Degradation of lipids, ketone bodies

Degradation of lipids, ketone bodies Josef Fontana EC - 56 Overview of the lecture • Energetic importance of TAG • Pathways of lipid metabolism – Li...
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Degradation of lipids, ketone bodies Josef Fontana EC - 56

Overview of the lecture • Energetic importance of TAG • Pathways of lipid metabolism – Lipids as a source of energy - TAG degradation in cells, β-oxidation – Synthesis and utilization of ketone bodies

Energetic importance of TAG

Triacylglycerols (TAG) • TAG store a large amount of chemical energy • TAG are excelent for energy storage - 1g of fat has 6 times more energy than 1g of hydrated glycogen • Complete oxidation of 1g of FA = 38 kJ • Complete oxidation of 1g of saccharides or proteins only 17 kJ

Triacylglycerols (TAG) • 70 kg man has an energy reserve of 420 000 kJ in TAG, 10 000 kJ in proteins (muscle), 2 500 kJ in glycogen and 170 kJ in glucose. (Total weight of TAG is around 11 kg) • Glycogen and glucose are sufficient to supply the body one day, TAG many weeks • The main site of TAG accumulation is adipocyte cytoplasm

Pathways of lipid metabolism Lipids as a source of energy TAG degradation in cells, βoxidation

Lipids as an energy source • The use of lipids has three stages: • 1) Mobilization of lipids - TAG hydrolysis to fatty acids and glycerol, transport in blood • 2) Activation of fatty acids in cytosol and their transport to the matrix of mitochondria • 3) β-oxidation: FA degradation to acetyl~CoA – enters the Krebs cycle

Mobilization of lipids • Hormone sensitive lipase • TAG → 3 FFA + glycerol • FFA are bound to plasma albumin • Glycerol is used in liver • Inhibition by insulin • Activation by epinephrine and glucagon

Glycerol is converted to intermediates of glycolysis CH2OH HO

C

H

CH2OH

Glycerolkinasa ATP

HO

C

H

L-Glycerol-3-fosfát

+

NAD

C

G

H 2-

CH2O PO3

L-Glycerol-3-fosfát

Glycerol-3-fosfátdehydrogenasa

2CH2O PO3

HO

ADP

Glycerol

CH2OH

CH2OH

+

NADH + H

CH2OH O

C 2-

CH2O PO3

Dihydroxyacetonfosfát

FA transport to the cell • SCFA (↓12C) – simple diffusion • FA with longer chain – different transport systems in the membrane - facilitated diffusion: – FATP (fatty acid transport protein) – FAT/CD36 (fatty acid translocase)

Activation of FA • Cytosol • Beginning of the metabolism • Constant concentration gradient of FA • Ester bond: FA + HSCoA: AcylCoAsynthetase • MK + ATP + HS-CoA → acyl-CoA + AMP + 2 Pi

FA oxidation • β-oxidation in the mitochondrial matrix has the major role • ω- a α- oxidation – ER membranes • Greek letters determine the carbon atom which the reactions

Entry of FA in the matrix • Acyl-CoA can go through the outer mitochondrial membrane but not through the inner • FA leaves CoA – carnitine • Carnitine acyltransferases (CAT) – transfer of FA between CoA and carnitine

Carnitine

Carnitine esterified with FA

Acylcarnitine synthesis - CAT I • Cytosolic side of the outer mitochondrial membrane • Transfer of acyl from HSCoA to carnitine

CH3 H3C

+

N CH3

CH2

OH

R

CH CH2 COO− +

C

carnitine

O

SCoA

Carnitine Palmitoyl Transferase R C CH3 H3C

+

N CH3

O

O CH2

CH CH2 COO−

fatty acyl carnitine

+ HSCoA

Carnitine acylcarnitine translocase Acyl-CoA

CoA

Karnitin

Acylkarnitin

Cytosol

Translokasa

Matrix

Karnitin Acyl-CoA

Acylkarnitin CoA

• Inner mitochondrial membrane • Exchange carnitine acylcarnitine

Carnitine acyltransferases II • Mitochondrial matrix • Transfer of FA from acylcarnitine to HSCoA • Free carnitine leaves the matrix by translocase – exchange with a new acylcarnitine • Acyl-CoA in the mitochondrial matrix - βoxidation

β-oxidation • Acyl~CoA dehydrogenase (prosthetic group is FAD) • Enoyl~CoA hydratase • L-3-Hydroxyacyl~CoA dehydrogenase (coenzyme is NAD+) • β-Ketothiolase

Acyl-CoA dehydrogenase R

C H2

H2 C

O C H2

C

S

CoA

• FAD → FADH2

Acyl-CoA FAD OXIDACE FADH2

R

C H2

H C

O C H

C

• New double bond between 2 (α) and 3 (β) carbon

S

Trans-∆ 2-Enoyl-CoA

CoA

• There are specific AcylCoA-dehydrogenases for FA with: – short (4-6 C) – medium (6-10 C) – long (12-18 C) chain

