Welcome to class of
Lipid metabolism
Dr. Meera Kaur
Learning objectives
• To understand
– How fatty acids are activated and transported into
mitochondria for oxidation.
– Oxidation of fatty acids.
– Role of lipoproteins in cholesterol metabolism.
Introduction
• Reserves of stored triglycerides are mobilized as needed for energy
production.
• Fat mobilization is stimulated by epinephrine. The triglycerides are
hydrolyzed to fatty acids and glycerol and enter the blood stream.
• Glycerol is converted to glycerol- 3 phosphate and then to
dihydroxyacetone phospahte, which enters glycolysis for energy
production.
• Free fatty acids are converted to fatty acyl CoA molecules, which are
broken down to acetyl CoA by beta oxidation. The acetyl CoA may
be used for energy production by way of the citric acid cycle and the
electron transport chain.
Fatty acid oxidation
Fatty acids are degraded to acetyl CoA
• Fatty acids enter tissue cells in need of energy. Fatty acids must
pass through the mitochondrial membrane to be oxidized and to
produce energy. The passage cannot occur until the fatty acid is
converted to its thioester with CoA. The product of this reaction
is fatty acyl CoA. The reaction is:
Fatty acid + HS – CoA+ ATP
Fatty acyl CoA + AMP + Pi
This is known as activation of fatty acid. Fatty acids must be
activated before they are degraded to produce energy. Fatty
acids are activated in the cytosol, but oxidation occurs in the
mitochondria.
Beta oxidation
•
The formation of fatty acyl CoA molecule prepares fatty acids for entry
into the mitochondria. Carnitine helps fatty acly CoA to enter
mitochondria. There they are degraded in the catabolic process called
beta oxidation. During beta oxidation, the third (or beta) carbon of the
saturated fatty acid chain of the fatty acyl CoA is oxidized to a ketone.
•
Beta oxidation is a spiral pathway. Each round consists of four enzymecatalyzed steps that yield one molecule of acetyl CoA and an acyl CoA
shortened by two carbons, which becomes the starting substrate for the
next round. Seven rounds of beta oxidation degrade a C16 fatty acid to
eight molecules of acetyl CoA.
Complete oxidation of one molecule of palmitic acid to carbon dioxide and
water yields 129 molecules of ATP. One round of beta oxidation yields
17 ATP.
Beta Oxidation is regulated by availability of free CoA, by the ratios of
NAD/NADH and Q2/QH.
The reactions of ß oxidation
Ketogenesis
Cholesterol synthesis
• Synthesis of cholesterol takes place in cytosol.
• The carbon skeleton of cholesterol is formed from
acetyl CoA. The pathway of cholesterol biosynthesis
has over 30 steps.
• The rate determining step of cholesterol synthesis
and the major control point is the conversion of HMGCOA to mevolonic acid.
• Some intermediate steps of cholesterol synthesis are
mevolonic acid— squalene— zymosterol—
cholesterol.
The fate of cholesterol
1. It can be incorporated
into a cell membrane.
2. It may be acylated to
form cholesteryl ester
for storage.
3. It is precursor of steroid
hormone (estrogen,
testosterone)
4. It is a precursor of bile
acids.
Lipoprotein function
Chylomicrons, which are mostly lipid, transport dietary lipids to the liver and
other tissues. Liver produces triacylglycerol-rich very- low- density
lipoproteins (VLDL). As they circulate in the tissues, VLDL give up their
triacylglycerol and become cholesterol-rich low- density lipoproteins (LDL),
which are taken up by tissues. High Density Lipoproteins transport
cholesterol from the tissues back to liver.
Theoretical model of lipoprotein structure
LDL
Cell can synthesize cholesterol as well as obtain it from circulating
LDL. When LDL dock with LDL receptor on the cell surface, the
lipoprotein-receptor complex undergoes endocytosis. Inside the cells,
the lipoprotein is degraded and cholesterol enters the cytosol.
Excess accumulation of cholesterol leads to atherosclerosis.
An atherosclerotic plaque blocking the lumen of an artery
HDL
HDL are essential for removing excess cholesterol from cells. A
transporter or flippase moves cholesterol from the cytosolic leaflet to
the extracellular leaflet, from which it can diffuse into the HDL. Defects
in the gene of the transporter cause Tangier disease, characterized by
accumulations of cholesterol in tissues and a high risk of heart attack.
Lipid metabolism in context
Summary of lipid metabolism