Unit 10 - Lipid Metabolism
Fatty acids have four major physiologic roles in the cell:
Building blocks of phospholipids and glycolipids
Added onto proteins to create lipoproteins, which targets them to membrane locations
Fuel molecules - source of ATP
Fatty acid derivatives serve as hormones and intracellular messengers
Absorption and Mobilization of Fatty Acids
Most lipids are triacylglycerols, some are phospholipids and cholesterol.
Digestion occurs primarily in the small intestine.
Fat particles are coated with bile salts (amphipathic) from gall bladder.
Degraded by pancreatic lipase (hydrolyzes C-1 and C-3 2 fatty acids and 2-
Can then be absorbed by intestinal epithelial cells; bile salts are recirculated after being absorbed
by the intestinal epithelial cells.
In the cells, fatty acids are converted by fatty acyl CoA molecules.
Phospholipids are hydrolyzed by pancreatic phospholipases, primarily phospholipase A .
Cholesterol esters are hydrolyzed by esterases to form free cholesterol, which is solubilized by
bile salts and absorbed by the cells.
Lipids are transported throughout the body as lipoproteins.
Lipoproteins consist of a lipid (tryacylglycerol, cholesterol, cholesterol ester) core with
amphipathic molecules forming layer on outside.
Both transported in form of lipoprotein particles, which solubilize hydrophobic lipids and contain
Lipoproteins classified according to their densities:
o chylomicrons - contain dietary triacylglycerols
o chylomicron remnants - contain dietary cholesterol esters
o very low density lipoproteins (VLDLs) - transport endogenous triacylglycerols, which are
hydrolyzed by lipoprotein lipase at capillary surface
o intermediate-density lipoproteins (IDL) - contain endogenous cholesterol esters, which are
taken up by liver cells via receptor-mediated endocytosis and converted to LDLs
o low-density lipoproteins (LDL) - contain endogenous cholesterol esters, which are taken up
by liver cells via receptor-mediated endocytosis; major carrier of cholesterol in blood;
regulates de novo cholesterol synthesis at level of target cell
o high-density lipoproteins - contain endogenous cholesterol esters released from dying cells
and membranes undergoing turnover
1 Storage of Fatty Acids
Triacylglycerols are transported as chylomicrons and VLDLs to adipose tissue; there, they are
hydrolyzed to fatty acids, which enter adipocytes and are esterified for storage.
Mobilization is controlled by hormones, particularly epinephrine, which binds to -adrenergic
receptors on adipocyte membrane protein kinase A activated phosphorylates hormone-
sensitive lipase converts triacylglycerols to free fatty acids and monoacylglycerols.
Insulin inhibits lipid mobilization (example of reciprocal regulation).
Monoacylglycerols formed are phosphorylated and oxidized to DHAP (intermediate of glycolysis
ATP ADP NAD NADH + H
glycerol glycerol 3-phosphate dihydroxyacetone phosphate
glycerol kinase glycerol phosphate
Can be converted to glucose (gluconeogenesis) or pyruvate (glycolysis) in the liver.
Fatty Acid Oxidation (-oxidation)
Fatty acids are degraded by oxidation of the carbon by -oxidation.
Pathway that removes 2-C units at a time acetyl CoA citric acid cycle ATP
There are three stages in -oxidation:
o Activation of fatty acids in cytosol catalyzed by acyl CoA synthetase; two high energy
bonds are broken to produce AMP
o 2) Transport of fatty acyl CoA into mitochondria via carnitine shuttle
o 3) -oxidation - cyclic pathway in which many of the same enzymes are used repeatedly
(see pathway sheet)
-oxidation of odd chain and unsaturated fatty acids
Odd chain fatty acids undergo -oxidation until propionyl CoA is formed.
Propionyl CoA is then converted to succinyl CoA, which then enters the Krebs cycle.
See pathway sheet for details
Unsaturated fatty acids need two additional enzymes besides those of -oxidation.
o enoyl-CoA isomerase
o 2,4-dienoyl-CoA reductase
How the pathway looks depends upon the location of the double bond, but there are two
See pathway sheets for details.
ATP generation from Fatty Acid Oxidation:
Can be estimated from the amount of acetyl CoA, QH , 2nd NADH produced.
See pathway sheet.
Regulation of Fatty Acid Oxidation
Already talked about fatty acid mobilization via epinephrine.
Net result is high concentrations of acetyl CoA and NADH via -oxidation.
Both molecules allosterically inhibit pyruvate dehydrogenase complex.
Most of acetyl CoA produced goes to Krebs cycle; during periods of fasting, excess acetyl CoA is
produced, too much for Krebs cycle.
2 Also in diabetes, oxaloacetate is used to form glucose by gluconeogenesis --> concentration of
oxaloacetate is lowered.
Result is the diversion of acetyl CoA to form acetoacetate and 3-hydroxybutyrate; these two
molecules plus acetone are known as ketone bodies.
Acetoacetate is formed via the following reactions:
CoA CoA acetyl CoA
2 acetyl CoA 3-hydroxy- acetoacetate
NADH + H + -hydroxy H
NAD butyrate CO 2