Fatty acid metabolism
Encyclopedia
Fatty acid
s are an important source of energy
and adenosine triphosphate
(ATP) for many cellular organisms. Excess fatty acids, glucose
, and other nutrients can be stored efficiently as fat
. Triglyceride
s yield more than twice as much energy for the same mass as do carbohydrate
s or protein
s. All cell membrane
s are built up of phospholipids, each of which contains two fatty acids. Fatty acids are also used for protein modification. The metabolism of fatty acids, therefore, consists of catabolic
processes that generate energy and primary metabolite
s from fatty acids, and anabolic processes that create biologically important molecules from fatty acids and other dietary carbon
sources.
Briefly, β-oxidation or lipolysis of free fatty acids is as follows:
This cycle repeats until the FFA has been completely reduced to acetyl-CoA
or, in the case of fatty acids with odd numbers of carbon atoms, acetyl-CoA
and 1 mol of propionyl-CoA
per mol of fatty acid.
and anhydrous
. The energy yield from a gram
of fatty acids is approximately 9 Kcal
(37 kJ), compared to 4 Kcal/g (17 kJ/g) for carbohydrates. Since the hydrocarbon
portion of fatty acids is hydrophobic, these molecule
s 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 67.5 lb
(31 kg) of hydrated glycogen to have the energy equivalent to 10 lb (5 kg) 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.
s, 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. People having had their gallbladder
removed
due to gall stones have, as a consequence, great difficulty digesting fats.
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 chylomicron
s or liposomes, which are released into the lacteals, the capillaries of the lymph system and then into the blood
. Eventually, they bind to the membranes of hepatocyte
s, adipocyte
s 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 receptor
s. 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:
When blood sugar is low, glucagon
signals 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.
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 lipase
s, such as hormone-sensitive lipase
,. However, when hormones such as epinepherine or glucagon
are secreted in response to low levels of glucose, this triggers an intracellular secondary messenger cascade that phosphorylates hormone-sensitive lipase
to break triglyceride
s into glycerol
and free fatty acid
s 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-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 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.
Besides β-oxidation, other oxidative pathways are sometimes employed. α-Oxidation
is used for branched fatty acids that cannot directly undergo β-oxidation. 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 peroxisome
s.
). However, more recently it has been shown that at most HSL converts triacylglycerides 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 receptor
s 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
.
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s are an important source of energy
Energy
In physics, energy is an indirectly observed quantity. It is often understood as the ability a physical system has to do work on other physical systems...
and adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP) for many cellular organisms. Excess fatty acids, glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
, and other nutrients can be stored efficiently as fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
. Triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s yield more than twice as much energy for the same mass as do carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
s or protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s. All cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s are built up of phospholipids, each of which contains two fatty acids. Fatty acids are also used for protein modification. The metabolism of fatty acids, therefore, consists of catabolic
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
processes that generate energy and primary metabolite
Primary metabolite
A primary metabolite is a kind of metabolite that is directly involved in normal growth, development, and reproduction.Conversely, a secondary metabolite is not directly involved in those processes, but usually has an important ecological function....
s from fatty acids, and anabolic processes that create biologically important molecules from fatty acids and other dietary carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
sources.
Overview
- LipolysisLipolysisLipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...
is carried out by lipases. - Once freed from glycerolGlycerolGlycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
, free fatty acids can enter blood and muscle fiber by diffusion. - Beta oxidationBeta oxidationBeta oxidation is the process by which fatty acids, in the form of Acyl-CoA molecules, are broken down in mitochondria and/or in peroxisomes to generate Acetyl-CoA, the entry molecule for the Citric Acid cycle....
splits long carbon chains of the fatty acid into acetyl CoA, which can eventually enter the TCA cycleCitric acid cycleThe citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
.
Briefly, β-oxidation or lipolysis of free fatty acids is as follows:
- Dehydrogenation by acyl-CoA dehydrogenase, yielding 1 FADH2FADIn biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states, which it converts between by accepting or donating electrons. The molecule consists of a riboflavin moiety bound to the phosphate...
- Hydration by enoyl-CoA hydrataseEnoyl-CoA hydrataseEnoyl-CoA hydratase is an enzyme that hydrates the double bond between the second and third carbons on acyl-CoA. This enzyme, also known as crotonase, is essential to metabolizing fatty acids to produce both acetyl CoA and energy. Note the crystal structure at right of enoyl-coa hydratase from a...
- Dehydrogenation by 3-hydroxyacyl-CoA dehydrogenase3-hydroxyacyl-CoA dehydrogenaseIn enzymology, a 3-hydroxyacyl-CoA dehydrogenase is an enzyme that catalyzes the chemical reaction-3-hydroxyacyl-CoA + NAD+ \rightleftharpoons 3-oxoacyl-CoA + NADH + H+...
