Fatty acid metabolism

Source: Wikipedia, the free encyclopedia.

Fatty acid metabolism consists of various

anabolic processes where they serve as building blocks for other compounds.[1]

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.[2] 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

local hormones. The prostaglandins made from arachidonic acid
stored in the cell membrane are probably the best-known of these local hormones.

Fatty acid catabolism

epinephrine
, as shown in the diagram.
free fatty acids in the blood attached to plasma albumin, its diffusion across the cell membrane using a protein transporter, and its activation, using ATP, to form acyl-CoA in the cytosol
. The illustration is, for diagrammatic purposes, of a 12 carbon fatty acid. Most fatty acids in human plasma are 16 or 18 carbon atoms long.
inner membrane of the mitochondrion by carnitine-acyl-CoA transferase (CAT). The illustrated acyl chain is, for diagrammatic purposes, only 12 carbon atoms long. Most fatty acids in human plasma are 16 or 18 carbon atoms long. CAT is inhibited by high concentrations of malonyl-CoA (the first committed step in fatty acid synthesis
) in the cytoplasm. This means that fatty acid synthesis and fatty acid catabolism cannot occur simultaneously in any given cell.
beta-oxidation of an acyl-CoA molecule in the mitochondrial matrix. During this process an acyl-CoA molecule which is 2 carbons shorter than it was at the beginning of the process is formed. Acetyl-CoA, water and 5 ATP molecules are the other products of each beta-oxidative event, until the entire acyl-CoA molecule has been reduced to a set of acetyl-CoA
molecules.

Fatty acids are stored as

triglycerides in the fat depots of adipose tissue
. Between meals they are released as follows:

  • epinephrine and glucagon levels in the blood (or norepinephrine secreted by sympathetic nerves in adipose tissue), caused by declining blood glucose levels after meals, which simultaneously lowers the insulin level in the blood.[1]
  • Once freed from glycerol, the free fatty acids enter the blood, which transports them, attached to plasma albumin, throughout the body.[4]
  • Long-chain free fatty acids enter metabolizing cells (i.e. most living cells in the body except
    interstitial fluids
    that bathe these cells.
  • Once inside the cell, long-chain-fatty-acid—CoA ligase catalyzes the reaction between a fatty acid molecule with ATP (which is broken down to AMP and inorganic pyrophosphate) to give a fatty acyl-adenylate, which then reacts with free coenzyme A to give a fatty acyl-CoA molecule.
  • In order for the acyl-CoA to enter the mitochondrion the carnitine shuttle is used:[10][11][12]
  1. Acyl-CoA is transferred to the hydroxyl group of carnitine by
    outer and inner mitochondrial membranes
    .
  2. Acyl-carnitine is shuttled inside by a carnitine-acylcarnitine translocase, as a carnitine is shuttled outside.
  3. Acyl-carnitine is converted back to acyl-CoA by carnitine palmitoyltransferase II, located on the interior face of the inner mitochondrial membrane. The liberated carnitine is shuttled back to the cytosol, as an acyl-CoA is shuttled into the mitochondrial matrix.
  • acetyl CoA, which condense with oxaloacetate to form citrate at the "beginning" of the citric acid cycle.[2] It is convenient to think of this reaction as marking the "starting point" of the cycle, as this is when fuel - acetyl-CoA - is added to the cycle, which will be dissipated as CO2 and H2O with the release of a substantial quantity of energy captured in the form of ATP, during the course of each turn of the cycle and subsequent oxidative phosphorylation
    .
Briefly, the steps in beta oxidation are as follows:[2]
  1. Dehydrogenation by acyl-CoA dehydrogenase, yielding 1 FADH2
  2. Hydration by enoyl-CoA hydratase
  3. Dehydrogenation by 3-hydroxyacyl-CoA dehydrogenase, yielding 1 NADH + H+
  4. Cleavage by thiolase, yielding 1 acetyl-CoA and a fatty acid that has now been shortened by 2 carbons (forming a new, shortened acyl-CoA)
This beta oxidation reaction is repeated 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. Each beta oxidative cut of the acyl-CoA molecule eventually yields 5 ATP molecules in oxidative phosphorylation.[13][14]
  • The acetyl-CoA produced by beta oxidation enters the citric acid cycle in the mitochondrion by combining with oxaloacetate to form citrate. Coupled to oxidative phosphorylation this results in the complete combustion of the acetyl-CoA to CO2 and water. The energy released in this process is captured in the form of 1 GTP and 11 ATP molecules per acetyl-CoA molecule oxidized.[2][10] This is the fate of acetyl-CoA wherever beta oxidation of fatty acids occurs, except under certain circumstances in the liver.
The propionyl-CoA is later converted into succinyl-CoA through biotin-dependant propionyl-CoA carboxylase (PCC) and Vitamin B12-dependant methylmalonyl-CoA mutase (MCM), sequentially.[15][16] Succinyl-CoA is first converted to malate, and then to pyruvate where it is then transported to the matrix to enter the citric acid cycle.

