Lipogenesis
Encyclopedia
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. Lipogenesis encompasses the processes of fatty acid synthesis
and subsequent triglyceride
synthesis (when fatty acid
s are esterified with glycerol
to form fats). The products are secreted from the liver
in the form of very-low-density lipoproteins (VLDL).
and builds up by the addition of two carbon units. The synthesis occurs in the cytoplasm
in contrast to the degradation (oxidation), which occurs in the mitochondria. Many of the enzymes for the fatty acid synthesis are organized into a multienzyme complex called fatty acid synthetase.
is an indicator of the blood sugar level of the body, as its concentration increases proportionally with blood sugar levels. Thus, a large insulin level is associated with the fed state. As one might expect, therefore, it increases the rate of storage pathways, such as lipogenesis. Insulin stimulates lipogenesis in two main ways: The enzymes pyruvate dehydrogenase
(PDH), which forms acetyl-CoA
, and acetyl-CoA carboxylase
(ACC), which forms malonyl-CoA
, are obvious control points. These are activated by insulin. So a high insulin level leads to an overall increase in the levels of malonyl-CoA, which is the substrate required for fatty acids synthesis.
As insulin binds to cellular surface transmembrane receptors that intracellularly activate the adenylate cyclase enzyme that catalyze cAMP (cyclic AMP) production from ATP. The increased intracellular cAMP, acts as a second messenger, in response to the insulin binding. cAMP activates protein kinase enzyme that in turn activates phosporylase enzyme that phosphorylates and in doing so activates a number of different intracellular enzymes such as the pyruvate dehydrogenase that dehydrates pyruvate to form AcCoa. So, an extracellular hormone, insulin, can in multistep activation (cascade) activate an enzyme in the cellular matrix.
This mechanism leads to the increased rate of catalysis of this enzyme, so increases the levels of acetyl-CoA. Increased levels of acetyl-CoA will increase the flux through not only the fat synthesis pathway but also the citric acid cycle.
has an antagonistic effect and increases phosphorylation, deactivation, thereby inhibiting ACC and slowing fat synthesis.
Affecting ACC affects the rate of acetyl-CoA conversion to malonyl-CoA. Increased malonyl-CoA level pushes the equilibrium over to increase production of fatty acids through biosynthesis. Long chain fatty acids are negative allosteric regulators of ACC and so when the cell has sufficient long chain fatty acids, they will eventually inhibit ACC activity and stop fatty acid synthesis.
AMP and ATP concentrations of the cell act as a measure of the ATP needs of a cell and as ATP levels get low it activates the ATP synthetase which in turn phosphorylates ACC. When ATP is depleted, there is a rise in 5'AMP. This rise activates AMP-activated protein kinase, which phosphorylates ACC, thereby inhibits fat synthesis. This is a useful way to ensure that glucose is not diverted down a storage pathway in times when energy levels are low.
ACC is also activated by citrate. This means that, when there is abundant acetyl-CoA in the cell cytoplasm for fat synthesis, it proceeds at an appropriate rate.
Note: Research now shows that glucose metabolism (exact metabolite to be determined), aside from insulin's influence on lipogenic enzyme genes, can induce the gene products for liver's pyruvate kinase, acetyl-CoA carboxylase, and fatty acid synthase. These genes are induced by the transcription factors ChREBP/Mlx via high blood glucose levels and presently unknown signaling events. Insulin induction is due to SREBP-1c, which is also involved in cholesterol metabolism.
About 100,000 metric tons of the natural fatty acids are consumed in the preparation of various fatty acid esters. The simple esters with lower chain alcohols (methyl-, ethyl-, n-propyl-, isopropyl- and butyl esters) are used as emollients in cosmetics and other personal care products and as lubricants. Esters of fatty acids with more complex alcohols, such as sorbitol, ethylene glycol, diethylene glycol and polyethylene glycol are consumed in foods, personal care, paper, water treatment, metal working fluids, rolling oils and synthetic lubricants.
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...
is converted to fats. The former is an intermediate stage 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...
of simple sugars, such as 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...
, a source of energy of living organisms. Through lipogenesis, the energy can be efficiently stored in the form of fats. Lipogenesis encompasses the processes of fatty acid synthesis
Fatty acid synthesis
Fatty acid synthesis is the creation of fatty acids from acetyl-CoA and malonyl-CoA precursors through action of enzymes called fatty acid synthases...
and subsequent 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....
synthesis (when 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 are esterified with 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...
to form fats). The products are secreted from 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...
in the form of very-low-density lipoproteins (VLDL).
Fatty acid synthesis
Fatty acids synthesis starts with acetyl-CoAAcetyl-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 builds up by the addition of two carbon units. The synthesis occurs in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
in contrast to the degradation (oxidation), which occurs in the mitochondria. Many of the enzymes for the fatty acid synthesis are organized into a multienzyme complex called fatty acid synthetase.
Control and regulation
InsulinInsulin
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....
is an indicator of the blood sugar level of the body, as its concentration increases proportionally with blood sugar levels. Thus, a large insulin level is associated with the fed state. As one might expect, therefore, it increases the rate of storage pathways, such as lipogenesis. Insulin stimulates lipogenesis in two main ways: The enzymes pyruvate dehydrogenase
Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the...