, yielding 1 NADHNicotinamide adenine dinucleotideNicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved... - Cleavage by thiolase, yielding 1 acetyl-CoAAcetyl-CoAAcetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
and a fatty acid that has now been shortened by 2 carbons (acyl-CoAAcyl-CoAAcyl-CoA is a group of coenzymes involved in the metabolism of fatty acids. It is a temporary compound formed when coenzyme A attaches to the end of a long-chain fatty acid inside living cells. The compound undergoes beta oxidation, forming one or more molecules of acetyl-CoA...
)
This cycle repeats until the FFA has been completely reduced to acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
or, in the case of fatty acids with odd numbers of carbon atoms, acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
and 1 mol of propionyl-CoA
Propionyl-CoA
Propionyl-CoA is a coenzyme A derivative of propionic acid.-Production:There are several different ways in which it is formed:* It is formed as a product of beta-oxidation of odd-chain fatty acids....
per mol of fatty acid.
Fatty acids as an energy source
Fatty acids, stored as triglycerides in an organism, are an important source of energy because they are both reducedRedox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
and anhydrous
Anhydrous
As a general term, a substance is said to be anhydrous if it contains no water. The way of achieving the anhydrous form differs from one substance to another...
. The energy yield from a gram
Gram
The gram is a metric system unit of mass....
of fatty acids is approximately 9 Kcal
Calorie
The calorie is a pre-SI metric unit of energy. It was first defined by Nicolas Clément in 1824 as a unit of heat, entering French and English dictionaries between 1841 and 1867. In most fields its use is archaic, having been replaced by the SI unit of energy, the joule...
(37 kJ), compared to 4 Kcal/g (17 kJ/g) for carbohydrates. Since the hydrocarbon
Hydrocarbon
In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons from which one hydrogen atom has been removed are functional groups, called hydrocarbyls....
portion of fatty acids is hydrophobic, these molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
s can be stored in a relatively anhydrous
Anhydrous
As a general term, a substance is said to be anhydrous if it contains no water. The way of achieving the anhydrous form differs from one substance to another...
(water-free) environment. Carbohydrates, on the other hand, are more highly hydrated. For example, 1 g of glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
can bind approximately 2 g of water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
, 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 67.5 lb
Pound (mass)
The pound or pound-mass is a unit of mass used in the Imperial, United States customary and other systems of measurement...
(31 kg) of hydrated glycogen to have the energy equivalent to 10 lb (5 kg) of fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
.
Hibernating
Hibernation
Hibernation is a state of inactivity and metabolic depression in animals, characterized by lower body temperature, slower breathing, and lower metabolic rate. Hibernating animals conserve food, especially during winter when food supplies are limited, tapping energy reserves, body fat, at a slow rate...
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.
Digestion and transport
Fatty acids are usually ingested as triglycerideTriglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s, which cannot be absorbed by the intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large 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
Colipase
Colipase is a protein co-enzyme required for optimal enzyme activity of pancreatic lipase. It is secreted by the pancreas in an inactive form, procolipase, which is activated in the intestinal lumen by trypsin...
, 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. People having had their gallbladder
Gallbladder
In vertebrates the gallbladder is a small organ that aids mainly in fat digestion and concentrates bile produced by the liver. In humans the loss of the gallbladder is usually easily tolerated....
removed
Cholecystectomy
Cholecystectomy is the surgical removal of the gallbladder. It is the most common method for treating symptomatic gallstones. Surgical options include the standard procedure, called laparoscopic cholecystectomy, and an older more invasive procedure, called open cholecystectomy.-Open surgery:A...
due to gall stones have, as a consequence, great difficulty digesting fats.
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 chylomicron
Chylomicron
Chylomicrons are lipoprotein particles that consist of triglycerides , phospholipids , cholesterol and proteins .They transport dietary lipids from the intestines to other locations in the body...
s or liposomes, which are released into the lacteals, the capillaries of the lymph system and then into the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
. Eventually, they bind to the membranes of hepatocyte
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s, adipocyte
Adipocyte
However, in some reports and textbooks, the number of fat cell increased in childhood and adolescence. The total number is constant in both obese and lean adult...
s or muscle fibers, where they are either stored or oxidized for energy. The liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
acts as a major organ for fatty acid treatment, processing chylomicron remnants and liposomes into the various lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
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 receptor
LDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...
s. 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, glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
signals the adipocytes to activate hormone-sensitive lipase
Hormone-sensitive lipase
Hormone-sensitive lipase also previously known as cholesteryl ester hydrolase is an enzyme that, in humans, is encoded by the LIPE gene....
, 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
Serum albumin
Serum albumin, often referred to simply as albumin is a protein that in humans is encoded by the ALB gene.Serum albumin is the most abundant plasma protein in mammals. Albumin is essential for maintaining the osmotic pressure needed for proper distribution of body fluids between intravascular...
