Lipids metabolism. Lipoproteins, their composition and role. The pathways of usage of glycerol and free fatty acids in cells

The formation, composition, role and metabolism of lipoproteins (LP)

LP are complexes between Proteins and different types of Lipids. Proteins of LP are named apoproteins. There are 5 groups of apoproteins. They're depicted as A, B, C, D, E. Each group is subdivided into subgroups (A1, A2 etc). There are following species of LP:

1. Very low density LP (VLDL), or pre-beta LP

2. Low density LP (LDL), or beta-LP

3. High density LP (HDL), or alfa-LP.

The differences between LP are:

1. quantitative composition and density which depends on content of proteins in LP. HDL has got 50% of Proteins; LDL – 20%; VLDL – 7%. VLDL consists of 55% of TAG; LDL contain 50% of Cholesterol

2. velocity of movement in electrical field: the fastest LP are HDL and slowest are VLDL

3. diameter: HDL are smallest and have diameter as 10-15nm; VLDL are biggest

4. function: VLDL transfer TAG and Cholesterol from liver to extrahepatic tissues. LDL transfer Cholesterol from liver to extrahepatic tissues. Hence they're named as atherogenic LP. HDL are synthesized by liver and small intestine. HDL transfer unused Cholesterol from extrahepatic tissues to liver where it is oxidized to bile acids. Hence HDL are named as antiatherogenic LP. The antiatherogenic function of HDL due to the action of enzyme Lecithine Cholesterol Acyl transferase (LHAT). It is enzyme of blood plasma. Apoproteins of HDL are activators of its.this enzyme catalyzes the reaction of Cholesterol esters formation: Cholesterol + Lecithine = Cholesterol esters + Lysolecithine. Cholesterol esters is insoluble compound and sinks in nucleus of HDL. The ratio LDL/HDL is determined in blood plasma, which is equal 3. This ratio is named atherogenic index. Increase of its shows the risk of atherosclerosis.

The conversion of Glycerol and FFA: formation of Triacylglycerols (TAG) and Phospholipids (PhL)

Lipogenesis is a process of formation of lipids. This process is being done on Phosphatidic pathway in many organs and tissues. The process is competitive, that is in deficiency of nitrogen-containing substances and polyunsaturated fatty acids (PUFA) the TAG-formation prevails. In sufficient quantity of nitrogen-containing substances and PUFA the Phospholipids synthesis predominantly occurs. The synthesis of triglicerides occurs from phosphatidic acid. This acid is formed during the process of phosphorylation of glycerol and addition of 2 molecules of FFA. Then, the phosphate is chipped off, causing the formation of DAG. The binding of DAG with FFA yields TAG. Alternative pathway of usage of phosphatidic acid includes addition of serine (choline or ethanolamine) in participation of CTP and as a result the according phospholipids are formed.

The oxidation of Glycerol and its energetic value

Glycerol is phosphorylated, yielding glycerolphosphate. It is oxidized to phosphoglyceraldehyde (PGA). PGA is oxidized and phosphorylated to 1,3-diphosphoglycerate. Then reactions are analogues to glycolysis up to formation of pyruvic acid, including formation of 2ATP in 2 reactions of substrate phosphorylation. Pyruvic acid undergoes oxidative decarboxylation, to give acetylCoA that goes in Crebs cycle. Reduced dehydrogenases of Crebs cycle are oxidized in Biologic oxidation. It results in formation of energy and endogenous water. Some of energy is used for formation of ATP in oxidative phosphorylation. Totally, this process gives 20(22) molecules of ATP

Beta-oxidation of FFA and its energetic value

FFA is activated in cytosol, yielding active fatty acid, or acylCoA. acylCoA enters the mitochondrions with carnitine. acylCoA is oxidized under action of FP(FAD), dehydroacylCoA is formed. It is hydrated to beta-hydroxyacylCoA. It is oxidized to beta-ketoacylCoA under action of NAD. ketoacylCoA is thiolyzed to a new acylCoA and acetylCoA.

