LIPID METABOLISM
Lipids are a large group of substances which dissolve well in organic solvents (acetone, chloroform,
benzene) and they are insoluble or slightly soluble in water. They contain acids with long chains (= fatty
acids).
Repeate the composition and function of lipids, structure and classification of fatty acids (FA).
Biological roles of lipids:
1. Lipids are an important source of energy. They are the energy reserve of the body. Adipocytes (fat
cells) are specialized for fat storage. Lipids serve as metabolic fuel. Their components are oxidized in
the mitochondria to water and CO2. In the process, ATP is produced in large amounts.
2. Amphipathic lipids (phospholipids, glycolipids) are building blocks of cellular membranes.
3. Lipids are excellent insulators.
Classification and metabolism of lipids:
I. SIMPLE LIPIDS:
Triacylglycerols (TAG, fats) are esters of glycerol and three fatty acids.
Waxes are esters of fatty alcohol and fatty acids and they are present in plants.
Degradation of TAG in adipose tissue (see Fig. 1)
The degradation of fats in adipose tissues (= lipolysis) is catalyzed by enzyme hormone sensitive
lipase  fatty acids released by adipose tissue are transported in the blood in unesterified form = free
fatty acids (FFA) – in complexes with albumin. Hormone-sensitive lipase is activated by hormones
glucagon and catecholamines. This enzyme is inhibited by insulin.
Fig. 1: Hormone-induced fatty acid mobilization in adipose tissue
Figure is found on http://web.indstate.edu/thcme/mwking/fatty-acid-oxidation.html
The tissues take up fatty acids from the blood to rebuild fats or to obtain energy from their oxidation.
Metabolism of fatty acids is especially intensive in the liver (hepatocytes).
In the cell, fatty acids are activated by conversion to their CoA derivatives  acyl-CoAs are formed in cell
cytoplasm (reaction takes place on outer mitochondria membrane and is catalyzed by enzyme acylCoA-synthetase). Transfer of acyl-CoAs from cytoplasm to the mitochondrial matrix is performed by a
carnitine transporter  carnitine carries acyl residues through the inner mitochondrial membrane 
matrix.
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Fig. 2: Function of carnitine transporter – transport of fatty acids from cytoplasm into matrix of
mitochondria.
Figure is found on http://web.indstate.edu/thcme/mwking/fatty-acid-oxidation.html
β - oxidation of fatty acids is the most important process for degradation of fatty acids. This pathway
occurs in mitochondrial matrix. It is an oxidative reaction cycle in which C2 units are succesively
released in the form of acetyl-CoA. Cleavage of the acetyl groups starts between C2 (α) and C3 (β)
= β – oxidation
Reactions of β – oxidation (see Fig. 3):
1. Oxidation (= dehydrogenation) of an activated fatty acid (= acyl-CoA) is catalyzed by enzyme
acyl-CoA dehydrogenase. In the process, two protons with their electrons are transferred to
FAD  FADH2, which passes them to the respiratory chain.
2. Hydration (= addition of water molecule) is catalyzed by enoyl-CoA hydratase.
3. Oxidation. Acceptor for reducing equivalents is NAD+  NADH + H+, which passes them to the
respiratory chain.
4. Thiolysis (thioclastic cleavage) - activated β-ketoacid is cleaved by acyl-CoA acetyl
transferase (thiolase) in the presence of CoA. The products are acetyl-CoA and an activated
fatty acid with one less C2 unit then the original acid.
For the complete degradation of long chain fatty acids, the cycle must go through multiple
rounds. (for example: for stearyl-CoA (C18) eight cycles are required).
The acetyl-CoA formed is condensed with an oxaloacetate to form citrate, which than enters to
the citric acid cycle.
Regulation of β-oxidation:
Regulation is performed on the carnitine acyltransferase I level. This enzyme is inhibited by malonyl-CoA
(= an intermediate of fatty acid synthesis).
