Triglycerides are hydrolyzed in the intestine thanks to the intervention of pancreatic lipase.
Once hydrolysed to glycerol and free fatty acids, they can be absorbed by the cells of the intestinal epithelium, which reconvert the glycerol and fatty acids into triglycerides.
The triglycerides are then released into the lymphatic circulation, associated with particular lipoprotein particles called chylomicrons.
Thanks to the catalytic intervention of lipoproteins lipase the triglycerides deposited by the chylomicrons are again hydrolyzed.
Glycerol and free fatty acids can be used as fuel to produce energy, deposited as lipid reserves in adipose tissue and be used as precursors for the synthesis of phospholipids, triacylglycerols and other classes of compounds.
Plasma albumin, the most abundant protein in plasma, is responsible for transporting free fatty acids into the circulation.
OXIDATION OF FATS
Oxidation of glycerol
As we have said, triglycerides are formed by the union of glycerol with three more or less long chains of fatty acids.
Glycerol has nothing to do with the fatty acid from a molecular point of view. It is removed and used in gluconeogenesis, a process that leads to the formation of glucose from non-carbohydrate compounds (lactate, amino acids and, indeed, glycerol).
The glycerol cannot accumulate and in the cytosol it is transformed into L-glycerol 3 phosphate at the expense of an ATP molecule, after which the glycerol 3- phosphate is converted into dihydroxyacetone phosphate which enters the glycolysis, where it is converted into pyruvate and possibly oxidized in the Krebs cycle.
Activation of fatty acids
The β-oxidation starts in the cytoplasm with the activation of the fatty acid by thioester bond with the CoA forming the acyl-SCoA and consuming 2 molecules of ATP. The acyl-SCoA that was formed is transported inside the mitochondria by carnitine acyltransferase.
Transport of fatty acids in the mitochondria
Although some small molecules of Acyl-SCoA are able to spontaneously cross the inner membrane of mitochondria, most of the acyl-SCoA produced is not able to cross this membrane. In these cases the acyl group is transferred to carnitine thanks to the catalytic intervention of carnitine acyltransferase I.
The regulation of the pathway is mainly carried out at the level of this enzyme located on the outer membrane of the mitochondria. It is particularly active during fasting when plasma glucagon and fatty acid levels are high.
The acyl bond + carnitine is called acyl-carnitine.
Acyl-carnitine enters the mitochondria and donates the acyl group to an internal CoASH molecule, by intervention of the enzyme carnitine acyltransferase II. Thus an acyl-SCoA molecule is formed again which will enter the process called β-oxidation.
Β-oxidation
The β-oxidation consists in separating from the fatty acid two carbon atoms at a time in the form of acetic acid always oxidizing the third carbon (C-3 or carbon β) starting from the carboxyl end (that atom which with the old nomenclature was indicated as carbon β). For this reason the whole process is called β-oxidation.
Β-oxidation is a process that takes place in the mitochondrial matrix and is closely linked to the Krebs cycle (for further oxidation of the acetate) and to the respiratory chain (for reoxidation of the NAD and FAD coenzymes).
PHASES OF β-oxidation
The first β-oxidation reaction is the dehydrogenation of fatty acid by an enzyme called acyl Coa dehydrogenase. This enzyme is a dependent FAD enzyme.
This enzyme allows the formation of a double bond between C2 and C3: the hydrogen atoms lost thanks to dehydrogenase bind to the FAD which becomes FADH2.
The second reaction consists in adding a water molecule to the double bond (hydration).
The third reaction is another dehydrogenation that transforms the hydroxyl group on C3 into a carbonyl group. The hydrogen acceptor this time is the NAD.
The fourth reaction involves the splitting of the ketoacid by a thiolase: an acetylCoA is formed and an acylCoA with a shorter chain (2 C less).
This series of reactions is repeated as many times as C of the chain / 2 minus one is, since at the bottom two acetylCoA are formed. Ex: palmityl CoA 16: 2-1 = 7 times.