New acylCoA enters the new cycle of beta-oxidation (in 2-nd reaction) again until Butyric acid formation. This acid undergoes the 1-st cycle of beta-oxidation and gives 2 AcetylCoA. Thus, the principle of beta-oxidation consists in active fatty acid is decreased on 2 Carbon atoms (in the kind of AcetylCoA) during 1-st cycle and 1NADH2, 1FPH2 are also formed. The number of cycles can be calculated on next formula: N= n(C)/2 – 1.

The quantity of AcetylCoA can be calculated on next formula: N= n(C)/2.

Thus, C15H31COOH gives C16/2 – 1= 7cycles; C16/2=8 AcetylCoA.

Each AcetylCoA gives 12ATP, therefore 8 AcetylCoA give 8x12=96ATP. 1 cycle gives 1FPH2 and 1NADH2, therefore 7 cycles give 7x2=14ATP; 7NADH2 give 7x3=21ATP. All together will be 14+21=35ATP: 35+96=131ATP. 1 ATP is used in 1-st reaction (activation of FFA). Therefore energetical balance (value) of beta-oxidation of 1 molecule of C15H31COOH is equal 131-1=130ATP.

Lipids peroxidation (LPO) and its role

Polyunsaturated fatty acids (PUFA) undergo the LPO. Initiators of LPO are active forms of oxygen (AFO) (see the theme “The types of oxidation in section Bioenergetics”).

LPO includes the following reactions:

1. interaction of PUFA with active forms of oxygen (free radicals), giving radicals of PUFA

2. radicals of PUFA interact with molecular oxygen, yielding peroxide radical of PUFA

3. peroxide radical of PUFA interacts with hydrogen and this results in formation of hydroperoxide of PUFA

4. hydroperoxide of PUFA can be used by 2 pathways: a) it is cleft to saturated and unsaturated aldehydes which are further oxidized to malondialdehyde. Malondialdehyde is eliminated as end product of LPO through the kidneys. This pathway occurs without any enzymes. B) hydroperoxide of PUFA can be utilized with enzyme Glutathione peroxidase. During this reaction it is reduced to hydroxyacids, simultaneously glutathione is oxidized. Restoration of glutathione occurs under action of glutathione reductase.

Diene conjugates, hydroperoxides of lipids, malonic aldehyde and hydrocarbons are natural metabolites of cells because LPO occurs in normal conditions with a small velocity which is regulated by antioxidant system (AOS).

LPO is a main pathway of PUFA degradation. Metabolites of LPO are necessary for synthesis of some hormones (for example thyroid hormones), proteins, prostanoids, function of phagocytes, regulation of permeability and composition of membrane, velocity of proliferation and secretory function of cells.

However it is need to consider that increase of LPO and concentration of LPO metabolites cause the lesion of cells and its death, for example, metabolites of LPO destroy DNA and RNA that results in mutations. LPO products cause the denaturation of Proteins, disconnect Biologic oxidation (BO) and oxidative phosphorylation (OP), destroy the structure of membranes

the pathways of usage of acetylCoA. the biosynthesis of free fatty acids, ketone bodies and cholesterol. the cholesterol metabolism. final products of lipids metabolism

The biosynthesis of FFA

90% of AcetylCoA is used for Citric acid cycle (CAC) which yields 3NADH2, FPH2, ATP and 2CO2. 10% of AcetylCoA is used for synthesis of FFA, ketone bodies and Cholesterol.

The biosynthesis of FFA is mainly located in cytosol of cells. This process occurs intensively in liver, adipose tissue, brain, lungs and mammary glands. Initial material for FFA synthesis is AcetylCoA.

The biosynthesis of FFA includes 3 stages:

1 – providing the initial material. The initial material is acetylCoA. It is formed in mitochondrions, then it removes to cytosol. This removal occurs due to formation of citric acid in mitochondrions (acetylCoA +oxaloacetic acidcitric acid). Citric acid halves to acetylCoA and oxaloacetic acid again in cytosol. Oxaloacetic acid can be returned in mitochondrions through the formation of malate or used as a source for formation of glucose, glycerol and amino acids;

2 – formation of substrate for biosynthesis of FFA. The substrate is malonylCoA. It is formed due to the interaction of acetylCoA with CO2. This reaction requires ATP;