Energy balance:
Degradation of palmitic acid (16 C)
FADH2 gives
2 ATP
NADH + H+ gives 3 ATP
----------5 ATP in one oxidation cycle
for complete degradation of palmitic acid the cycle must go 7 times  7 x 5 = 35 ATP
The product of β - oxidation is acetyl-CoA, in case palmitic acid is yielded 8 acetyl-CoAs (12 ATP per 1
acetyl-CoA)  8 x 12 = 96 ATP
Total: 35 ATP + 96 ATP = 131 ATP - 2 ATP for activation of palmitic acid = 129 ATP
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Fig. 3: β-oxidation of fatty acids in mitochondrion.
Figure is found on http://www.peroxisome.org/Scientist/Biochemistry/boxidationtext.html
β - oxidation is the main pathway for degradation of fatty acids. But there are also other special pathways
for degradation of a) unsaturated fatty acids and b) degradation of odd-numbered fatty acids.
a) degradation of unsaturated fatty acids
Unsaturated FA usually contain cis double bond at positions 9 or 12 (i. e. linoleic acid). Cis double
bonds have to convert into trans double bonds and degradation of these FA occurs via β - oxidation.
b) degradation of odd numbered fatty acids
These fatty acids are degradated by β - oxidation as the "normal" even-numbered FA. The products are
n acetyl-CoAs and propionyl-CoA. Propionyl-CoA is carboxylated to form methylmalonyl-CoA, which is
converted to succinyl-CoA (= intermediate of CAC).
α- and ω- oxidation are only minor importance. The α- oxidation of FA serves for degradation of methylbranched fatty acids. ω - oxidation serves for oxidation of the end of the fatty acid.
Fatty acid synthesis
The biosynthesis of FA is catalyzed by enzyme fatty acid synthase. It is a multifunctional enzyme that
is located in the cytoplasm of the cell.
Fatty acid synthase is composed of 2 identical peptide chains. Each of peptide chains catalyzes 7
different partial reactions that are required for palmitate synthesis. Each half of fatty acid synthase
contains a cysteine residue (Cys-SH) and a 4´phosphopantetheine group (Pan-SH), which is very
similar to CoA, is bound to a domain of the enzyme that is called as the acyl-carrier protein (ACP).
Biosynthesis of palmitate (see Fig. 4) :
Acetyl-CoA is transferred to the functional cysteine residue of the enzyme.
1. Acetyl-CoA is carboxylated by HCO3- to yield malonyl-CoA by enzyme acetyl-CoA carboxylase.
Enzyme acetyl-CoA carboxylase is a regulatory enzyme of fatty acid synthesis. It is activated by
citrate and inhibited by end-product = palmitoyl-CoA.
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2. Malonyl unit is transferred to the 4´phosphopantetheine group of ACP. Another acetyl group is
transferred to cysteine residue.
3. This acetyl group is transferred to the malonyl unit, during this process the carboxyl group is cleaved
off as CO2.
4. Reduction of 3-oxogroup by NADPH + H+  NADP+
5. Dehydration
6. Reduction by NADPH + H+  NADP+ to yield of fatty acid with 4 carbons (= butyryl)
Butyryl unit is relocated from ACP to the functional cysteine  ACP can bind another malonyl residue 
after 7 cycles the product = palmitate is released. One turn of the "cycle" adds a -CH2-CH2- unit to the
growing acyl chain.
Most of the reductant, NADPH + H+, is supplied by the pentose phosphate pathway.
Acetyl-CoA (= principal substrate of fatty acid synthesis) is produced in the pyruvate
dehydrogenase reaction (located in mitochondria). It is transported from mitochondria into cytoplasm
via the citrate shuttle (acetyl-CoA + oxaloacetate → citrate).
Fatty acid synthesis is activated by hormone insulin and inhibited by hormones glucagon and
catecholamines.
Fig. 4: Biosynthesis of FA (1 cycle)
Figure is found on http://138.192.68.68/bio/Courses/biochem2/FattyAcid/FASynthesis.html
Metabolism of triacylglycerols (TAG)
TAG are esters of glycerol and three FA.
