in saturated straight chain fatty acid synthesis, and is subject to both phosphorylation and allosteric regulation. Regulation by phosphorylation occurs mostly in mammals, while allosteric regulation occurs in most organisms. Allosteric control occurs as feedback inhibition by palmitoyl CoA and activation by citrate. When there are high levels of palmitoyl CoA, the final product of saturated fatty acid synthesis, it allosterically inactivates acetyl CoA carboxylase to prevent a build up of fatty acids in cells. Citrate acts to activate acetyl CoA carboxylase under high levels, because high levels indicate that there is enough acetyl CoA to feed into the Krebs cycle and produce energy. High plasma levels of insulin in the blood plasma (e. g. after meals) cause the dephosphorylation and activation of acetyl CoA carboxylase, thus promoting the formation of malonyl CoA from acetyl CoA, and consequently the conversion of carbohydrates into fatty acids, while epinephrine and glucagon (released into the blood during starvation and exercise) cause the phosphorylation of this enzyme, inhibiting lipogenesis in favor of fatty acid oxidation via beta oxidation. and mitochondrial fatty acid oxidation (FAO) that are involved in diverse aspects of tumorigenesis and cell growth.