Enoyl-CoA hydratase • Addidion of water

R

• New OH- group

C H2

H C

O C

C H

S

CoA

Trans-∆ 2-Enoyl-CoA

H2O

HO R

C H2

HYDRATACE

O

H C

C

C H

S

H

L-3-Hydroxyacyl-CoA

CoA

Hydroxyacyl-CoA dehydrogenase HO

• Oxidation of OHgroup to keto group • NAD+ → NADH + H+

R

C H2

O

H C

C

C

S

CoA

H H L-3-Hydroxyacyl-CoA NAD+ OXIDACE H+ + NADH

R

C H2

O

O

C

C

C H

S

H

3-Ketoacyl-CoA

CoA

β-Ketothiolase R

C H2

O

O

C

C

C

H H 3-Ketoacyl-CoA

CoA

HS

S

C H2

C

• SH group of HSCoA attacks βketo carbon

THIOLÝZA

O

O R

• Catalyzes thiolytic cleavage

CoA

S

CoA

+

Acyl-CoA (zkrácený o 2 uhlíkové atomy)

H

C

C H

S

H Acetyl-CoA

CoA

• AcCoA + Acyl~CoA (2C shorter)

One rotation of β-oxidation • β-oxidation is a cyclic process: • acyl-CoA + FAD + NAD+ + HS-CoA → acyl-CoA (2 C shorter) + FADH2 + NADH + H+ + Ac-CoA • Acyl-CoA (2 C shorter) enters next rotation • FA has mostly an even number of C - last rotation converts butyryl-CoA to 2 AcCoA

Regulation of β-oxidation • At the entrance of FA to MIT - CAT I • Malonyl-CoA inhibits - (intermediate of FA synthesis) • Principle: • 1) synthesis of FA is in the cytosol, as well as reaction of CAT I • 2) malonyl-CoA is produced in the first reaction of FA synthesis • 3) cross regulation prevents the simultaneous FA synthesis and FA degradation

Omegaoxidation of fatty acids (endoplasmic reticulum; minority pathway for long chain FA)

The figure was found at http://www.biocarta.com/pathfiles/omegaoxidationPathway.asp (January 2007)

Pathways of lipid metabolism Synthesis and utilization of ketone bodies

Synthesis and function of ketone bodies • Acetoacetate, β-hydroxybutyrate and acetone • Liver mitochondria • Ketone bodies are water-soluble form of FA

Synthesis and function of ketone bodies • Entry of AcCoA to KC depends on the availability of oxaloacetate • OAA is produced by pyruvate carboxylation • During starvation or DM is OAA consumed in gluconeogenesis • Lack of saccharides – reduction of OAA – decrease of KC rate

Synthesis and function of ketone bodies • ↑ lipolysis (HSL)→ ↑ FA → β-oxidation → excess of AcCoA → ketogenesis • Condensation of 2 AcCoA → acetoacetyl~CoA • Reaction with another AcCoA → 3-hydroxy3-methylglutaryl~CoA (HMG~CoA) • Cleavage of HMG-CoA → AcCoA a acetoacetate

β-Ketothiolase • The last step of β-oxidation – reverse reaction in ketone bodies synthesis • 2 → AcCoA ~ acetoacetyl CoA O H3C

C

O S

Acetyl-CoA

CoA

+

H3C

C

S

Acetyl-CoA

CoA

1 H3C CoA

O

O

C

C

C H2

S

Acetoacetyl-CoA

CoA

3-hydroxy-3-methylglutaryl-CoA synthase H3C

O

O

C

C

C H2

O S

Acetoacetyl-CoA

CoA

+

H3C

C

S

Acetyl-CoA

O

2

CoA

-

O H2O

CoA

C

HO C H2

CH3 C

C H2

O C

S

CoA

3-Hydroxy-3-methylglutaryl-CoA

• Catalyzes the condensation on the 3rd carbon in AcAcCoA

3-hydroxy-3-methylglutaryl-CoA lyase O -

O

C

HO C H2

CH3 C

C H2

O C

S

3

CoA

-

O O

3-Hydroxy-3-methylglutaryl-CoA H3C

C

O

O

C

C

C H2

Acetoacetát S

CoA

HMG-CoA is cleaved to acetoacetate and AcCoA

CH3

β-hydroxybutyratedehydrogenase • Catalyzes the reversible conversion of ketone bodies: acetoacetate and β-hydroxybutyrate • Massive formation of KB - βhydroxybutyrate is quantitatively the most important KB in the blood • Acetoacetate → acetone (spontaneously)

β-hydroxybutyratedehydrogenase O -

O

C

O C H2

C

Acetoacetát

O

4

-

CH3

O H+ + NADH

NAD+

C

H C H2

OH C

CH3

D-3-Hydroxybutyrát

O H3C CO2

C Aceton

CH3

Ketone bodies activation Acetoacetát • Extrahepatic: reconversion to AcCoA – to the KC CoA-transferasa

• Acetoacetate activated by CoA – transfer from Suc~CoA • Cleavage by thiolase – two AcCoA • Transferase is not in liver!

Sukcinyl-CoA Sukcinát

Acetoacetyl-CoA CoA Thiolasa

2 Acetyl-CoA

Role of acetoacetate • Cardiac muscle and kidney cortex prefer acetoacetate before glucose • Brain adapts to acetoacetate during starvation (long term starvation – up to 50% of energy from acetoacetate) • Regulatory role: high levels of acetoacetate in blood - signal of presence of large amounts of AcCoA – decrease in lipolysis

Regulation of ketogenesis • 1) HSL – lipolysis in adipose tissue • 2) CAT I – FA entry to MIT (βoxidation) • 3) Use of AcCoA: in KC or in ketogenesis • 4) Mitochondrial HMG-CoA synthase

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