Monoacylglycerol – one FA is esterified with glycerol. Esterification with futher FA gives
diacylglycerols, and ultimately triacylglycerols.
TAG are synthetized in the liver cells and fat cells. Adipocytes containing large droplets of TAG. TAG are
degradated (hydrolysis) to glycerol and FA in adipocytes. These hydrolysis is catalyzed by hormonesensitive lipase. FA are released into the blood  FA + albumin complexes  to the liver, heart muscle,
kidneys, skeletal muscle. Glycerol is transferred to the liver by blood.
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Biosynthesis of TAG:
a) de novo synthesis of TAG occurs in cytoplasm and endoplasmatic reticulum of liver and fat cells.
This way is less usual (see Fig. 5).
b) reacylation from monoacylglycerols occurs in endoplasmatic reticulum of enterocytes.
Monoacylglycerols enter to the enterocytes from lumen of intestine by diffusion through cytoplasmic
membrane.
Fig. 5: De novo synthesis of TAG from dihydroxyacetone phosphate with formation of phosphatidic acid
Figure is found on http://web.indstate.edu/thcme/mwking/lipid-synthesis.html
II. COMPLEX LIPIDS
Complex lipids contain alcohol (glycerol, sphingosine), fatty acids and polar residue (phosphate residue,
amino alcohol, sugar).
a) Phospholipids are the main constituents of cellular membranes.
Composition of phospholipids: glycerol + 2 fatty acids + phosphate group. They contain a phosphate
residue. Phosphate residue is esterified with a hydroxyl group at C-3 of glycerol. This residue gives a
negative charge to phospholipids.
Phosphatidic acid (phosphatidate) is the simpliest phospholipid, it is phosphate ester of diacylglycerol.
It is an important intermediate in the biosynthesis of fats and phospholipids. All other phospholipids are
derived from phosphatidic acid by esterification of the phosphate group with the –OH group of an amino
alcohol (choline, ethanolamine, serine) or inositol.
Phosphatidylcholine (= lecithin) is the most abundant phospholipid in membranes.
Phosphatidylethanolamine (cephalin) has an ethanol-amine residue.
Phosphatidylinositol contains inositol (= sugar-like alcohol).
Biosynthesis of phospholipids:
Biosynthesis of complex lipids begins with glycerol-3-P. Glycerol-3-P is esterified with a long chain fatty
acid at C-1. This intermediate is esterified with another long chain fatty acid to form phosphatidate.
Phosphatidates are key molecules in the biosynthesis of fats, phospholipids and glycolipids.
For the synthesis of fats the phosphate group of phosphatides is first removed by hydrolysis 
diacylglycerol is then converted to a triacylglycerol (TAG) by transfer of a futher fatty acid from acylCoA.
For the synthesis of phosphatidylcholine: phosphate group of phosphatides is first removed by hydrolysis
 diacylglycerol  CDP-choline is transferred to the diacylglycerol  phosphatidylcholine.
Phosphatidylethanolamine is synthetized from a diacylglycerol and CDP-ethanolamine.
Degradation of phospholipids:
Degradation of phospholipids is catalyzed by enzymes phospholipases. Phospholipases are divided
according to the type of the bond which is cleaved.
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Phospholipase A1 catalyzes the cleavage of fatty acid from phospholipid in position 1.
Phospholipase A2 catalyzes the cleavage of fatty acid from phospholipid in position 2.
Phospholipase C catalyzes the cleavage of phosphate group from phospholipid.
b) Sphingophospholipids are found in large amounts in the brain and nervous tissue.
In these compounds, sphingosine (an amino alcohol with a long side chain) replaces glycerol and one
of the acyl residues. Amide bond formation between sphingosine and a fatty acid yields ceramide
(= precursor of the sphingolipids).
