Metabolism of lipids.ppt

Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid metabolism. Atherosclerosis.

Lipids are water-insoluble organic biomolecules that can be extracted from cells and tissues by nonpolar solvents, e.g., chloroform, ether, or benzene.

Classification of lipids, based on their backbone structures:

Simple lipids:Acylglycerols, steroids, waxes.Complex lipids:phospholipidsglycerophospholipids, sphingophospholipids.glycolipidsglycosylglycerols, glycosphingolipids.

Triacylglycerols (Triglycerides)Fatty acid esters of the alcohol glycerol are called acylglycerols or glycerides; they are sometimes referred to as "neutral fats," a term that has become archaic. When all three hydroxyl groups of glycerol are esterified with fatty acids, the structure is called a triacylglycerol: Triacylglycerols are the most abundant family of lipids and the major components of depot or storage lipids in plant and animal cells. Triacylglycerols that are solid at room temperature are often referred to as "fats" and those which are liquid as "oils."

Storage and Mobilization of Fatty AcidsTGs are delivered to adipose tissue in the form of chylomicrones and VLDL, hydrolyzed by lipoprotein lipase into fatty acids and glycerol, which are taken up by adipocytes. Then fatty acids are reesterified to TGs.TGs are stored in adipocytes.To supply energy demands fatty acids and glycerol are released mobilisation of TGs.

At low carbohydrate and insulin concentrations (during fasting), TG hydrolysis is stimulated by epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone.

TG hydro-lysis is inhibited by insulin in fed state

Lipolysis - hydrolysis of triacylglycerols by lipases. A hormone-sensitive lipase converts TGs to free fatty acids and monoacylglycerolMonoacylglycerol is hydrolyzed to fatty acid and glycerol or by a hormone-sensitive lipase or by more specific and more active monoacylglycerol lipase

Oxidation of Glycerol

Glycerol is absorbed by the liver.

Steps: phosphorylation, oxidation and isomerisation.

Glyceraldehyde 3-phosphate is an intermediate in: glycolytic pathway gluconeogenic pathways

ATP Generation from Glycerol Oxidation

glycerol glycerol 3-phosphate - 1 ATPglycerol 3-phosphate - dihydroxyaceton phosphate 2.5ATP (1 NADH)

glyceraldehyde 3-phosphate pyruvate 4,5 ATP (1NADH + 2 ATP)

pyruvate acetyl CoA 2.5 ATP (1 NADH)

acetyl CoA in Krebs cycle 10 ATP (3NADH + 1 FADH2 + 1GTP)

Total 19,5-1 = 18,5 ATP

Reaction sequence in the b-oxidation

Connections to Electron Transport and ATP. One turn of the fatty acid spiral produces ATP from the interaction of the coenzymes FAD (step 1) and NAD+ (step 3) with the electron transport chain. Total ATP per turn of the fatty acid spiral is

Step 1 - FAD into e.t.c. = 2 ATP Step 3 - NAD+ into e.t.c. = 3 ATP Total ATP per turn of spiral = 5 ATPExample with Palmitic Acid = 16 carbons = 8 acetyl groupsNumber of turns of fatty acid spiral = 8-1 = 7 turnsATP from fatty acid spiral = 7 turns and 5 per turn = 35 ATP.

NET ATP from Fatty Acid Spiral = 35 - 1 = 34 ATP

Fatty Acid SynthesisOccurs mainly in liver and adipocytes, in mammary glands during lactationOccurs in cytoplasmFA synthesis and degradation occur by two completely separate pathways

Three stages of fatty acid synthesis:

A. Transport of acetyl CoA into cytosolAcetyl CoA from catabolism of carbohydrates and amino acids is exported from mitochondria via the citrate transport system Cytosolic NADH also converted to NADPHTwo molecules of ATP are expended for each round of this cyclic pathway

B. Carboxylation of acetyl CoAC. Assembly of fatty acid chain

Sources of NADPH for Fatty Acid Synthesis1. One molecule of NADPH is generated for each molecule of acetyl CoA that is transferred from mitochondria to the cytosol (malic enzyme). 2. NADPH molecules come from the pentose phosphate pathway.

B. Carboxylation of Acetyl CoAEnzyme: acetyl CoA carboxylase Prosthetic group - biotin

A carboxybiotin intermediate is formed. ATP is hydrolyzed. The CO2 group in carboxybiotin is transferred to acetyl CoA to form malonyl CoA.Acetyl CoA carboxylase is the regulatory enzyme.

