Lipogenesis

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).^[1] 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.

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.^[2] The major sites of fatty acid synthesis are adipose tissue and the liver.^[3]

Control and 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.

PDH dephosphorylation

Insulin stimulates the activity of pyruvate dehydrogenase phosphatase. This enzyme removes the phosphate from pyruvate dehydrogenase, 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^[4] 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.^[5]

In industry

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.

References

Metabolism map
Carbon Fixation Photo- respiration Pentose Phosphate Pathway Citric Acid Cycle Glyoxylate Cycle Urea Cycle Fatty Acid Synthesis Fatty Acid Elongation Beta Oxidation Peroxisomal Beta Oxidation Glyco- genolysis Glyco- genesis Glyco- lysis Gluconeo- genesis Decarb- oxylation Fermentation Keto- lysis Keto- genesis feeders to Gluconeo- genesis Direct / C4 / CAM Carbon Intake Light Reaction Oxidative Phosphorylation Amino Acid Deamination Citrate Shuttle Lipogenesis Lipolysis Steroidogenesis MVA Pathway MEP Pathway Shikimate Pathway Transcription & Replication Translation Proteolysis Glycosy- lation Sugar Acids Double/Multiple Sugars & Glycans Simple Sugars Inositol-P Amino Sugars & Sialic Acids Nucleotide Sugars Hexose-P Triose-P Glycerol P-glycerates Pentose-P Tetrose-P Propionyl -CoA Succinate Acetyl -CoA Pentose-P P-glycerates Glyoxylate Photosystems Pyruvate Lactate Acetyl -CoA Citrate Oxalo- acetate Malate Succinyl -CoA α-Keto- glutarate Ketone Bodies Respiratory Chain Serine Group Alanine Branched-chain Amino Acids Aspartate Group Homoserine Group & Lysine Glutamate Group & Proline Arginine Creatine & Polyamines Ketogenic & Glucogenic Amino Acids Amino Acids Shikimate Aromatic Amino Acids & Histidine Ascorbate (Vitamin C) δ-ALA Bile Pigments Hemes Cobalamins (Vitamin B12) Various Vitamin B's Calciferols (Vitamin D) Retinoids (Vitamin A) Quinones (Vitamin K) & Carotenoids (Vitamin E) Cofactors Vitamins & Minerals Antioxidants PRPP Nucleotides Nucleic Acids Proteins Glycoproteins & Proteoglycans Chlorophylls MEP MVA Acetyl -CoA Polyketides Terpenoid Backbones Terpenoids & Carotenoids (Vitamin A) Cholesterol Bile Acids Glycero- phospholipids Glycerolipids Acyl-CoA Fatty Acids Glyco- sphingolipids Sphingolipids Waxes Polyunsaturated Fatty Acids Neurotransmitters & Thyroid Hormones Steroids Endo- cannabinoids Eicosanoids Major metabolic pathways in metro-style map. Click any text (name of pathway or metabolites) to link to the corresponding article. Single lines: pathways common to most lifeforms. Double lines: pathways not in humans (occurs in e.g. plants, fungi, prokaryotes). Orange nodes: carbohydrate metabolism. Violet nodes: photosynthesis. Red nodes: cellular respiration. Pink nodes: cell signaling. Blue nodes: amino acid metabolism. Grey nodes: vitamin and cofactor metabolism. Brown nodes: nucleotide and protein metabolism. Green nodes: lipid metabolism.