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GLYCOLYSIS

GLUCOSE-6-P

PYRUVATE

ACETYLCoA

TCA CYCLEETC

ATP

ADPGLYCOGEN

PPP

2,3-BPGALANINE

ACETYLCoA

-OXIDATION

CAT I

CAT II

FATTY ACYLCoA

FATTY ACID

SYNTHESIS

GLUCONEOGENESIS

LACTATE

MITOCHONDRION

CYTOSOL

PLASMA

KETONES

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LIPID DIGESTION AND ABSORPTION

The vast majority (95%) of dietary lipid istriacylglycerols (TAG). The rest isphosphoglycerides (PG), sterols, sterol esters,sphingolipids and free fatty acids.

No significant digestion of lipids occurs beforethe duodenum. There are lingual (tongue-associated) lipases and gastric lipases, butthey do not break down significant amounts of

lipids, and are largely involved in emulsificationof lipids.

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Being insoluble in water lipids are largelyinaccessible to water-soluble enzymes.

To increase the surface area of lipid dropletsand thus increase the rate of their digestion

requires prior emulsification by the churningaction of the stomach. The higher temperatureof the stomach also helps to liquify lipids.

The emulsion then passes to the duodenumwhere the detergent action of the bile saltsand lysophosphoglycerides in the bile from theliver further reduce the lipid droplet sizes.

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Once droplets of lipid are small enough theyare taken up by the bile semi-crystallinestructure, they are now known as micelles.

This process ensures a much greater surface

area of lipid is accessible to the digestiveenzymes in the duodenum. These have beensecreted by the pancreas in the pancreaticjuice, and start to digest the lipid.

They only act on the surface of the droplet asthey are water-soluble, but are fast actingand lipid digestion is complete by the time thejejunum has been reached.

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In triacylglycerol digestion the main enzyme ispancreatic lipase, which is linked to the micelle

and activated by another pancreatic enzyme,colipase. Initially it removes the fatty acidsfrom the 1 and 3 positions of the glyceride.The fatty acid in the 2 position is sometimes

removed as well, but this does not have tohappen to allow for the absorption of the lipid.

H2C-O-R1 H2C-O-H + R1

HC-O-R2 HC-O-R2PANCREATIC LIPASE

H2C-O-R3 H2C-O-H + R3

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In phosphoglyceride digestion there are aseries of enzymes that work at specific siteswithin the molecule:

Phospholipase A1 removes the fatty acid in the1 position.Phospholipase A2 removes the fatty acid in the

2 position.Phospholipase B can remove either or bothfatty acids.Phospholipase C removes the phosphate/basecomplex entirely.Phospholipase D removes just the base group.

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PHOSPHOLIPASE A1

H2C-O-R1 PHOSPHOLIPASE BPHOSPHOLIPASE A2

HC-O-R2 PHOSPHOLIPASE CPHOSPHOLIPASE D

H2C-O-PO3-X

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Phosphoglycerides are initially converted to the 2-lyso form. These are highly amphipathic and aidwith the emulsification of the TAGs.

Sphingomyelin is digested initially by phospholipaseC to remove the phosphate-base complex. Othersphingolipids have the saccharide chain removed by

cerebrosidase. The resulting ceramides from bothsources are then de-acylated by ceraminidase toyield sphingosine and fatty acids.

Sterols, including cholesterol, are not digested.

All of the digestion products, as well as some ofthe original components, also aid in theemulsification of the TAGs.

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WHAT IF IT DOESNT WORK THAT WAY?The vast majority of dietary lipid is TAG, so aproblem with pancreatic lipase will cause a failure of

lipid digestion. This will mean that most of the lipidwill remain in the intestinal lumen and not beabsorbed. It will pass into the cecum and will beacted on by the intestinal flora, but even thebacteria are overloaded, so a lot of the fat remains.The bacterial action causes the formation of largevolumes of gas, which with the extra mass from thelipid leads to very bulky, light, even floating, foulsmelling feces. This is a form of maldigestion. Asimilar profile emerges if bile salt release isimpaired. A parallel situation occurs if digestion isok, but the intestinal lining is impaired. The digestedlipid is still not properly absorbed. This is a form ofmalabsorption.

All forms are known as steattorhea.

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LIPID ABSORPTION

The final products of digestion are

monoacylglycerols (MAG), free fatty acids (FFA),phosphate/base complexes and some free glycerol.

The MAG and FFA move across the intestinal cell

membrane and into the intracellular matrix(cytosol). This is largely by diffusion, but can beassisted by a Na+-fatty acid symporter.

An enzyme, acylCoA synthetase, localised on theinner side of the membrane converts the FFA toacylCoA.

