Biosynthesis and Oxidation of Lipids

• Body lipids are generally found compartmentalized due to their insolubility in aqueous solutions, such as in the case of membrane-associated lipids or droplets of triacylglycerol in white adipocytes.
• Ketoacidosis rarely may also be seen in cases of fasting.
• An elevation of the ketone body concentration in the blood results in acidemia.
• Each ketone body loses a proton (H+) as it circulates in the blood, which lowers the pH of the body.
• Lipids are a major source of stored energy for the body, and they also provide the hydrophobic barrier that permits partitioning of the aqueous contents of cells and subcellular structures.
• Lipids serve additional functions in the body, for example, some fat-soluble vitamins have regulatory or coenzyme functions, and the prostaglandins and steroid hormones play major roles in the control of the body’s homeostasis.
• A fatty acid consists of a hydrophobic hydrocarbon chain with a terminal carboxyl group.
• At physiologic pH, the terminal carboxyl group (–COOH) ionizes, becoming –COO–.
• This anionic group has an affinity for water, giving the fatty acid its amphipathic nature (having both a hydrophilic and a hydrophobic region).
• The first product in the cytosol for Fatty acid synthesis is malonyl - CoA (3C).
• Each FAS monomer is a multicatalytic polypeptide and the enzyme has seven different enzymatic activities plus a domain that covalently binds a molecule of 4' - phosphopantetheine.
• Fatty acid synthesis involves seven steps: condensation, reduction, dehydration, reduction, reduction, reduction, and reduction.
• The first step going to fatty acid synthesis is irreversible and involves the carboxylation of acetyl CoA to form malonyl CoA.
• Citrate is produced by the condensation of oxaloacetate (OAA) and acetyl CoA.
• 4' - Phosphopantetheine, a derivative of the vitamin pantothenic acid, carries acyl units on its terminal thiol (–SH) group during fatty acid synthesis.
• Fatty acid synthase (FAS) is a multifunctional enzyme in eukaryotes.
• Fatty acid synthesis is catalyzed by fatty acid synthase (FAS), which catalyzes a repeating four-step sequence that elongates the fatty acyl chain by two carbons at each step.
• 4' - Phosphopantetheine also is a component of CoA transfer onto the enzyme.
• The carboxylation of acetyl CoA to form malonyl CoA is catalyzed by acetyl CoA carboxylase, which requires CO2 and ATP.
• The coenzyme in the carboxylation of acetyl CoA to form malonyl CoA is the vitamin biotin, which is covalently bound to a lysyl residue of the carboxylase.
• In every four steps of fatty acid synthesis, 2C are added to the fatty acid.
• Fatty acid chains may contain no double bonds — that is, saturated — or contain one or more double bonds — that is, mono- or polyunsaturated.
• When double bonds are present, they are nearly always in the cis rather than in the trans configuration.
• The introduction of a cis double bond causes the fatty acid to bend or “kink” at that position.
• If the fatty acid has two or more double bonds, they are always spaced at three-carbon intervals.
• In general, the addition of double bonds decreases the melting temperature (Tm) of a fatty acid, while increasing the chain length increases the Tm.
• Membrane lipids typically contain Long Chain Fatty Acid, and the presence of double bonds in some fatty acids helps maintain the fluid nature of those lipids.
• The free (unesterified) fatty acids move through the cell membrane of the adipocyte, and bind to plasma albumin.
• Because β-oxidation occurs in the mitochondrial matrix, the fatty acid must be transported across the inner mitochondrial membrane that is impermeable to CoA.
• A specialized carrier transports the long-chain acyl group from the cytosol into the mitochondrial matrix.
• DHAP can participate in glycolysis or gluconeogenesis.
• The mobilization of stored fat is initiated by hormone-sensitive lipase, which removes a fatty acid from carbon 1 and/or carbon 3 of the TAG.
• cAMP is produced in the adipocyte when one of several hormones (such as epinephrine or glucagon) binds to receptors on the cell membrane, and activates adenylyl cyclase.
• Rather, glycerol is transported through the blood to the liver, where it can be phosphorylated.
• Hormone-sensitive lipase (HSL) is activated when phosphorylated by a cAMP-dependent protein kinase.
• Because acetyl CoA carboxylase is inhibited by hormone-directed phosphorylation when the cAMP-mediated cascade is activated, fatty acid synthesis is turned off when TAG degradation is turned on.
• The resulting glycerol phosphate can be used to form TAG in the liver, or can be converted to DHAP by reversal of the glycerol phosphate dehydrogenase reaction.
• They are transported to the tissues, enter cells, get activated to their CoA derivatives, and are oxidized for energy.
• The glycerol released during TAG degradation cannot be metabolized by adipocytes because they apparently lack glycerol kinase.
• After a long-chain fatty acid (LCFA) enters a cell, it is converted in the cytosol to its CoA derivative by long-chain fatty acyl CoA synthetase (thiokinase), an enzyme of the outer mitochondrial membrane.