Lipogenesis is the process by which acetyl-CoA is converted to fatty acids. The former is an intermediate stage in metabolism of simple sugars, such as glucose, a source of energy of living organisms. Through lipogenesis and subsequent triglyceride synthesis, the energy can be efficiently stored in the form of fats.
Lipogenesis encompasses both the process of fatty acid synthesis and triglyceride synthesis (where fatty acids are esterified to glycerol). The products are secreted from the liver in the form of very-low-density lipoproteins (VLDL). VLDL particles are secreted directly into blood, where they mature and function to deliver the endogenously derived lipids to peripheral tissues.
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Fatty acid synthesis
Fatty acids synthesis starts with acetyl-CoA and builds up by the addition of two-carbon units. The synthesis occurs in the cytoplasm of the cell, 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 synthase. The major sites of fatty acid synthesis are adipose tissue and the liver.
Control and regulation
Hormonal regulation
Insulin is a peptide hormone that is critical for managing the body's metabolism. Insulin is released by the pancreas when blood sugar levels rise, and it has many effects that broadly promote the absorption and storage of sugars, including lipogenesis.
Insulin stimulates lipogenesis primarily by activating two enzymatic pathways. Pyruvate dehydrogenase (PDH), converts pyruvate into acetyl-CoA. Acetyl-CoA carboxylase (ACC), converts acetyl-CoA produced by PDH into malonyl-CoA. Malonyl-CoA provides the two-carbon building blocks that are used to create larger fatty acids.
Insulin stimulation of lipogenesis also occurs through the promotion of glucose uptake by adipose tissue. The increase in the uptake of glucose can occur through the use of glucose transporters directed to the plasma membrane or through the activation of lipogenic and glycolytic enzymes via covalent modification. The hormone has also been found to have long term effects on lipogenic gene expression. It is hypothesized that this effect occurs through the transcription factor SREBP-1, where the association of insulin and SREBP-1 lead to the gene expression of glucokinase. The interaction of glucose and lipogenic gene expression is assumed to be managed by the increasing concentration of an unknown glucose metabolite through the activity of glucokinase.
Another hormone that may affects lipogenesis through the SREBP-1 pathway is leptin. It is involved in the process by limiting fat storage through inhibition of glucose intake and interfering with other adipose metabolic pathways. The inhibition of lipogenesis occurs through the down regulation of fatty acid and triglyceride gene expression. Through the promotion of fatty acid oxidation and lipogenesis inhibition, leptin was found to control the release of stored glucose from adipose tissues.
Other hormones that prevent the stimulation of lipogenesis in adipose cells are growth hormones (GH). Growth hormones result in loss of fat but stimulates muscle gain. One proposed mechanism for how the hormone works is that growth hormones affects insulin signaling thereby decreasing insulin sensitivity and in turn down regulating fatty acid synthase expression. Another proposed mechanism suggests that growth hormones may phosphorylate with STAT5A and STAT5B, transcription factors that are a part of the Signal Transducer And Activator Of Transcription (STAT) family.
There is also evidence suggesting that acylation stimulating protein (ASP) promotes the aggregation of triglycerides in adipose cells. This aggregation of triglycerides occurs through the increase in the synthesis of triglyceride production.
Transcriptional regulation
SREBPs have been found to play a role with the nutritional or hormonal effects on the lipogenic gene expression. SREBP-2 has a well defined mode of action of the different members of this transcriptional family. At high levels of free cholesterol in the cell SREBP-2 is found bound to the endoplasmic reticulum as an immature precursor. when the level of cholesterol drops then the SREBP-2 is proteolytically cleaved releasing the mature fragment so it can move to the nucleus and bind to the sterol response element in the promoter region of target genes. These genes are then activated for transcription.
It has been indicated that SREBP-2 promote the expression of genes involved in cholesterol metabolism in liver cells. It has been indicated that SREBP-1 plays a role in the activation of genes connected with lipogenesis in liver. Studies have found that an over expression of SREBP-1a or SREBP-1c in mouse liver cells results in the build-up of hepatic triglycerides and higher expression levels of lipogenic genes.
Lipogenic gene expression in the liver via glucose and insulin is moderated by SREBP-1. The effect of glucose and insulin on the transcriptional factor can occur through various pathways. There is evidence suggesting that insulin promotes SREBP-1 mRNA expression in adipocytes and hepatocytes, it has also been suggested that the hormone increases transcriptional activation by SREBP-1 through MAP-kinase-dependent phosphorylation regardless of changes in the mRNA levels. Along with insulin glucose also have been shown to promote SREBP-1 activity and mRNA expression.
PDH dephosphorylation
Insulin stimulates the activity of pyruvate dehydrogenase phosphatase. The phosphatase removes the phosphate from pyruvate dehydrogenase activating it and allowing for conversion of pyruvate to acetyl-CoA. 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 via activation of PP2A phosphatase whose activity results in the activation of the enzyme. Glucagon 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. When ATP is depleted, there is a rise in 5'AMP. This rise activates AMP-activated protein kinase, which phosphorylates ACC and 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. 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 of SREBP-1c 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.
In industry
About 100,000 metric tonnes 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.
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