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LUMEN INTRACELLULAR LYMPH

LONG CHAIN CoASH

FFA FFA ACYLCoAACYLCoA

SYNTHETASE

MAG MAG TAG

S.E.R.

CHYLOMICRON

CHOLESTEROLCHOLESTEROL ESTER

APOPROTEINS

LYSO-PGS PGS

GLYCEROL

SHORT/MEDIUM

CHAIN FFA PLASMA

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WHY EXOCYTOSIS INTO LYMPHATIC SYSTEM?

Unlike carbohydrates, where the digestedmonosaccharides are destined initially for storage asglycogen in the liver, digested lipid is not stored inthe liver but rather in adipose tissue. Thus to passthe chylomicrons into the portal vein system and

through the liver is unnecessary.

By feeding into the lymphatic system the liver isbypassed and the chylomicrons are next metabolised

by adipose tissue and muscle after the drainage ofthe lymphatic system into the circulation via thesubclavian veins.

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Any short and medium chain fatty acids are fairlywater soluble and pass into the portal circulation and

go to the liver where some gets used for liver energysupply and the remainder packaged into lipoproteinsfor export for storage in muscle and adipose tissue.

Any free glycerol is transported in the circulation insolution and is converted in the liver to eitherpyruvate or glucose, depending on prevailing hormonalstatus.

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LIPID STORAGE

Prior to chylomicrons arriving at their destination,either muscle or predominantly adipose tissue, they

are initially donated apoprotein E from high densitylipoprotein (HDL). This apoprotein E is required forthe recognition of the chylomicron by lipoproteinlipase. This enzyme is localised in the capillary

membrane and hydrolyses the TAGs to free fattyacids and glycerol. The fatty acids pass into the celland are esterified by acylCoA synthetase to formacylCoA. This acylCoA is then incorporated into TAGSvia TAG synthase in the cytosol.

Both lipoprotein lipase and TAG synthase arestimulated by insulin and inhibited by the anti-insulinhormones (adrenaline, cortisol, glucagon, growthhormone).

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PLASMA INTRACELLULAR

CoASH

FFA ACYLCoAACYLCoA

FFA SYNTHETASE TAGSYNTHASE

TAG LIPOPROTEIN TAGLIPASE

GLYCEROL DIHYDROXYACETONE-PO4

GLUCOSE-6-PO4

LIVER

Lipoprotein lipase is stimulated by insulin and inhibited by glucagon and adrenaline

Tag synthase is stimulated by insulin and inhibited by glucagon and adrenaline

CHYLOMICRON

CHYLOMICRON

REMNANT

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LIPID MOBILISATION

Between meals or during fasting/starvation the

body needs to mobilise fatty acids to beoxidised to provide energy.

The process is stimulated by adrenaline andglucagon.

There are two enzymes responsible for thebreakdown of TAGs in adipose tissue -hormone-sensitive lipase and adipose TAGlipase. Both are sensitive to hormone stimulus

but to different degrees.

Once the fatty acids have been liberated theypass into the circulation and are transportedassociated with albumin.

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Albumin has 8 association sites for fattyacids. 4 are high affinity and bind fatty acidseasily. 4 are low affinity and only bind fatty

acids when large amounts requiretransportation.

The fatty acids are not chemically bonded tothe albumin, merely associated by mutualhydrophobocity.

HYDROPHOBIC CLEFTS

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GLYCEROLADIPOSE TAG

LIPASETAG

HORMONE

SENSITIVE

LIPASE

ALBUMIN

FFA

ALBUMIN-FFA

HORMONE SENSITVE (HS) LIPASE IS INHIBITED BY INSULIN AND STIMULATED BY GLUCAGONAND ADRENALINE

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But acylCoA cannot cross the mitochondrial

membrane, so the CoA is removed and replacedby the amino acid carnitine, this complex thencrosses the membrane. Once inside, thecarnitine is removed and replaced by anothercoenzyme A. In this form it can feed in to -oxidation. Both the addition of carnitine andits removal require an ATP, hence it costs youtwo ATP to get the fatty acid into -oxidation.

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CoASH

ALBUMIN-FFA FFAACYLCoA

ADPATP CoASH

CARNITINE CARNITINE MITOCHONDRIALACYL MATRIX

TRANSFERASE CARNITINE

I (CAT I) ACYL TRANSFERASE

II (CAT II) CoASHATP

CARNITINEADP

ACYLCoA

CARNITINE ACYL TRANSFERASE I IS INHIBITED BY MALONYL CoA

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FATTY ACID CATABOLISMOnce the fatty acid has been taken in to themitochondrial matrix it is committed to being

hydrolysed to produce acetylCoA, FADH2and NADH2.

