Transcript Lecture 35 - Lipid Metabolism 1

Lipid Metabolism 1:
Overview of lipid transport in animals, fatty acid
oxidation, ketogenesis in liver mitochondria
Bioc 460 Spring 2008 - Lecture 35 (Miesfeld)
Prime rib contains large
amounts of saturated fats in
the form of triacylglycerols
Adipose tissue is the primary
triacylglycerol storage depot in
animals, fats are an excellent
form of redox energy
Stored fat comes from the
conversion of carbohydrates
into fatty acids in the liver
Key Concepts in Lipid Metabolism
• Stored lipids is the primary source of energy in most organisms.
• The three sources of triacylglycerols in animals are dietary lipids, stored
triacylglycerols in adipose tissue, and fatty acids synthesized in the liver.
 -oxidation is the mitochondrial process by which fatty acids are
oxidized to yield NADH, FADH2, and acetyl-CoA.
• Ketogenesis takes place in liver mitochondria when acetyl-CoA levels
are high and oxaloacetate levels are low.
Overview of Lipid Transport in Animals
Fat is stored in fat cells
(adipocytes). Obesity,
especially childhood obesity,
can be due to both more fat
storage per cell, and to a
larger number of adipocytes.
Not all fat is the same
Review of lipid structures:
Fatty acids are stored as triacylglycerols
Glycerol
Fatty acid #2
Fatty acid #1
Fatty acid #3
Glycerol esterification of fatty acids
protects cell membranes from the
amphipathic nature of fatty acids. Soap
is made out of fatty acids and works well
to remove oils from hands and clothes by
forming micelles that trap the lipids in a
water soluble particle.
Homemade soap is made from animal fat
Soap is made from fatty acids through a
process called saponification. Fatty acids
are amphipathic molecules that break up
grease by partitioning the fat and water into
micelles.
Saponification neutralizes the fatty acid
carboxylate group with Na+, however, Mg2+
and Ca2+ ions present in "hard" water cause
the formation of fatty acid precipitates called
soap scum.
Lipid Metabolism
Lipid Metabolism
Pathway Questions
1. What purpose does fatty acid metabolism serve in animals?
– Fatty acid oxidation in mitochondria is responsible for providing
energy to cells when glucose levels are low. Triacylglycerols
stored in adipose tissue of most humans can supply energy to
the body for ~3 months during starvation.
– Fatty acid synthesis reactions in the cytosol of liver and adipose
cells convert excess acetyl CoA that builds up in the
mitochondrial matrix when glucose levels are high into fatty
acids that can be stored or exported as triacylglycerols.
Pathway Questions
2. What are the net reactions of fatty acid degradation and
synthesis for the C16 fatty acid palmitate?
Fatty acid oxidation:
Palmitate + 7 NAD+ + 7 FAD + 8 CoA + 7 H2O + ATP →
8 acetyl CoA + 7 NADH + 7 FADH2 + AMP + 2 Pi + 7 H+
Fatty acid synthesis:
8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H+ →
Palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP+ + 6 H2O
Pathway Questions
3. What are the key enzymes in fatty acid metabolism?
Fatty acyl CoA synthetase – enzyme catalyzing the "priming" reaction in
fatty acid metabolism which converts free fatty acids in the cytosol into
fatty acyl-CoA using the energy available from ATP and PPi hydrolysis.
Carnitine acyltransferase I - catalyzes the commitment step in fatty acid
oxidation which links fatty acyl-CoA molecules to the hydroxyl group of
carnitine. The activity of carnitine acyltransferase I is inhibited by malonylCoA, the product of the acetyl-CoA carboxylase reaction, which signals
that glucose levels are high and fatty acid synthesis is favored.
Pathway Questions
3. What are the key enzymes in fatty acid metabolism?
Acetyl CoA carboxylase - catalyzes the commitment step in fatty acid
synthesis using a biotin-mediated reaction mechanism that carboxylates
acetyl-CoA to form the C3 compound malonyl-CoA. The activity of acetyl
CoA carboxylase is regulated by both reversible phosphorylation (the
active conformation is dephosphorylated) and allosteric mechanisms
(citrate binding stimulates activity, palmitoyl-CoA inhibits activity).
