Metabolism of lipids

Vladimíra Kvasnicová

Lipids

= group of biological molecules that are insoluble in aqueous solutions

and soluble in organic solvents

• structural components of biological membranes

• energy reserves, predominantly in the form of

triacylglycerols (TAG)

• excellent mechanical and thermal insulators

• biologically active compounds

(vitamins, hormones, bile acids, visual pigment)

The figure was adopted from: J.Koolman, K.H.Röhm / Color Atlas of Biochemistry, 2nd edition, Thieme 2005

Structural components of lipids

• alcohols� glycerol (a)

� sfingosine (b)

� cholesterol (c)

� inositol (d)

• long chain carboxylic acids(= fatty acids)

The figures are adopted from http://en.wikipedia.org (April 2007)

a) b)

c) d)

The figure is found at http://www.tvdsb.on.ca/saunders/courses/online/SBI3C/Cells/Lipids.htm (Jan 2007)

Free Fatty Acids(FFA)

The figure was adopted from: J.Koolman, K.H.Röhm / Color Atlas of Biochemistry, 2nd edition, Thieme 2005

The figure is found at http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-2/ch11_lipid-struct.jpg(Jan 2007)

Strcture of lipids

The figure is found at http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-2/ch11_cholesterol.jpg (Jan 2007)

The figure was adopted from: J.Koolman, K.H.Röhm / Color Atlas of Biochemistry, 2nd edition, Thieme 2005

The figure is found at http://www.mie.utoronto.ca/labs/lcdlab/biopic/fig/3.21.jpg (Jan 2007)

Structure of

phospholipid

The figure is found at http://web.indstate.edu/thcme/mwking/lipid-synthesis.html#phospholipids (Jan 2007)

sphingosine

ceramide

= amide formed from sphingosine and fatty acid

Choose compounds counting among lipids

a) glycerol

b) triacylglycerols

c) ketone bodies

d) cholesterol

Choose compounds counting among lipids

a) glycerol

b) triacylglycerols

c) ketone bodies

d) cholesterol Aceton

The fiugure is from the book: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2

The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990.

The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990.

The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990.

The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990.

The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990.

The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990.

The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990.

The figure was accepted from the book: Grundy, S.M.: Atlas of lipid disorders, unit 1. Gower Medical Publishing, New York, 1990.

cholesterol from tissues back to the liver

A-I, E, C-IIcholesterol, phospholipids,store of apoprot.

liverHDL

cholesterol to extrahepat. tissues

B-100cholesterolVLDLLDL

VLDL remnants to other tissues

B-100cholesterol, TAG, phospholip.

VLDLIDL

newly synthetized TAG to other tissues

C-II, B-100TAGliverVLDL

remnants of chylomicronsto the liver

B-48, Echolesterol, TAG, phospholipids

chylo-microns (CHM)

CHMremnants

TAG from a diet to various tissues

B-48, C-II, E

TAGintestinechylo-microns

they transport:important apoproteins

principal lipidssourcetype

Lipoproteins

Choose correct statements about a transport of lipids in blood

a) triacylglycerols are transfered mainly bychylomicrons and VLDL

b) free fatty acids are bound to albumin

c) cholesterol is transfered mainly by HDL and LDL

d) ketone bodies do not need a transport protein

Choose correct statements about a transport of lipids in blood

a) triacylglycerols are transfered mainly by chylomicrons and VLDL

b) free fatty acids are bound to albumin

c) cholesterol is transfered mainly by HDL and LDL

d) ketone bodies do not need a transport protein

The figure is found at http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-3/ch17_lipid-adipocytes.jpg (Jan 2007)