The process is a stepwise cycle involving sequentialremoval of 2 carbon fractions as acetylCoA. This

explains why most lipid metabolism occurs with evencarbon numbered fatty acids.

The pathway is known as beta () oxidation because itinvolves the formation of a keto group from the beta

methylene group.

Trans unsaturated fatty acids can be hydrolysed bythe pathway as all the double bonds inserted during

the oxidation process are in the trans configuration.

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The acetylCoA then feeds into the TCA cycleand electron transport chain to produce ATP.

Assuming an initial chain length of 18 carbons,this will yield 9 acetylCoA, 8 FADH2and 8NADH2.

Each acetylCoA will yield 3 NADH2, 1 FADH2

and 1 ATP via the TCA cycle; thus 27 NADH2,9 FADH2and 9 ATP.

The total is thus 35 NADH2, 17 FADH2and 9ATP.

Each NADH2yields 3 ATP, thus 105 ATP.

Each FADH2yields 2 ATP, thus 34 ATP.

Thus one 18 carbon fatty acid yields 148 ATP.

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The only other organelle where any significantoxidation of fatty acids occurs are the peroxisomes.

These derive their energy by oxidation of mediumchain dicarboxylic fatty acids, produced via the -and -oxidation pathways. They also carry out some-oxidation, but not for energy production. The 2

steps that produce FADH2and NADH2are ratherlinked to the formation of H2O2. This is then used inreactions requiring oxidative capacity.

They can also shorten very long chain saturatedfatty acids, ones too long to enter the carnitinetransport system.

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In times of food intake deprivation glucose canbe in short supply.

Because of the total dependance oferythrocytes on only glucose the amountproduced by gluconeogenesis is predominantlyreserved for erythrocyte metabolism. The

brain therefore requires an alternative fuel.

Food deprivation is a stress situation thusstress hormones (adrenaline, glucagon) are

released and stimulate the mobilisation of fattyacids. These are then oxidised and produce alot of acetylCoA for each fatty acid oxidised.

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In liver some of this acetylCoA is converted toketones which are exported to the brain for it to

use for energy.

Now remember acetylCoA cannot cross amembrane, thus cannot get out of the liver cell,

so the CoA must be got rid of.Two acetylCoA are combined via acetoacetylCoAthiolase to make acetoacetylCoA and CoASH.

AcetoacetylCoA is combined via HMGCoA

synthase with another acetylCoA to makehydroxymethylglutarylCoA (HMGCoA) and CoASH.

Up to this point the pathway is the same as insterol synthesis.

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Next acetylCoA is removed again leavingacetoacetate. This gets rid of the last CoASH,which means the acetoacetate can now be released

through the plasma membrane of the hepatocyteinto the circulation.

In the circulation some acetoacetate breaks downto acetone which is lost through the lungs. Some

more isomerises to -(2-) hydroxybutyrate.Both acetoacetate and -hydroxybutyrate aretaken up by the brain, reconverted to acetylCoA,and fed into the TCA cycle.

But this misses out on the 2 ATP and 2 NADH2from glycolysis, so energy generation from ketonesin the brain is less efficient than from glucose.

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HMGCoA

HMGCoA LYASE

ACETOACETATE ACETYLCoA

-HYDROXYBUTYRATE ACETONE + CO2

+ ACETOACETATE

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-HYDROXYBUTYRATE

+ ACETOACETATE SUCCINYLCoA

SUCCINYLCoA-ACETOACETATE CoA TRANSFERASE

SUCCINATE

ACETOACETYLCoA CoASH

THIOLASE

2 ACETYLCoA

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Very little complete degradation ofphosphoglycerides usually occurs. In most casesthey are rather modified, either in situ or ex situ.

The ability to modify the fatty acids and the basegroup of a PG is very important as these controlthe shape of the molecule and its fluidity. Boththese factors, along with cholesterol and

glycolipids, control the ultimate shape, thicknessand flexibility of the membrane.

Choline is a large group while serine is small, thusexchanging them changes both the packing and

shape of the PGs. Replacing a saturated fatty acidwith a polyunsaturate increases membrane fluidity.

The enzymes are the same as in the digestiveprocess.

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XP

XP

X

P

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Sphingolipid catabolism involves specific enzymes

depending on the sphingolipid.As examples, GM1 degradation requires-galactosidase and produces GM2. This is thendegraded by -hexosaminidase (hexosaminidaseA) to produce GM3. GM3 is degraded to gal-glu-

ceramide by neuraminidase. -galactosidase thenremoves the gal to leave glu-ceramide. Lastly,-glucosidase removes the glu to leave ceramide.

Deficiencies of any of these enzymes cause raregenetic conditions (eg. Tay-Sachs).

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