Top Banner
Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid metabolism. Atherosclerosis.
47

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

Dec 23, 2015

Download

Documents

Aron Boyd
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Page 1: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and

phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology

of lipid metabolism. Atherosclerosis.

Page 2: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

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

Page 3: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Classification of lipids, based on their backbone structures:

Simple lipids:

Acylglycerols, steroids, waxes.

Complex lipids:

phospholipids

glycerophospholipids, sphingophospholipids.

glycolipids

glycosylglycerols, glycosphingolipids.

Page 4: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.
Page 5: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Triacylglycerols (Triglycerides)• Fatty acid esters of the alcohol

glycerol are called acylglycerols or glycerides; they are sometimes re ferred 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."

Page 6: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Storage and Mobilization of Fatty Acids

• TGs 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.

Page 7: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

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

Page 8: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

• Lipolysis - hydrolysis of triacylglycerols by lipases.

• A hormone-sensitive lipase converts TGs to free fatty acids and monoacylglycerol

• Monoacylglycerol is hydrolyzed to fatty acid and glycerol or by a hormone-sensitive lipase or by more specific and more active monoacylglycerol lipase

Page 9: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

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

Page 10: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Isomerase

Page 11: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

ATP Generation from Glycerol Oxidation

• glycerol – glycerol 3-phosphate - 1 ATP• glycerol 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

Page 12: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.
Page 13: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.
Page 14: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Reaction sequence in

the b-oxidation  

Page 15: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

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 ATPStep 3 - NAD+ into e.t.c. = 3 ATP Total ATP per turn of spiral = 5 ATP

• Example with Palmitic Acid = 16 carbons = 8 acetyl groups

• Number of turns of fatty acid spiral = 8-1 = 7 turns• ATP from fatty acid spiral = 7 turns and 5 per turn = 35 ATP.

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

Page 16: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.
Page 17: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.
Page 18: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Fatty Acid Synthesis

• Occurs mainly in liver and adipocytes, in mammary glands during lactation

• Occurs in cytoplasm

• FA synthesis and degradation occur by two completely separate pathways

Page 19: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

• 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 CoA• C. Assembly of fatty acid chain

Page 20: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.
Page 21: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Sources of NADPH for Fatty Acid Synthesis

1. 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.

Page 22: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

B. Carboxylation of Acetyl CoA

Enzyme: 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.

Page 23: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

C. The Reactions of Fatty Acid Synthesis

n Five separate stages:(1) Loading of precursors via thioester derivatives(2) Condensation of the precursors(3) Reduction(4) Dehydration(5) Reduction

Page 24: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

• 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

Page 25: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

• Condensation reaction.

• Acetyl ACP and malonyl ACP react to form acetoacetyl ACP.

• Enzyme - acyl-malonyl ACP condensing enzyme.

Page 26: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

• Reduction.

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

• NADPH is the reducing agent

• Enzyme: -ketoacyl ACP reductase

Page 27: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

• Dehydration.

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

• Enzyme: 3-hydroxyacyl ACP dehydratase

Page 28: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

• 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).

Page 29: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

• 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.

Page 30: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Final reaction of FA synthesis

• Rounds of synthesis continue until a C16 palmitoyl group is formed

• Palmitoyl-ACP is hydrolyzed by a thioesterase

Page 31: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

The overall equation for palmitic acid biosynthesis

starting from acetyl-S-CoA:

8 Acetyl—S—CoA + 14NADPH + 14H+ + 7ATP + H2O palmitic acid + 8CoA + 14NADP+ + 7ADP + 7P.

Page 32: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Ketogenesis

• The ketone bodies are

• acetoacetate• b-hydroxybutyrate • acetone

Page 33: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Ketogenesis is the process by which ketone bodies are

produced as a result of fatty acid breakdown

Page 34: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.
Page 35: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.
Page 36: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

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 + ADP• 2. 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

Page 37: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

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:

H2C

HC

OH

OH

H2C O P

R1 - COSKoA KoA - SH H2C

HC

O

OH

H2C O P

C

O

R1

Page 38: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Lysophosphotidic acid Phosphatidic acid

H2C

HC

O

OH

H2C O P

R2 - COSKoA KoA - SHH2C

HC

O

O

H2C O P

C

O

R1C

O

R1

C R2

O

Page 39: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

• 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. 

Page 40: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

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.

Page 41: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Pathway of cholesterol biosynthesis

Page 42: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

 Bile acids perform such functions:

1. eliminating cholesterol from the body; driving the flow of bile to eliminate catabolites from the liver;

2. emulsifying lipids and fat soluble vitamins in the intestine;

3. and aiding in the reduction of the bacteria flora found in the small intestine and biliary tract.

Page 43: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.
Page 44: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.
Page 45: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

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

Page 46: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.

Atherosclerosis• Atherosclerosis - the process in which deposits

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 they become fragile and rupture. Plaques that rupture cause blood clots to 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.

Page 47: Metabolism of lipids: tryacylglycerols, fatty acids, cholesterol and phospholipids metabolism. Ketogenesis and ketolysis. Regulation and pathology of lipid.