Releasing of freefatty acids from TAG

of fatty tissue

and their followed transport

to target cells

acidic pH-optimum

hydrolysis of TAGlysosomesvarious tissues

acidic lipase

activated by phosphory-lation

hydrolysis of reservetriacylglycerols

cytoplasm of adipocytes

adipocyteshormonsensitive lipase

activated byapoC-II

hydrolysis of TAGfound in VLDL and chylomicrons

inner surface of blood vessels

extra-hepatic tissues

lipoproteinlipase

needs pancreatic colipase

hydrolysis of TAGto 2 fatty acids and 2-monoacylglycerol

small intestine

pancreaspancreaticlipase

stability in low pH

hydrolysis of TAGcomposed of short chain fatty acids

stomachstomachacid stable lipase

propertiesfunctionlocation of its action

sourcename

Lipases

Degradation of

phospholipids

(hydrolysis)

The figure is found at http://web.indstate.edu/thcme/mwking/lipid-synthesis.html#phospholipids (Jan 2007)

• insulin• apolipoprotein C-II

(apoC-II)

lipoprotein lipase(inner surface of blood vessels)

• insulin• prostaglandins

• catecholamines, glucagon(phosphorylation)

hormone sensitivelipase(in adipocytes)

inhibitionactivationregulatory enzyme

Regulation of lipolysis

The figure is found at http://www.biocarta.com/pathfiles/betaoxidationPathway.asp (Jan 2007)

ββββ-oxidation of fatty acids (1 cycle)

The figure was accepted from the book: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley-Liss, Inc., New York, 1997. ISBN 0-471-15451-2

Transport of fatty acids into a mitochondrion

CARNITINE TRANSPORTER

cytoplasm

Carnitine acyltransferaseregulates ββββ-oxidation

• malonyl-CoA(= intermediate of FA synthesis)

carnitinpalmitoyltransferase I(carnitin acyltransferase)

inhibitionactivationregulatory enzyme

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

Omega-oxidation of fatty acids

(endoplasmic reticulum; minority pathway for long

chain FA)

ββββ-oxidation of fatty acids

a) proceeds only in the liver

b) produces NADPH+H+

c) is localized in mitochondria

d) is activated by malonyl-CoA

ββββ-oxidation of fatty acids

a) proceeds only in the liver

b) produces NADPH+H+

c) is localized in mitochondria

d) is activated by malonyl-CoA

The figure is found at http://en.wikipedia.org/wiki/Image:Ketogenesis.png

(Jan 2007)

Ketone bodies synthesis(= ketogenesis)

• proceeds if ββββ-oxidation is ↑↑↑↑

• ounly in the liver: mitochondria

Acetyl-CoA

OH

The figure is found at http://en.wikipedia.org/wiki/Image:Ketogenesis.png

(Jan 2007)

Ketone bodies synthesis(= ketogenesis)

• proceeds if ββββ-oxidation is ↑↑↑↑

• ounly in the liver: mitochondria

HMG-CoA is formed also in a cytoplasm during cholesterol synthesis !

Acetyl-CoA

OH

• malonyl-Co A • ↑ ratio

insulin / glucagon

carnitinacyltransferase I(transfer of fatty

acids into mitochondria)

•↑ ratioinsulin / glucagon

• ↑ ratioglucagon / insulin

• catecholamines

hormon sensitivelipase(lipolysis in fatty

tissue)

inhibitionactivationregulatory enzyme

Regulation of ketogenesis

The figure is found at http://www.richmond.edu/~jbell2/19F18.JPG (Jan 2007)

Ketone bodies degradation(oxidation)

proceeds during starvationin extrahepatic tissuesas an alternative energy

source

(in a brain as well)

Citratecycle

Ketone bodies

a) are synthesized from acetyl-CoA

b) are produced by muscle tissue as a consequence of increased fatty acid oxidation

c) serve as an energy substrate for erythrocytes

d) can be excreted with urine

Ketone bodies

a) are synthesized from acetyl-CoA

b) are produced by muscle tissue as a consequence of increased fatty acid oxidation

c) serve as an energy substrate for erythrocytes

d) can be excreted with urine

The figure is found at http://herkules.oulu.fi/isbn9514270312/html/graphic22.png (Jan 2007)

Fatty acid synthesis

(1 cycle)

