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. Lipogenesis encompasses the processes of fatty acid synthesis and subsequent triglyceride synthesis (when fatty acids are esterified with glycerol to form fats). The products are secreted from the liver in the form of very-low-density lipoproteins (VLDL).

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 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
Insulin 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.

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 phosphorylation, activation. But as the fatty acid is synthesised it will have a negative feedback on its own enzyme, by dephosporylation, deactivation of protein kinase and in so deactivation of ACC. Glucagon has an antagonistic effect and increases dephosphorylation, 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.

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 synthease 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
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.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.