Fatty acid synthase - this large multi-functional enzyme is responsible for
catalyzing a series of reactions that sequentially adds C2 units to a
growing fatty acid chain covalently attached to the enzyme complex. The
mechanism involves the linking malonyl-CoA to an acyl carrier protein,
followed by a decarboxylation and condensation reaction that extends the
hydrocarbon chain.
Pathway Questions
4. What are examples of fatty acid metabolism in real life?
A variety of foods are prominently advertised as "non-fat," even though they
can contain a high calorie count coming from carbohydrates. Eating too
much of these high calorie non-fat foods (e.g., non-fat bagels) activates the
fatty acid synthesis pathway resulting in the conversion of acetyl-CoA to
fatty acids, which are stored as triacylglycerols.
Transport and storage of fatty acids and triacylglycerols
Transport and storage of fatty acids and triacylglycerols
The fatty acid  oxidation pathway in mitochondria
Fatty acid are transported into mitochondria by carnitine
Carnitine acyltransferase I replaces CoA with carnitine to form fatty acyl
carnitine which is translocated across the inner mitochondrial membrane
by the carnitine translocating protein. Lastly, carnitine acyltransferase II
release the carnitine and it is shuttled back across the membrane.
-oxidation yields
large amounts of ATP
The energy conversion
process of fatty acid --> ATP
involves oxidation of fatty
acids by sequential
degradation of C2 units
leading to the generation
FADH2, NADH, and acetyl
CoA.
Palmitate
(C16)
The subsequent oxidation of
these reaction products by the
citrate cycle and oxidative
phosphorylation generates
lots of ATP.
106 ATP - WOW!
-oxidation reactions
OXIDATION
The -oxidation pathway occurs
at the  carbon of the fatty acid,
thereby releasing the C-1
carboxyl carbon and  carbon
as the acetate component of
acetyl CoA.
HYDRATION
OXIDATION
THIOLYSIS
-oxidation reactions for palmitate (C16)
Palmitoyl-CoA + 7 CoA + 7 FAD + 7 NAD+ + 7 H2O -->
8 acetyl CoA + 7 FADH2 + 7 NADH + 7 H+
ATP currency exchange ratios
31 NADH (31 x ~2.5 ATP) = ~77.5 ATP
15 FADH2 (15 x ~1.5 ATP) = ~22.5 ATP
For a grand total = 100 ATP
After subtracting the 2 ATP required for fatty acyl CoA
activation (AMP --> PPi)
And adding the 8 ATP obtained from eight turns of the
citrate cycle;
The total payout for the complete oxidation
of palmitate is 106 ATP
-oxidation is a chemical source of water for desert animals
Besides the payout of ATP that comes from fatty acid oxidation,
another benefit is the generation of H2O that occurs when O2 is
reduced by the final reaction in the electron transport system, as well
as, the formation of H2O in oxidative phosphorylation.
2 NADH + 2 H+ + O2 --> 2 H2O
2 FADH2 + O2 --> 2 H2O
ADP + PO42- --> ATP + H2O
Ketogenesis
When fatty acid oxidation produces
more acetyl-CoA than can be combined
with OAA to form citrate, then the
"extra" acetyl-CoA is converted to
acetoacetyl-CoA and ketone bodies,
including acetone. Ketogenesis
(synthesis of ketone bodies) takes
place primarily in the liver.
Ketogenesis
Acetyl-CoA derived from fatty acid oxidation enters
the Citrate Cycle only if carbohydrate metabolism
is properly balanced.
When fatty acid oxidation produces more acetylCoA than can be combined with OAA to form
citrate, then the "extra" acetyl-CoA is converted
to acetoacetyl-CoA and ketone bodies, including
acetone. Ketogenesis (synthesis of ketone bodies)
takes place primarily in the liver.
Ketones are an energy
source for tissues
How many total ATP
from 2 acetyl-CoA?
6 NADH
2 FADH2
2 GTP
15 ATP
3 ATP
2 ATP
20 ATP
Ok, now what
happens to these
two acetyl-CoA?
per Acetyl-CoA
PowerPoint slide from lecture 28
Ketogenesis occurs when glycogen
stores are depleted such as during
fasting and in undiagnosed diabetics
Diabetics can have high
levels of acetone in their
blood which can be
detected on their breath as
a fruity odor. Acetone is a
spontaneous breakdown
product of acetoacetate
(decarboxylation), or it is
formed by enzymatic
cleavage of acetoacetate by
the enzyme acetoacetate
decarboxylase.