In the liver oxaloacetate can be wholly or partially diverted into the

ketone bodies (as they are not "bodies" at all, but water-soluble chemical substances). The ketones are released by the liver into the blood. All cells with mitochondria can take up ketones from the blood and reconvert them into acetyl-CoA, which can then be used as fuel in their citric acid cycles, as no other tissue can divert its oxaloacetate into the gluconeogenic pathway in the way that this can occur in the liver. Unlike free fatty acids, ketones can cross the blood–brain barrier and are therefore available as fuel for the cells of the central nervous system, acting as a substitute for glucose, on which these cells normally survive.[10] The occurrence of high levels of ketones in the blood during starvation, a low carbohydrate diet, prolonged heavy exercise, or uncontrolled type 1 diabetes mellitus is known as ketosis, and, in its extreme form, in out-of-control type 1 diabetes mellitus, as ketoacidosis
.

The glycerol released by lipase action is
triose phosphate isomerase converts this compound to glyceraldehyde 3-phosphate, which is oxidized via glycolysis, or converted to glucose via gluconeogenesis
.

Fatty acids as an energy source

alpha-linolenic acid
. Chemical formula: C55H98O6

Fatty acids, stored as triglycerides in an organism, are a concentrated

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 binds 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 stored 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.[10]

Hibernating animals provide a good example for utilization of 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.[17]

The fat stores of young adult humans average between about 10–20 kg, but vary greatly depending on gender and individual disposition.[18] 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.[10] 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.[1] Nonetheless, lipolysis releases glycerol which can enter the pathway of gluconeogenesis.

Carbohydrate synthesis from glycerol and fatty acids

Fatty acids are broken down to acetyl-CoA by means of beta oxidation inside the mitochondria, whereas

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.[1] Only plants possess the enzymes to convert acetyl-CoA into oxaloacetate from which malate can be formed to ultimately be converted to glucose.[1]

However, acetyl-CoA can be converted to acetoacetate, which can decarboxylate to

isotopic labelling.[21] Up to 11% of the glucose can be derived from acetone during starvation in humans.[21]

The glycerol released into the blood during the

triose phosphate isomerase. From here the three carbon atoms of the original glycerol can be oxidized via glycolysis, or converted to glucose via gluconeogenesis.[10]

Other functions and uses of fatty acids

Intracellular signaling

Chemical structure of the diglyceride 1-palmitoyl-2-oleoyl-glycerol

Fatty acids are an integral part of the phospholipids that make up the bulk of the

diacylglycerol (DAG) and inositol trisphosphate (IP3) through hydrolysis of the phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2), by the cell membrane bound enzyme phospholipase C (PLC).[24]

Eicosanoid paracrine hormones

Arachidonic acid
Prostaglandin E1 - Alprostadil

One product of fatty acid metabolism are the

5-carbon ring. They are a subclass of eicosanoids and form the prostanoid class of fatty acid derivatives.[25]

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

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 O2. The resulting molecule is prostaglandin G2, which is converted by the hydroperoxidase component of the enzyme complex into prostaglandin H2. This highly unstable compound is rapidly transformed into other prostaglandins, prostacyclin and thromboxanes.[25]
These are then released into the interstitial fluids surrounding the cells that have manufactured the eicosanoid hormone.

If arachidonate is acted upon by a

leukotrienes
are formed. They also act as local hormones.

Prostaglandins have two derivatives:

vasoconstrictors and facilitate platelet aggregation. Their name comes from their role in clot formation (thrombosis
).

Dietary sources of fatty acids, their digestion, absorption, transport in the blood and storage

Dietary fats are emulsified in the duodenum by soaps in the form of bile salts and phospholipids, such as phosphatidylcholine. The fat droplets thus formed can be attacked by pancreatic lipase.
Structure of a bile acid (cholic acid), represented in the standard form, a semi-realistic 3D form, and a diagrammatic 3D form
Diagrammatic illustration of mixed micelles formed in the duodenum in the presence of bile acids (e.g. cholic acid) and the digestion products of fats, the fat soluble vitamins and cholesterol.

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

bile salts for optimal activity of these enzymes.[28] 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).[27][29]

The contents of these micelles (but not the bile salts) enter the

lymph system of the intestines).[30] 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.[31]

A schematic diagram of a chylomicron.

