Cholesterol
Compounds containing 27 carbon cyclopentanoperhydrophenanthrene structures with four
rings labeled A to D. Steroids are complex fat-soluble molecules, which are present in the
plasma lipoproteins and outer cell membrane. Cholesterol is one of the important non fatty
acid lipid that is grouped with steroids.
Cholesterol is important in many ways:
- For the synthesis of bile salts that are important in lipid digestion and absorption.
- For the synthesis of steroid hormones that are biologically important like the sex hormones estrogen and progesterone.
- For the synthesis of vitamin D3
- As a structural material in biological membranes.
- As a component of lipoproteins as transport forms of lipid based energy.
Digestion and Absorption of Lipids
Diet contains triglycerides, cholesterol and its ester, phospholipids, fattyacids etc.Mouth and
gastric juice has got lipase. It can hydrolyse fats without emulsification with bile salts.Milk fat and
butter fat is digested by the enzyme.
Major part of fats are digested by pancreatic lipase. It acts on emulsified lipids only. The products
are monoglyceride and 2 fatty acids. Monoglyceride is further hydrolyzed by another lipase. Thus
3 fatty acids and one glycerol molecule is produced from the digestion of dietary triglyceride.
hospholipids are digested by phospholipases, secreted by pancreas and intestines.
They are four in number, A (A1, A2) B, C, and D. The action of these enzymes are shown down
below.
The products of Phospholipase A1 or A2 are Lysophosphosphatidyl choline and one fatty acid,
when the substrate is PC.
Phospholipase B acts on Lysophospholipid, produces glycerophosphoryl choline and free fatty
acid.
Phospholipase C acts on phospholipids produce diglyceride and Phosphoryl choline.
Phospholipase D acts on phospholipids, produce choline and phosphatidic acid.
Cholesterol esterase hydrolyses cholesterol ester to free cholesterol and one fatty acid. The
digested products are water soluble but some are insoluble.
Glycerol, short chain fatty acids enter portal blood directly. Cholesterol, long chain fatty acids are
esterified and absorbed in form of micelles .Bile salts are required for the process. Impaired
secretion of lipases from the pancreas and bile salts from liver results in failure in fat absorption
and causes steatorrea (excessive passage fatty stool). Absorption products of lipid digestion are
absorbed from micelles. The micelles, through the intestinal lumen move to the brush border of
the mucosal cells where they are absorbed into the intestinal epithelium.
The bile salts are reabsorbed and reach by enterohepatic circulation to the liver to be used over
again. Their absorption is maximum in the ileum and jejunum. The free fatty acids and
monoayclglycerols are absorbed through the epithelial cells lining the small intestine and pass to
the lymphatic system where they join the systemic blood via the thoracic duct. The intestinal
mucosa secretes into the lymph, the absorbed lipids as chylomicrons and VIDL. The former have
short life in blood (<lhr) and make plasma milky after rich mea1. The free fatty acids in blood
(long chain) are bound to albumin and transported by blood to the liver
Metabolism of Fatty Acids and Triacylglycerols
The triacylglycerols play an important role in furnishing energy in animals. They have the highest
energy content over 9kcal/mole. They provide more than half the energy need of some organs
like the brain, liver, heart and resting skeletal muscle.
Mobilization of Fatty Acids from Adipocytes
When the energy supply from diet is limited, the body responds to this deficiency through
hormonal signals transmitted to the adipose tissue by release of glucagon, epinephrine, or
adrenocorticotropic hormone.
The hormones bind to the plasma membranes of adipocyte cells and stimulate synthesis of
cyclicAMP (cAMP). The cAMP activates a protein kinase that phosphorylates and in turn
activates hormone-sensitive triacylglycerol lipases (see the mechanism action of Hormones).
These lipases hydrolyze the triacylglycerols at position 1 or 3 to produce diacylglycerols (DAG)
and fatty acid, which is the rate limiting step in the hydrolysis. The diacylglycerol lipases
hydrolyze the DAG to monoacylglycerols (MAG) and a fatty acid. Finally MAG lipases hydrolyze
MAG to fatty acid and glycerol.
The free fatty acids (FFA) produced by lipolysis move through the plasma membranes of the
adipose cells and endothelial cells of blood capillaries by simple diffusion and bind to albumin in
the blood plasma, which are transported to peripheral tissues. The glycerol produced is taken up
by liver, phosphorylated and oxidized to dihydroxyacetone phosphate, which is isomerised to
glyceraldehydes-3-phosphate, an intermediate of both glycolysis and gluconeogenesis.
Therefore, the glycerol is either converted to glucose (gluconeogenesis) or to pyruvate
(glycolysis).