, binds free fatty acids, increasing their effective solubility to ~ 1 mM. Thus, serum albumin
Serum albumin
Serum albumin, often referred to simply as albumin is a protein that in humans is encoded by the ALB gene.Serum albumin is the most abundant plasma protein in mammals. Albumin is essential for maintaining the osmotic pressure needed for proper distribution of body fluids between intravascular...
transports fatty acids to organs such as muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
and liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
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 sterolSterol
Sterols, also known as steroid alcohols, are a subgroup of the steroids and an important class of organic molecules. They occur naturally in plants, animals, and fungi, with the most familiar type of animal sterol being cholesterol...
esters and triacylglycerols surrounded by a monolayer of phospholipids, are coated with perilipin
Perilipin
Perilipin, also known as lipid droplet-associated protein or PLIN, is a protein that, in humans, is encoded by the PLIN gene.- Function :Perilipin is a protein that coats lipid droplets in adipocytes, the fat-storing cells in adipose tissue...
, a protein that acts as a protective coating from the body’s natural lipase
Lipase
A lipase is an enzyme that catalyzes the formation or cleavage of fats . Lipases are a subclass of the esterases.Lipases perform essential roles in the digestion, transport and processing of dietary lipids in most, if not all, living organisms...
s, such as hormone-sensitive lipase
Hormone-sensitive lipase
Hormone-sensitive lipase also previously known as cholesteryl ester hydrolase is an enzyme that, in humans, is encoded by the LIPE gene....
,. However, when hormones such as epinepherine or glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
are secreted in response to low levels of glucose, this triggers an intracellular secondary messenger cascade that phosphorylates hormone-sensitive lipase
Hormone-sensitive lipase
Hormone-sensitive lipase also previously known as cholesteryl ester hydrolase is an enzyme that, in humans, is encoded by the LIPE gene....
to break triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s into glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
and free fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s for use in metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, a process called lipolysis.
The free fatty acids move into the blood stream where they are bound by serum albumin
Serum albumin
Serum albumin, often referred to simply as albumin is a protein that in humans is encoded by the ALB gene.Serum albumin is the most abundant plasma protein in mammals. Albumin is essential for maintaining the osmotic pressure needed for proper distribution of body fluids between intravascular...
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
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
. 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:
- Activation and transport into the mitochondria
- β-Oxidation
- Electron transport chainElectron transport chainAn electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
Fatty acids are transported across the outer mitochondrial membrane
Outer mitochondrial membrane
thumb|300px|Mitochondria structure :1) [[Inner membrane]]2) Outer membrane3) [[Crista]]4) [[Matrix |Matrix]]The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to the eukaryotic plasma membrane...
by carnitine-palmitoyl transferase I (CPT-I), and then couriered across the inner mitochondrial membrane
Inner mitochondrial membrane
The mitochondrial inner membrane forms internal compartments known as cristae, which allow greater space for the proteins such as cytochromes to function properly and efficiently. The electron transport chain is located on the inner membrane of the mitochondria...
by carnitine
Carnitine
Carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy. It is widely...
. Once inside the mitochondrial matrix
Mitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...
, the fatty acyl-carnitine (such as palmitoylcarnitine
Palmitoylcarnitine
Palmitoylcarnitine is an ester derivative of carnitine involved in the metabolism of fatty acids.Carnitine O-palmitoyltransferase breaks it down into palmitoyl CoA....
) reacts with coenzyme A
Coenzyme A
Coenzyme A is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All sequenced genomes encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it as a substrate...
to release the fatty acid and produce acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
. 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 acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
are repeatedly cleaved from the fatty acid. Acetyl-CoA can then enter the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
, which produces NADH and FADH2. NADH and FADH2 are subsequently used in the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
to produce ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, the energy currency of the cell.
Besides β-oxidation, other oxidative pathways are sometimes employed. α-Oxidation
Alpha oxidation
Enzymatic steps of alpha oxidation|right|thumb|250pxAlpha oxidation is a process by which certain fatty acids are broken down by removal of a single carbon from the carboxyl end...
is used for branched fatty acids that cannot directly undergo β-oxidation. The smooth ER of the liver can perform ω-oxidation
Omega oxidation
Omega oxidation is a process of fatty acid metabolism in some species of animals. It is an alternative pathway to beta oxidation that, instead of involving the β carbon, involves the oxidation of the ω carbon...
, 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 peroxisome
Peroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
s.
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 (lipolysisLipolysis
Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...
). However, more recently it has been shown that at most HSL converts triacylglycerides 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
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
, norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, and epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
.
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 receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s that activate adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
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
Phosphodiesterase
A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...
, 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
Lipogenesis
Lipogenesis is the process by which acetyl-CoA is converted to fats. The former is an intermediate stage in metabolism of simple sugars, such as glucose, a source of energy of living organisms. Through lipogenesis, the energy can be efficiently stored in the form of fats...
.
See also
- Fatty acid synthaseFatty acid synthaseFatty acid synthase is an enzyme that in humans is encoded by the FASN gene.Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis...
- Essential fatty acidEssential fatty acidEssential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health but cannot synthesize them...
- List of fatty acid metabolism disorders