Composition of sphingophospholipids: sphingosine + fatty acid + phosphate residue + amino
alcohol or sugar alcohol
Sphingomyelin (= the most important sphingolipid) contain choline (= amino alcohol) which is
connected to the phosphate group of ceramide part.
c) Glycolipids are present in all tissues on the outer surface of the plasma membrane.
These lipids are composed of sphingosine + fatty acid + sugar or oligosaccharide residue. The
phosphate group is absent.
Galactosylceramides and glucosylceramides are examples of glycolipids. The sugar can be esterified
with sulfuric acid  sulfatides.
Gangliosides are the most complex glycolipids. They form a large family of membrane lipids with
receptor function.
III. ISOPRENOIDS AND STEROIDS
All lipids are derived from acetyl-CoA („activated acetic acid“). The major pathway leads from acetylCoA to fatty acids. Their CoA-derivatives are the basic building blocks for fats, phospholipids,
glycolipids and other derivatives. The second pathway leads from acetyl-CoA to isopentenyl
diphosphate, the basic building block for the isoprenoids and steroids.
Isoprenoids are derived from isoprene (= 2-methyl-1,3-butadiene). From activated isoprene, the main
pathway leads to geraniol and farnesol. Farnesol is converted to squalene  cholesterol and the
steroids.
Some of the isoprenoids have essential roles in metabolism, but cannot be synthetized by animals. This
group includes vitamins A, D, E and K. Vitamin D is now usually classified as a steroid hormone.
Steroids are divided into 3 classes: sterols, bile acids, steroid hormones.
A. Sterols are steroid alcohols. The most important sterol in animals is cholesterol. Cholesterol is
present in all animal tissues. It is a major constituent of cellular membranes. Cholesterol is esterified
with fatty acid to form esters (in lipoproteins). Cholesterol is a normal constituent of the bile.
B. Bile acids are synthetized from cholesterol in the liver. Their structures are derived from cholesterol.
Bile acids increase the solubility of cholesterol and promote the digestion of lipids in the intestine.
(i. e. cholic and chenodeoxycholic acid).
C. Steroid hormones are a group of lipophilic signal molecules, which regulate metabolism, growth
and reproduction. The steroid hormones of vertebrate animals are progesterone, estradiol,
testosterone, aldosterone, cortisol and calcitriol.
Cholesterol biosynthesis (see Fig. 6):
Cholesterol biosynthesis is located in the smooth ER and this pathway can be divided into 4 phases:
1. Formation of mevalonate: 3 acetyl-CoA are converted to 3-hydroxy-3-methyl-glutaryl-CoA
(3-HMG-CoA). The conversion of 3-HMG-CoA to mevalonate is catalyzed by enzyme 3-HMG-CoA
reductase (= key regulatory enzyme in cholesterol biosynthesis). Synthesis of the enzyme is
inhibited by final products of the pathway (cholesterol). Action of this enzyme is regulated by
hormones – insulin and thyroxine stimulate the enzyme and glucagon inhibits it.
2. Formation of isopentenyl diphosphate: The conversion of mevalonate to isopentenyl diphosphate
(5 C) involves two phosphorylation reactions followed by decarboxylation. Isopentenyl diphosphate
is the precursor of all isoprenoids.
3. Formation of squalene: 2 Isopentenyl diphosphate are converted to geranyl diphosphate (10 C)
 futher isopentenyl diphosphate is added to give farnesyl diphosphate (15 C). Farnesyl
diphosphate undergoes isomeration to yield squalene (30 C).
4. Formation of cholesterol: Cholesterol (27 C) is a compound that is formed from the linear
isoprenoid squalene (30 C) via a complicated series of reactions. The first intermediate is
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lanosterol. The reaction is catalyzed by enzymes cytochrome P 450 (Cyt P 450). Later steps lead
to yield cholesterol.
Reducing agent for these reactions is NADPH + H+.