„activated carbon“

The figure is found at http://web.indstate.edu/thcme/mwking/lipid-synthesis.html#synthesis (Jan 2007)

Transport of acetyl-CoA from a mitochondrion to the cytoplasm

FA synthesis

NADPHfrom pentose

cycle

• glucagon (phosphorylation,

repression)• lipid rich diet,

starvation(repression)

• phosphorylated saccharides

• low-fat, energy rich high saccharide diet

(induction)

fatty acid synthase

• acyl-CoA (C16- C18)• glucagon (phosphorylation,

repression)• lipid rich diet,

starvation(repression)

• citrate• insulin• low-fat, energy

rich high saccharide diet

(induction)

acetyl CoA carboxylase

(key enzyme)

inhibitionactivationregulatory enzyme

Regulation of fatty acid synthesis

The pathway of synthesis of fatty acids

a) produces NADPH+H+

b) starts by carboxylation of acetyl-CoA: malonyl-CoA is formed

c) is localized in mitochondria

d) includes reduction steps

The pathway of synthesis of fatty acids

a) produces NADPH+H+

b) starts by carboxylation of acetyl-CoA: malonyl-CoA is formed

c) is localized in mitochondria

d) includes reduction steps

acetyl-CoApalmitic acidproduct

- /malonyl-CoA

citrate /acyl-CoA

activator /inhibitor

acetyl-CoA= product

malonyl-CoA = donor of acetyl

C2 donor/product

NAD+, FAD+NADPHcoenzymes of oxidoreductases

CoAACP-domain, CoAacyl is bound to

acyl-carnitin(= acyl to matrix)

citrate(= acetyl to cytoplasm)

transport through a mitochondrial membrane

mitochondriacytoplasmcellular location

muscles, liverliverthe most active tissue

lowhighratio insulin/glucagon

starvationsaccharide rich dietactive under the conditions

ββββ-oxidationsynthesis

Comparision of fatty acid synthesis and degradation

Biosynthesis of triacylglycerols

The figure is found at http://web.indstate.edu/thcme/mwking/lipid-synthesis.html#phospholipids (Jan 2007)

• insulin• apolipoprotein C-II

lipoprotein lipase(important for storage ofTAG in a fatty tissue)

• steroid hormones(induction)

phosphatidic acid phosphatase

inhibitionactivationregulatory enzyme

Regulation of TAG metabolism

Biosynthesis of cholesterol

The figure is found at http://web.indstate.edu/thcme/mwking/cholesterol.html (Jan 2007)

regulatory enzyme

The figure is found at http://amiga1.med.miami.edu/Medical/Ahmad/Figures/Lecture9/Slide23.jpg (Jan 2007)

cholesterol synthesis

ketone bodies

The figure is found at http://www.apsu.edu/reedr/Reed%20Web%20Pages/Chem%204320/Lecture%20Outlines/cholesterol_synthesis.htm (Jan 2007)

activated isoprene

Synthesis of cholesterol consumes ATP

The figure is found at http://www.apsu.edu/reedr/Reed%20Web%20Pages/Chem%204320/Lecture%20Outlines/cholesterol_synthesis.htm (Jan 2007)

activated isoprene: two frorms

The figure is found at http://www.apsu.edu/reedr/Reed%20Web%20Pages/Chem%204320/Lecture%20Outlines/cholesterol_synthesis.htm (Jan 2007)

• cholesterol• glucagon

(repression)• oxosterols

(repression)

• insulin, thyroxine(induction)

HMG-CoA reductase

inhibitionactivationregulatory enzyme

Regulation of cholesterol synthesis

Cholesterol

a) is synthesized in mitochondria

b) synthesis includes the same intermediateas ketogenesis: acetone

c) can be broken down to acetyl-CoA

d) is synthesized if the ratio insulin/glucagon is low

Cholesterol

a) is synthesized in mitochondria

b) synthesis includes the same intermediateas ketogenesis: acetone

c) can be broken down to acetyl-CoA

d) is synthesized if the ratio insulin/glucagon is low