AcetylCoA produced with β-oxidation can enter the Krebs cycle where it binds to oxalacetate for further oxidation up to carbon dioxide and water. For each acetylCoA oxidized in the Krebs cycle 12 ATP are produced
Ketone bodies formation
When acetyl CoA is in excess of the reception capacity of the Krebs cycle (oxalacetate deficiency) it is transformed into ketone bodies. Conversion to glucose through gluconeogenesis is not possible.
In particular the excess acetyl CoA condenses into two molecules of acetyl CoA forming acetoacetyl-CoA.
Starting from acetoacetyl-CoA, an enzyme produces acetoacetate (one of the three ketone bodies) that can be transformed into 3-hydroxybutyrate, or by decarboxylation, can be transformed into acetone (the other two ketone bodies). The ketone bodies thus formed can be used by the body in extreme conditions as alternative energy sources.
Oxidation of fatty acids at odd number of carbon atoms
If the number of carbon atoms of the fatty acid is odd, at the end a Propionyl CoA molecule with 3 carbon atoms is obtained. The propionyl-CoA in the presence of biotin is carboxylated and is transformed into D-methylmalonyl-CoA. By an epimerase, D methylmalonyl CoA will be transformed into L methylmalonyl coa. L methylmalonyl CoA by a mutase and in the presence of cyanocoballamin (vitamin B 12) will be transformed into succinyl CoA (intermediate of the Krebs cycle).
Succinyl-CoA can be used directly or indirectly in a wide variety of metabolic processes such as gluconeogenesis. From propionylCoA therefore, unlike acetylCoA it is possible to synthesize glucose.
BIOSYNTHESIS OF FATTY ACIDS
The biosynthesis of fatty acids occurs mainly in the cytoplasm of liver cells (hepatocytes) starting from the acetyl groups (acetyl CoA) generated inside the liver. Since these groups can be derived from glucose it is possible to convert carbohydrates into fats. However it is not possible to convert fats into carbohydrates since the human organism does not possess those enzymes necessary to convert Acetyl-SCoA derived from β-oxidation into precursors of gluconeogenesis.
As we have said in the introductory part, while β-oxidation takes place within the mitrochondrial matrix, the biosynthesis of fatty acids takes place in the cytosol. We also stated that to form a fatty acid, acetyl groups are needed which are produced within the mitochondrial matrix.
A specific system is therefore needed that can transfer the acetyl CoA from the mitochondria to the cytoplasm. This system, dependent ATP, uses citrate as an acetyl transporter. The citrate after transporting the acetyl groups into the cytoplasm transfers them to the CoASH forming the acetyl-SCoa.
The onset of fatty acid biosynthesis takes place thanks to a key condensation reaction of acetyl-SCoA with carbon dioxide to form Malonyl-SCoA.
The carboxylation of acetyl CoA occurs by an extremely important enzyme, acetyl CoA carboxylase. This enzyme, dependent ATP, is heavily regulated by allosteric activators (insulin and glucagon).
The synthesis of fatty acids does not use the CoA but a transporter protein of acyclic groups called ACP which will transport all the intermediates of the fatty acid biosynthesis.
There is a multi-enzyme complex called fatty acid synthase which through a series of reactions leads to the formation of fatty acids with no more than 16 carbon atoms. Longer chain fatty acids and some unsaturated fatty acids are synthesized starting from palmitate by the action of enzymes called elongases and desaturases.
REGULATION OF OXIDATION AND BIOSYNTHESIS OF FATTY ACIDS
Low blood glucose levels stimulate the secretion of two hormones, adrenaline and glucagon, which promote the oxidation of fatty acids.
Insulin, on the other hand, has the opposite action and with its intervention it stimulates the biosynthesis of fatty acids. An increase in blood glucose causes an increase in insulin secretion which, with its action, facilitates the passage of glucose into the cells. Excess glucose is converted into glycogen and deposited as a reserve in the muscles and liver. An increase in hepatic glucose causes the accumulation of malonyl-SCoA which inhibits carnitine acyltransferase by slowing the rate of fatty acid oxidation