D. Transport of Fatty Acids to the Mitochondria
The fatty acids transported to the different tissue cells must first be activated or primed by
reaction with CoenzymeA at the expense of ATP. The reaction is catalyzed by AcylCoA
synthetase or also called thiokinase, found in the cytosol and mitochondria of cells. The
pyrophosphate generated from ATP favors more Acyl CoA formation by further hydrolysis. In
order to undergo β-oxidation, the fatty acids must enter the mitochondria. But they cannot easily
cross it as such by passive diffusion.
There are two fatty acid sources viz., those coming from absorption of FFA and those from
hydrolysis of triacylglycerols from adipose tissue. The transport of acyl derivatives across the
mitochondrial membrane needs three acyltransferases (shuttles).
1. Specific for short chain acyl groups, does not require carnitine
2. Specific for the long chain acyl groups. The shuttles for long chain acyl groups are
carnitine acyltransferase I and II. Therefore, long chain acyl groups cross the mitochondrial
membrane in combination with carnitine.
The carnitine pools are in the cytosol and mitochondria, abundant in muscle and it is synthesized
from the amino acids lysine and methionine in the liver and kidney. The other name of carnitine is
β-hydroxy-γ- trimethyl ammonium butyrate. Carnitine acyl transferase I, found in the surface of
the outer mitochondrial membrane, catalyzes the acyl transferase reaction from acylCoA to the
carnitine. It passes through the outer membrane to the inner membrane of mitochondrion. In the
final stage of the transport, the fatty acyl group is released from the carnitine to the
intramitochodrial CoASH by carnitine acyltransferase II, which is found in internal surface of the
inner mitochondrial membrane. The regenerated acyl CoA is released to the matrix. It is worth
noting that acyltransferase I is a regulatory enzyme in β-oxidation. The acyl CoA present in the
matrix of the mitochondrion is now ready for β-oxidation.
β-oxidation of Fatty Acids
The successive oxidative removal of two carbons in the form of acetyl–CoA beginning from the
carboxyl end is called β-oxidation.It requires a set of enzymes. The oxidation is so called because
the β carbon is oxidized during the oxidation process. It takes place in the matrix of mitochondria.
Energy needs of tissues are met by the oxidation of free fatty acids, released by adipose tissue.
Fatty acids are activated with the help of thiokinase, prior to transport to mitochondria. Overall
activation of fatty acid requires hydrolysis of two phosphodiester bonds.
1. Acyl CoA dehydrogenase converts acyl CoA to acyl trans enoyl CoA
2. Hydratase converts it to 3-hydroxy acyl CoA.
3. Hydroxy acyl CoA dehydrogenase converts it to 3keto acyl CoA.
4. It is further converted to acyl CoA and acetyl CoA.by Thiolase
The cycle is repeated 7 times for palmitic acid for complete oxidation. See the figure
The FADH2 and NADH +H+
join the electron transport chain as high energy electron carriers. The
latter donates its reducing equivalents (hydrogens) to NADH dehydrogenase to produce 3ATP
per pair of electrons and the former produces only 2ATPS.
Complete oxidation of fatty acid can be divided in to two stages.
A. Formation of acetyl CoA.
B. Oxidation of acetyl CoA to CO2, water via TCA cycle.
Stochiometry of the reaction:
Palmitoyl CoA + 7FAD + 7 NAD +7CoA = 8 Acetyl CoA+7FADH2 +7 NADHH.
Energetics of palmitate oxidation:
Reduced equivalents enter ETC and produce energy rich phosphate bonds. Acetyl CoA release
energy through TCA cycle.
7 FADH2 → 7 x 2 = 14 ATPs
7NADHH → 7 x 3 = 21 ATPs
8 Acetyl CoA → 8 x 12 = 96 ATPs
Total ATP produced from one molecule of palmitic acid is 131. Two ATPs (Two energy rich
bonds) are utilized, during activation of fatty acid. Therefore total gain of ATPs is 129.
Oxidation of Unsaturated Fatty Acids
The oxidation of unsaturated fatty acids requires two additional enzymes called isomerase and
reductase. Most naturally occurring unsaturated fatty acids are in cis- configuration, which are not
suitable for the action of enoyl-CoA hydratases and hence they must be changed to their trans
isomer by an isomerase. The rest of the enzymes are needed for the oxidation in addition to
these two for the oxidation are the same.
Oxidation of Fatty Acids with Odd Number of Carbons
Ruminant animals can oxidize them by B- oxidation producing acetylCoAs until a three carbon
propionylCoA residue is left.The acetylCoAs produced are funneled to the Krebs cycle but the
propionylCoA produced is converted to succinylCoA by three enzymatic steps. SuccinoyCoA is
an intermediate in the Kreb’s cycle and it can be metabolized.
The fates of acetyl-CoA formed by b-oxidation of fatty acids are:
1. Oxidation to CO2 and H2O by citric acid cycle.
2. Synthesis of lipids like cholesterol, fatty acids and other steroids.
3. Formation of ketone bodies in the liver.