Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...

macronutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excr ...

category. These processes can mainly be divided into (1)

catabolic Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lip ...

processes that generate energy and (2)

anabolic Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breakin ...

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 Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms ...

(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 The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and prot ...

.Oxidation of fatty acids
/ref> Fatty acids (mainly in the form of

triglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other vertebrates, as ...

s) 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 The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...

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 In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...

within the cells, such as the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: * Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

, the mitochondria,

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...

, and the

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...

. In another type of anabolism, fatty acids are modified to form other compounds such as second messengers and

local hormone ''B))'' Local hormones are a large group of signaling molecules that do not circulate within the blood. Local hormones are produced by nerve and gland cells and bind to either neighboring cells or the same type of cell that prod ...

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

Fatty acid catabolism

Fatty acids are stored as triglycerides in the fat depots of adipose tissue. Between meals they are released as follows: * Lipolysis, the removal of the fatty acid chains from the glycerol to which they are bound in their storage form as triglycerides (or fats), is carried out by lipases. These lipases are activated by high epinephrine and glucagon levels in the blood (or

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

secreted by

sympathetic nerves The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of the ...

in adipose tissue), caused by declining blood

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

levels after meals, which simultaneously lowers the insulin level in the blood. * Once freed from

glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...

, the free fatty acids enter the blood, which transports them, attached to plasma

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Album ...

, throughout the body.Mobilization and cellular uptake of stored fats (triacylglycerols) (with animation)
/ref> * Long-chain free fatty acids enter metabolizing cells (i.e. most living cells in the body except red blood cells and neurons in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

) through specific transport proteins, such as the SLC27 family fatty acid transport protein. Red blood cells do not contain mitochondria and are therefore incapable of metabolizing fatty acids; the tissues of the central nervous system cannot use fatty acids, despite containing mitochondria, because long-chain fatty acids (as opposed to medium-chain fatty acids) cannot cross the

blood brain barrier Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the ...

into the 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: # Acyl-CoA is transferred to the hydroxyl group of carnitine by carnitine palmitoyltransferase I, located on the cytosolic faces of the

outer {{Short pages monitor

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

s cannot be absorbed by the

intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans an ...

.Digestion of fats (triacylglycerols)
/ref> They are broken down into

mono- Numeral or number prefixes are prefixes derived from numerals or occasionally other numbers. In English and many other languages, they are used to coin numerous series of words. For example: * unicycle, bicycle, tricycle (1-cycle, 2-cycle, 3-cy ...

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

micelle A micelle () or micella () (plural micelles or micellae, respectively) is an aggregate (or supramolecular assembly) of surfactant amphipathic lipid molecules dispersed in a liquid, forming a colloidal suspension (also known as associated coll ...

s, in the watery duodenal contents (see diagrams on the right). The contents of these micelles (but not the bile salts) enter the

enterocytes Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase i ...

(epithelial cells lining the small intestine) where they are resynthesized into triglycerides, and packaged into

chylomicrons Chylomicrons (from the Greek χυλός, chylos, meaning ''juice'' (of plants or animals), and micron, meaning ''small particle''), also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85 ...

which are released into the lacteals (the capillaries of the lymph system of the intestines). These lacteals drain into the

thoracic duct In human anatomy, the thoracic duct is the larger of the two lymph ducts of the lymphatic system. It is also known as the ''left lymphatic duct'', ''alimentary duct'', ''chyliferous duct'', and ''Van Hoorne's canal''. The other duct is the rig ...

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. 2512 Chylomicrons Contain Triglycerides Cholesterol Molecules and Other Lipids

2512 Chylomicrons Contain Triglycerides Cholesterol Molecules and Other Lipids

The chylomicrons circulate throughout the body, giving the

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the int ...

a milky or creamy appearance after a fatty meal.

Lipoprotein lipase Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water-solubl ...

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 The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

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 lipoprotein Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, low-density l ...

s (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 Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densi ...

(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 gland A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in ...

s 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 A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pi ...

hormone

prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pi ...

. 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

will almost certainly have the capability of manufacturing their own fatty acids, as these molecules cannot reach them through the

. 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

Much like

beta-oxidation In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, ...

, straight-chain fatty acid synthesis occurs via the six recurring reactions shown below, until the 16-carbon

palmitic acid Palmitic acid (hexadecanoic acid in IUPAC nomenclature) is a fatty acid with a 16-carbon chain. It is the most common saturated fatty acid found in animals, plants and microorganisms.Gunstone, F. D., John L. Harwood, and Albert J. Dijkstra. The ...

is produced.Dijkstra, Albert J., R. J. Hamilton, and Wolf Hamm. "Fatty Acid Biosynthesis." Trans Fatty Acids. Oxford: Blackwell Pub., 2008. 12. Print. The diagrams presented show how fatty acids are synthesized in microorganisms and list the enzymes found in

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...

. These reactions are performed by fatty acid synthase II (FASII), which in general contains multiple enzymes that act as one complex. FASII is present in prokaryotes, plants, fungi, and parasites, as well as in mitochondria. 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. 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. 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

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 In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is co ...

, but the four principal successive steps of the elongation are performed by individual proteins, which may be physically associated. 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

(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 Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell memb ...

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.

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 adipose tissue, as well as in the mammary glands during lactation. The pyruvate produced by glycolysis is an important intermediary in the conversion of carbohydrates into fatty acids and cholesterol. This occurs via the conversion of pyruvate into acetyl-CoA in the mitochondrion. However, this acetyl CoA needs to be transported into cytosol where the synthesis of fatty acids and cholesterol occurs. This cannot occur directly. To obtain cytosolic acetyl-CoA, citrate (produced by the condensation of acetyl CoA with oxaloacetate) is removed from the

and carried across the inner mitochondrial membrane into the cytosol. There it is cleaved by

ATP citrate lyase ATP citrate synthase (also ATP citrate lyase (ACLY)) is an enzyme that in animals represents an important step in fatty acid biosynthesis. By converting citrate to acetyl-CoA, the enzyme links carbohydrate metabolism, which yields citrate as an ...

into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as malate (and then converted back into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion). The cytosolic acetyl-CoA is carboxylated by acetyl CoA carboxylase into malonyl CoA, the first committed step in the synthesis of fatty acids.

Regulation of fatty acid synthesis

Acetyl-CoA is formed into malonyl-CoA by

acetyl-CoA carboxylase Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme () that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is ...

, 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 biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride s ...

in favor of fatty acid oxidation via

Disorders

Disorders of fatty acid metabolism can be described in terms of, for example, hypertriglyceridemia (too high level of

s), 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 acid oxidation disorders or as a ''

lipid storage disorder A lipid storage disorder (or lipidosis) is any one of a group of inherited metabolic disorders in which harmful amounts of fats or lipids accumulate in some body cells and tissues. People with these disorders either do not produce enough of one o ...

s'', and are any one of several

inborn errors of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substra ...

that result from enzyme defects affecting the ability of the body to

oxidize Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or ...

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

s in order to produce energy within muscles, liver, and other cell types. Moreover, cancer cells can display irregular fatty acid metabolism with regard to both

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

References

{{DEFAULTSORT:Fatty Acid Metabolism Metabolism Fatty acids Hepatology