C. The Reactions of Fatty Acid SynthesisFive separate stages: (1) Loading of precursors via thioester derivatives (2) Condensation of the precursors (3) Reduction (4) Dehydration (5) Reduction

The elongation phase of fatty acid synthesis starts with the formation of acetyl ACP and malonyl ACP. Acetyl transacylase and malonyl transacylase catalyze these reactions.Acetyl CoA + ACP acetyl ACP + CoA Malonyl CoA + ACP malonyl ACP + CoA

Condensation reaction.

Acetyl ACP and malonyl ACP react to form acetoacetyl ACP.

Enzyme - acyl-malonyl ACP condensing enzyme.

Reduction.

Acetoacetyl ACP is reduced to D-3-hydroxybutyryl ACP.

NADPH is the reducing agent

Enzyme: -ketoacyl ACP reductase

Dehydration.

D-3-hydroxybutyryl ACP is dehydrated to form crotonyl ACP

Enzyme: 3-hydroxyacyl ACP dehydratase

Reduction.

The final step in the cycle reduces crotonyl ACP to butyryl ACP.

NADPH is reductant.Enzyme - enoyl ACP reductase.

This is the end of first elongation cycle (first round).

In the second round butyryl ACP condenses with malonyl ACP to form a C6--ketoacyl ACP.

Reduction, dehydration, and a second reduction convert the C6--ketoacyl ACP into a C6-acyl ACP, which is ready for a third round of elongation.

Final reaction of FA synthesisRounds of synthesis continue until a C16 palmitoyl group is formedPalmitoyl-ACP is hydrolyzed by a thioesterase

The overall equation for palmitic acid biosynthesis starting from acetyl-S-CoA:8 AcetylSCoA + 14NADPH + 14H+ + 7ATP + H2O palmitic acid + 8CoA + 14NADP+ + 7ADP + 7P.

Ketogenesis The ketone bodies are acetoacetate b-hydroxybutyrate acetone

Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown

The ways of formation of active form of glycerol.There are two ways of formation of active form of glycerol.1. Phosphorilation of glycerol through the action of glycerol kinase:ATP + glycerol glycerol 3-phosphate + ADP2. Reduction of dihydroxyacetone phosphate which is the product of the aldolase reaction of glycolysis. Dihydroxyacetone phosphate is reduced to glycerol 3-phosphate by the NAD-linked glycerol-3-phosphate dehydrogenase of the cytosol:Dihydroxyacetone phosphate + NADH + H+ glycerol 3-phosphate + NAD

Biosynthesis of triacylglycerols

The first stage in triacyglycerol formation is the acylation of the free hydroxyl groups of glycerol phosphate by two molecules of fatty acyl-CoA to yield first a lysophosphotidic acid and then a phosphatidic acid:

Lysophosphotidic acid Phosphatidic acid

The activity of acetyl-CoA carboxylase depends on its phosphorylation status . In its inactive form acetyl-CoA carboxylase is phosphorylated in serine, whereas the active form is not phosphorylated.

The phosporylation of acetyl CoA carboxylase is catalyzed by an AMP-dependent protein kinase (AMPK).High AMP levels induce the phosphorylation and inactivation of acetyl-CoA carboxylase.

Pathway of cholesterol biosynthesis

Bile acids perform such functions: eliminating cholesterol from the body; driving the flow of bile to eliminate catabolites from the liver; emulsifying lipids and fat soluble vitamins in the intestine; and aiding in the reduction of the bacteria flora found in the small intestine and biliary tract.

Obesity is a major risk factor for coronary heart disease, which can lead to heart attack.

AtherosclerosisAtherosclerosis - the process in whichdeposits of fatty substances, cholesterol, cellular waste products, calcium and other substances build up in the inner lining of an artery. It usually affects large and medium-sized arteries. Plaques can grow large enough to significantly reduce the blood's flow through an artery. But most of the damage occurs when theybecome fragile and rupture. Plaques that rupture causeblood clotsto form that can block blood flow or break off and travel to another part of the body. If either happens and blocks a blood vessel that feeds the heart, it causes a heart attack. If it blocks a blood vessel that feeds the brain, it causes a stroke. And if blood supply to the arms or legs is reduced, it can cause difficulty walking and eventually lead to gangrene.