(PDH), which forms 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 acetyl-CoA carboxylase
Acetyl-CoA carboxylase
Acetyl-CoA carboxylase is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase and carboxyltransferase...
(ACC), which forms malonyl-CoA
Malonyl-CoA
Malonyl-CoA is a coenzyme A derivative.-Functions:It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis....
, are obvious control points. These are activated by insulin. So a high insulin level leads to an overall increase in the levels of malonyl-CoA, which is the substrate required for fatty acids synthesis.
PDH dephosphorylation
Pyruvate dehydrogenase dephosphorylation is increased with the release of insulin. The dephosphorylated form is more active.As insulin binds to cellular surface transmembrane receptors that intracellularly activate the adenylate cyclase enzyme that catalyze cAMP (cyclic AMP) production from ATP. The increased intracellular cAMP, acts as a second messenger, in response to the insulin binding. cAMP activates protein kinase enzyme that in turn activates phosporylase enzyme that phosphorylates and in doing so activates a number of different intracellular enzymes such as the pyruvate dehydrogenase that dehydrates pyruvate to form AcCoa. So, an extracellular hormone, insulin, can in multistep activation (cascade) activate an enzyme in the cellular matrix.
This mechanism leads to the increased rate of catalysis of this enzyme, so increases the levels of acetyl-CoA. Increased levels of acetyl-CoA will increase the flux through not only the fat synthesis pathway but also the citric acid cycle.
Acetyl-CoA carboxylase
Insulin affects ACC in a similar way to PDH. It leads to its dephosphorylation which activates the enzyme. GlucagonGlucagon
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...
has an antagonistic effect and increases phosphorylation, deactivation, thereby inhibiting ACC and slowing fat synthesis.
Affecting ACC affects the rate of acetyl-CoA conversion to malonyl-CoA. Increased malonyl-CoA level pushes the equilibrium over to increase production of fatty acids through biosynthesis. Long chain fatty acids are negative allosteric regulators of ACC and so when the cell has sufficient long chain fatty acids, they will eventually inhibit ACC activity and stop fatty acid synthesis.
AMP and ATP concentrations of the cell act as a measure of the ATP needs of a cell and as ATP levels get low it activates the ATP synthetase which in turn phosphorylates ACC. When ATP is depleted, there is a rise in 5'AMP. This rise activates AMP-activated protein kinase, which phosphorylates ACC, thereby inhibits fat synthesis. This is a useful way to ensure that glucose is not diverted down a storage pathway in times when energy levels are low.
ACC is also activated by citrate. This means that, when there is abundant acetyl-CoA in the cell cytoplasm for fat synthesis, it proceeds at an appropriate rate.
Note: Research now shows that glucose metabolism (exact metabolite to be determined), aside from insulin's influence on lipogenic enzyme genes, can induce the gene products for liver's pyruvate kinase, acetyl-CoA carboxylase, and fatty acid synthase. These genes are induced by the transcription factors ChREBP/Mlx via high blood glucose levels and presently unknown signaling events. Insulin induction is due to SREBP-1c, which is also involved in cholesterol metabolism.
Fatty acid esterification
Experiments were conducted to study in vivo the over-all fatty acid specificity of the mechanisms involved in chylomicron cholesterol ester and triglyceride formation during fat absorption in the rat. Mixtures containing similar amounts of two, three, or four C14-labeled fatty acids (palmitic, stearic, oleic, and linoleic acids), but with varying ratios of unlabeled fatty acids, were given by gastric intubation to rats with cannulated thoracic ducts. The chyle or chylomicron lipid so obtained was chromatographed on silicic acid columns to separate cholesterol esters and glycerides (the latter being 98.2% triglycerides). After assaying each lipid class for total radioactivity, gas-liquid chromatography was employed to measure the total mass and the distribution of mass and of radioactivity in the individual fatty acid components of each lipid fraction. The specific radioactivity of each fatty acid in each fraction could then be calculated. The data provided quantitative information on the relative specificity of incorporation of each fatty acid into each chylomicron lipid class and on the relative extent to which each fatty acid in each lipid fraction was diluted with endogenous fatty acid. With the exception of a slight discrimination against stearic acid, the processes of fatty acid absorption and chylomicron triglyceride formation displayed no specificity for one fatty acid relative to another. In contrast, chylomicron cholesterol ester formation showed marked specificity for oleic acid, relative to the other three fatty acids. This specificity was not significantly altered by varying the composition of the test meal, by including cholesterol in the test meal, or by feeding the animal a high-cholesterol diet for several weeks preceding the study. Considerable dilution of the dietary fatty acids with endogenous fatty acids was observed. In one experiment, 43% of the chylomicron triglyceride fatty acids was of endogenous origin. Relatively more (54%) of the cholesterol ester fatty acids was of endogenous origin.About 100,000 metric tons of the natural fatty acids are consumed in the preparation of various fatty acid esters. The simple esters with lower chain alcohols (methyl-, ethyl-, n-propyl-, isopropyl- and butyl esters) are used as emollients in cosmetics and other personal care products and as lubricants. Esters of fatty acids with more complex alcohols, such as sorbitol, ethylene glycol, diethylene glycol and polyethylene glycol are consumed in foods, personal care, paper, water treatment, metal working fluids, rolling oils and synthetic lubricants.