Download Lipid Metabolism: Power Point presentation

Fat Mobilization
Fat mobilization
• Breaks down triacylglycerols
in adipose tissue.
• Forms fatty acids and glycerol.
• Hydrolyzes fatty acid initially
from C1 or C3 of the fat.
triacylglycerols + 3 H2O
glycerol + 3 fatty acids
Triacylglycerol lipase inhibited by insulin,
stimulated by glucagon and epinephrine.
Metabolism of Glycerol
glyerol
kinase
H2C OH
H2C OH
C OH + ATP
H2C OH
glycerol
C OH O
glycerol
transported
to the liver
+
ADP
H 2C O P O Oglycerol-3-phosphate
NAD+
dehydrogenase
NADH + H+
H2C OH
C O O
dihydroxyacetone phosphate
H2C O P O Oglycolysis
gluconeogenesis
Fatty Acid Oxidation
Activation
H2O
O
RCH2CH2CH2C OH + HS
ATP
CoA
AMP + PPi
acyl-CoA
synthetase
2 Pi
O
RCH2CH2CH2C SCoA
Occurs in the cytoplasm
Requires the input of 2 ATP equivalents
Fatty Acid Oxidation
Transport Across Mitochondrial Membrane
CoASH
carnitine
carnitine
CoASH
Fatty Acid Oxidation
First Oxidation: Double Bond Formation
O
RCH2CH2CH2C SCoA + FAD
O
RCH2CH CH C
Addition of Water to the Double Bond
SCoA + FADH2
Fatty Acid Oxidation
Second Oxidation: Ketone Formation
OH H
O
RCH2CH CH C
SCoA + NAD +
O
O
RCH2C
CH2 C
SCoA + NADH + H +
Cleavage Step
O
O
RCH2C
CH2 C
SCoA + HS
CoA
O
O
RCH2C
SCoA + CH3 C
SCoA
acetyl–CoA
These four reactions (oxidation, hydration, oxidation, cleavage)
repeat removing two carbons at a time, producing acetyl–CoA.
Fatty Acid Oxidation Cycle
O
FAD
FADH2
RCH2CH2CH2C SCoA
Cycle repeats, removing
two carbons each time and
making acetyl-CoA, FADH2,
and NADH.
first
oxidation
H2O
hydration
OH H
O
RCH2CH CH C
cleavage
acetyl–CoA
HSCoA
second
oxidation
NAD+
NADH + H+
SCoA
Fatty Acid Oxidation
Summary of fatty acid oxidation for stearic acid (C18:0)
Number of cycles required = 8
First oxidation x 8:
8 FADH2 =
16 ATP
Second oxidation x 8:
8 NADH =
24 ATP
Eight cycles yields 9 acetyl-CoA
1 acetyl-CoA = 3 NADH,
1 FADH2, 1GTP = 12 ATP
Acetyl-CoA x 9 =
108 ATP
Initial activation cost =
(2 ATP)
Net energy produced =
146 ATP
Other Roles of Acetyl–CoA:
Precursor of Sterols, Steroids, and Ketone Bodies
First condensation
sterols, steroids
Second condensation
HMG-CoA
reductase
(inhibited by statins)
CO2
NADH + H+
ketone bodies
NAD+
Lipogenesis: Fatty Acid Synthesis
Lipogenesis
Is the synthesis of fatty acids from acetyl CoA.
Occurs in the cytosol.
Uses reduced coenzyme NADPH.
Requires an acyl carrier protein (ACP).
Fatty Acid Synthesis: Lipogenesis
CoASH
CO2
C
O
CH2
cytoplasm
CO2
ADP + Pi
intermembrane
space
matrix
ATP
Fatty Acid Synthesis
Activation of Acetyl–CoA
Acetyl–CoA
carboxylase
(coenzyme: biotin)
Acetyl CoA carboxylase is stimulated by insulin
and inhibited by glucagon and epinephrine
Transfer to Acyl Carrier Protein in Fatty Acid Synthase
Fatty Acid Synthesis
Condensation Reaction
First Reduction Reaction
Reducing agent is NADPH (corresponding oxidation reaction
in fatty acid oxidation pathway uses NAD+ as the oxidizing agent)
Fatty Acid Synthesis
Dehydration Reaction
Second Reduction Reaction
CH3 CH CH
O
C S ACP + NADPH + H+
CH3 CH2 CH2
O
C S ACP + NADP+
Reducing agent is NADPH (corresponding oxidation reaction
in fatty acid oxidation pathway uses FAD as the oxidizing agent)
This cycle repeats using another malonyl–ACP and adding two more carbons.
Fatty acid released after seven cycles.
Summary of Lipogenesis
Fatty Acid Length and
Unsaturation
In fatty acid synthesis
• Shorter fatty acids undergo fewer cycles.
• Longer fatty acids are produced from
palmitate using special enzymes.
• Unsaturated cis bonds are incorporated into
a 10-carbon fatty acid that is elongated
further.
Regulation of Fatty Acid Synthesis
In fatty acid synthesis
• A high level of blood glucose and insulin
stimulates glycolysis and pyruvate
oxidation.
• More acetyl CoA is available to form fatty
acids.
Fatty Acid Synthesis
Comparison of oxidation and biosynthesis
Reaction sequence:
Oxidation: oxidation hydration
oxidation
cleavage
Biosynthesis: reduction
dehydration
reduction
condensation
Electron acceptors and donors:
Oxidation: NAD+, FAD
Biosynthesis: NADPH
Cellular location:
Oxidation: inside mitochondrion
Biosynthesis: in cytoplasm
Energy produced or used for C16:0:
Oxidation: C16:0 8 acetyl–CoA
7 cycles = 7 NADH (21 ATP) + 7 FADH (14 ATP) – 2 ATP = 33 ATP
Biosynthesis: 8 acetyl–CoA
C16:0
Transport of 8 acetyl–CoA to cytoplasm: 8 ATP
Synthesis of 7 malonyl–CoA: 7 ATP
7 cycles: 14 NADPH (42 ATP)
Total required = 57 ATP
Synthesis of Triacylglycerols
Site: liver
Substrates:
Activated fatty acids
fatty acid + CoSASH + ATP
fatty acyl CoA + AMP + 2 Pi
Glycerol phosphate
from dihydroxyacetone phosphate
Reaction:
3 fatty acyl CoA + glycerol phosphate
triacylglycerol + Pi
Transport:
Assembled into very-low-density lipoprotein complexes (VLDL) and
these used to transport fatty acids to tissues for fuel and to adipocytes
for storage.