3 - condensation of AcetylCoA with MalonylCoA and consecutive lengthening of the chain of FFA. This stage includes the following reactions: a) condensation of acetylCoA with malonylCoA due to the binding with acyl-carrier protein (ACP). It results in formation of acetoacetylACP. B) acetoacetylACP is reduced by NADPH2, yielding beta-hydroxybutyrylACP; C) beta-hydroxybutyrylACP undergoes dehydration (removal of water), yielding dehydrobutyrylACP; d) dehydrobutyrylACP is reduced by NADPH2 to butyrylACP. Then, the other malonylCoA binds to free SH-group of ACP and reactions are repeated by the same way (decarboxylation of malonylCoA and condensation of residue of malonylCoA with butyryl, reduction, dehydration, reduction). Thus, during one cycle of biosynthesis of FFA the chain of fatty acid is enlarged on 2 carbon atoms and 1 ATP and 2 NADPH2 used. We can account the quantity of ATP and NADPH2 used for synthesis of FFA. For example, for the synthesis of palmitic acid (C16) we need 7 ATP and 14 NADPH2 (7 cycles of synthesis). Each cycle demands 1 ATP for formation of malonylCoA and uses 2 NADPH2. Altogether will be 7 ATP and 14 NADPH2

The biosynthesis and oxidation of ketone bodies

Acetoacetic acid, Acetone and beta-oxybutyric acid belong to ketone bodies. Their formation occurs in mitochondrions of hepatocytes only:

1. 2 acetylCoA are condensed into acetoacetylCoA;

2. acetoacetylCoA binds with acetylCoA giving beta-hydroxy-beta-methyl-glutarylCoA (HMG). The usage of this compound depends on expenditure of energy. If the energy needs, HMG is used for synthesis of ketone bodies. In hypodynamia HMG converts in cholesterol.

3. HMG is deacetylated to give acetoacetic acid (1-st ketone body). It is decarboxylated giving acetone (2-nd ketone body) or reduced to beta-hydroxybutyric acid (3-rd ketone body)

Acetoacetic and beta-oxybutyric acids are sources of energy. The oxidation of them occurs in muscular tissue and myocardium. But in starvation and diabetes mellitus ketone bodies are oxidized in brain too.

The oxidation of ketone bodies:

1. beta-oxybutyric acids is oxidized by HAD yielding acetoacetic acid

2. acetoacetic acid interacts with HSCoA giving acetoacetylCoA

3. acetoacetylCoA is splitted to 2 acetylCoA

4. each acetylCoA is oxidized in Crebs cycle giving 12 ATP (see the account of ATP through Crebs cycle in topic “Bioenergetics”. Thus, the oxidation of acetoacetic acid gives 24 ATP, and beta-hydroxybutyric acid – 27 ATP due to NADH2 forming in oxidation of beta-hydroxybutyryc acid

The biosynthesis and metabolism of Cholesterol

There are 5 stages of biosynthesis of Cholesterol:

1. formation of Mevalonic acid

2. formation of active Isoprene

3. formation of Squalene

4. formation of Lanosterol

5. formation of Cholesterol

The Metabolism of Cholesterol:

Exogenic Cholesterol makes up approximately 500mg/d. but only 30% from this quantity is absorbed. Cholesterol is absorbed by Micelles. Then it is transported by Chylomicrons to liver. Almost half of Cholesterol of the body is synthesized (it is endogenic Cholesterol – 700-1000mg/d). thus, total pool of Cholesterol of the body makes up 1.2-1.5g. 90% of Cholesterol occurs in plasma membranes and is used for plastical purpose. 10% of Cholesterol occurs in blood plasma. LDL transfer Cholesterol from liver to extrahepatic tissues. Cholesterol is used for synthesis of Steroid’s hormones (incl. Sexual hormones, Glucocorticoids and Mineralocorticoids), vitamin D3. Unused Cholesterol is transported from extrahepatic tissues to liver by HDL. This Cholesterol is oxidized to bile acids.

Cholesterol occurs in bile and its makes up 0.5% from all substances of bile. Maxiaml solubility of Cholesterol of bile occurs in next relation: 5% of cholesterol:15% of Lecithine;80% of bile salts. The solubility of Cholesterol is decreased in deminishing of bile acids, Lecithine and water in bile. It results in the formation of bile stones.

About 500mg of Cholesterol per day is excreted by feces and 100mg through the skin.