The chylomicrons circulate throughout the body, giving the blood plasma a milky or creamy appearance after a fatty meal.[citation needed] 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[citation needed], 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[citation needed], where they are resynthesized into triglycerides using glycerol derived from glucose in the glycolytic pathway[citation needed]. These triglycerides are stored, until needed for the fuel requirements of other tissues, in the fat droplet of the adipocyte.

The

steroid hormones). The remainder of the LDLs is removed by the liver.[32]

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.[33] 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

blood brain barrier.[34] However, it is unknown how they are reached by the essential fatty acids, which mammals cannot synthesize themselves but are nevertheless important components of cell membranes (and other functions
described above).

Fatty acid synthesis

Main article: Fatty acid synthesis
Synthesis of saturated fatty acids via Fatty Acid Synthase II in E. coli

Much like

beta-oxidation, straight-chain fatty acid synthesis occurs via the six recurring reactions shown below, until the 16-carbon palmitic acid is produced.[35][36]

The diagrams presented show how fatty acids are synthesized in microorganisms and list the enzymes found in

mitochondria.[37]

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.[37] Enzymes, acyltransferases and transacylases, incorporate fatty acids in phospholipids, triacylglycerols, etc. by transferring fatty acids between an acyl acceptor and donor. They also have the task of synthesizing bioactive lipids as well as their precursor molecules.[38]

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.[39][40]

Step Enzyme Reaction Description
(a) Acetyl CoA:ACP transacylase
Activates acetyl CoA for reaction with malonyl-ACP
(b) Malonyl CoA:ACP transacylase Center 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

nucleic acids, or it can be catabolized to pyruvate.[34]

Glycolytic end products are used in the conversion of carbohydrates into fatty acids

Main article: Citric acid cycle § Glycolytic end products are used in the conversion of carbohydrates into fatty acids

In humans, fatty acids are formed from carbohydrates predominantly in the liver and

acetyl CoA carboxylase into malonyl CoA, the first committed step in the synthesis of fatty acids.[41][42]

Regulation of fatty acid synthesis

Acetyl-CoA is formed into

Krebs cycle and produce energy.[43]

High plasma levels of

beta-oxidation.[34][42]

Disorders

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

oxidize fatty acids in order to produce energy within muscles, liver, and other cell types. When a fatty acid oxidation disorder affects the muscles, it is a metabolic myopathy
.

Moreover, cancer cells can display irregular fatty acid metabolism with regard to both

fatty acid oxidation (FAO)[45]
that are involved in diverse aspects of tumorigenesis and cell growth.

References

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  2. ^ a b c d Oxidation of fatty acids
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  11. ^ Activation and transportation of fatty acids to the mitochondria via the carnitine shuttle (with animation)
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  13. ^ Oxidation of odd carbon chain length fatty acids
  14. ^ Oxidation of unsaturated fatty acids
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  20. ^ a b c Glew, Robert H. "You Can Get There From Here: Acetone, Anionic Ketones and Even-Carbon Fatty Acids can Provide Substrates for Gluconeogenesis". Nigerian Journal of Physiological Science. 25 (1). Invited review: 2–4. Archived from the original on 26 September 2013. Retrieved 7 August 2016.
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  35. ^ a b Dijkstra, Albert J., R. J. Hamilton, and Wolf Hamm. "Fatty Acid Biosynthesis." Trans Fatty Acids. Oxford: Blackwell Pub., 2008. 12. Print.
  36. ^ "MetaCyc pathway: superpathway of fatty acids biosynthesis". MetaCyc Metabolic Pathway Database. BioCyc. (E. coli).
  37. ^ a b Christie, William W. (20 April 2011). "Fatty Acids: Straight-chain Saturated, Structure, Occurrence and Biosynthesis". In American Oil Chemists' Society (ed.). AOCS Lipid Library. Archived from the original on 2011-07-21. Retrieved 2011-05-02.
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  39. ^ "MetaCyc pathway: stearate biosynthesis I (animals)". MetaCyc Metabolic Pathway Database. BioCyc.
  40. ^ "MetaCyc pathway: very long chain fatty acid biosynthesis II". MetaCyc Metabolic Pathway Database. BioCyc.
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  43. ^ Diwan, Joyce J. "Fatty Acid Synthesis." Rensselaer Polytechnic Institute (RPI) :: Architecture, Business, Engineering, IT, Humanities, Science. Web. 30 Apr. 2011. <"Fatty Acid Synthesis". Archived from the original on 2011-06-07. Retrieved 2011-05-02.>.
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