Fig. 6: Cholesterol biosynthesis
Figure is found on http://web.indstate.edu/thcme/mwking/cholesterol.html
Lipid metabolism and formation of ketone bodies
The liver is the most important site for the formation of FA, fats, ketone bodies and cholesterol. The
metabolism of lipids in the liver is closely linked to carbohydrate and amino acid metabolism.
In the well-fed (= absorptive) state, the liver converts Glc via acetyl-CoA into FA. FA are converted into
fats and phospholipids.
In the postabsorptive state, especially during prolonged fasting, starvation, or in the case of diabetes
mellitus, there is a shift of lipid metabolism. Since Glc and lipids are no longer being supplied in the diet,
the organism has to fall back on its own reserves. Under these conditions, the adipose tissue releases
fatty acids that are taken up by the liver from the blood. FA are degraded to acetyl-CoA, and finally
converted to ketone bodies.
Ketone bodies are acetoacetate, 3-hydroxybutyrate and acetone.
Biosynthesis of ketone bodies (see Fig. 7):
1. When the concentration of acetyl-CoA in the liver mitochondria is high, two molecules condense to
form acetoacetyl-CoA.
2. The addition of a futher acetyl group gives 3-hydroxy-3-methyl-glutaryl-CoA, which removes
acetyl-CoA to yield acetoacetate.
Acetoacetate can be converted to 3-hydroxybutyrate by reduction or breaks down to acetone by
nonenzymatic decarboxylation.
Compounds acetoacetate, 3-hydroxybutyrate and acetone are called ketone bodies. The ketone
bodies are released by the liver into the blood, in which they are soluble. Levels of ketone bodies in the
blood are elevated during periods of starvation. Acetoacetate and 3-hydroxybutyrate then serve as
key metabolites in energy production. Acetone, which has no metabolic significance, is exhaled
via lungs. After 1-2 weeks of starvation, the nerve tissue also begins to utilize the ketone bodies as
energy sources.
The excess acids (acetoacetate, 3-hydroxybutyrate) in the blood decreases pH  ketoacidosis.
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Fig. 7: Ketogenesis = formation of ketone bodies in the liver
Figure is found on http://en.wikipedia.org/wiki/Ketogenesis
Lipoproteins
Lipoproteins are spherical complexes of lipids and proteins. They consist of a core of apolar lipids (=
TAG and acyl esters of cholesterol) and a shell made up of phospholipids and apoproteins (Apo A, B, C,
E). The shell is polar on its outside, and thus keeps the lipids dissolved in the plasma (see Fig. 8).
Fig. 8: Structure of LDL.
Figure is found on http://www.rpi.edu/dept/bcbp/molbiochem/MBweb
Lipoprotein complexes are divided into 5 different groups according to their increasing density
(see Fig. 9):
● chylomicrons and chylomicrons remnants transport dietary lipids from intestine to tissues. In
peripheral vessels – particularly in muscle and adipose tissue enzyme lipoprotein lipase on the surface
of the vascular endothelia hydrolyzes most of TAG → chylomicrons remnants → liver.
● VLDL (= very low density lipoproteins) are formed in the liver and can be converted to IDL or LDL.
VLDL transport TAG, cholesterol and phospholipids to other tissues. They are gradually converted into
IDL and LDL under the influence of lipoprotein lipase.
● IDL (= intermediate density lipoproteins)
● LDL (= low density lipoproteins) are produced from VLDL and supply the cholesterol to tissues.
● HDL (= high density lipoproteins) transport excess of cholesterol from peripheral tissues back to the
liver. Cholesterol is acylated (+ acyl = esterification) by enzyme lecithin cholesterol acyltransferase
(LCAT). Cholesterol esters can be transported in the core of the lipoproteins.
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Fig. 9: Overview of lipoprotein functions
Figure is found on http://courses.cm.utexas.edu/archive/Fall1997/CH339K/Browning/lec34/lec34.htm
References:
Koolman, J., Roehm, K-H.: Color Atlas of Biochemistry, 2nd edition, Thieme, Stuttgart (2004)
Pavla Balínová
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