Transcript Document

BIOC 460 - DR. TISCHLER LECTURE 33
LIPOLYSIS: FAT OXIDATION & KETONES
OBJECTIVES
1. Lipolysis
a) describe the pathway;
b) location
c) principal enzyme
d) role
e) role of albumin and FABP in transport/metabolism of FFA
2. Degradation of fatty acyl CoA
a) roles of acyl CoA synthetase, CPT-I and CPT-II, and CAT
b) relationship of -oxidation products to energy production.
c) degradation of odd- vs even-chain FA
d) vitamins for metabolizing propionyl CoA to succinyl CoA
3. Ketone body metabolism
a) where ketogenesis occurs
b) when ketogenesis occurs
c) role of keotgenesis
d) why normal individuals do not usually develop ketacidosis
even when producing ketone bodies.
FAT FACTS
fat (lipid) makes up 37% of the calories in the American
diet
energy rich and provides 9 kcal/gm
dietary lipids 90% triacylglycerols (TAGs) also include
cholesterol esters, phospholipids, essential
unsaturated fatty acids; fat-soluble vitamins
most dietary fat transported to adipose for storage
dietary TAGs hydrolyzed in the intestine by pancreatic
lipases; then reassembled in the intestinal cells
dietary fats transported to tissues as TAG or cholesterol
via chylomicrons
at peripheral tissues (e.g., adipose or muscle), FA removed
from the TAG by a lipoprotein lipase in the capillary
walls; released fatty acids diffuse into the cell
saturated fatty acid:
unsaturated fatty acid:
polyunsaturated fatty acid:
CH3-(CH2)n-COOH
CH3-CH=CH-(CH2)n-COOH
CH3-CH=CH-CH2-CH=CH-(CH2)n-COOH

CH2----OOC-R1
 |
HOOC-R1
|
Lipolysis
R2-COO----CH
|
CH2OH

CH2----OOC-R3
Triacylglycerol
CHOH
HOOC-R2
|
CH2OH
Glycerol
HOOC-R3
Fatty acids
Figure 1. General structures of fatty acids and
triacylglycerol. Lipolysis of stored triacylglycerol by
lipases produces fatty acids plus glycerol.
LIPOLYSIS
fatty acids hydrolytically cleaved from triacylglycerol
largely in adipose to release fatty acids as a fuel
may also occur in muscle or liver - smaller amounts of
fatty acids are stored
hormone-sensitive (cyclic AMP-regulated) lipase
initiates lipolysis – cleaves first fatty acid
this lipase and others remove remaining fatty acids
fatty acids/glycerol released from adipose to the blood
hydrophobic fatty acids bind to albumin, in the blood,
for transport
CAPILLARY
Lipoproteins
(Chylomicrons
or VLDL)
FA
FA
albumin
FA
[1]
from
fat
cell
L
P
L
[2]
FA
FABP
FA
MITOCHONDRION
acetyl-CoA TCA [7]
cycle
A
[3]
[4] C
-oxidation
[6]
S
FA
acyl-CoA
acyl-CoA
FABP
FABP
[5]
carnitine
CYTOPLASM
transporter
cell membrane
FA = fatty acid
LPL = lipoprotein lipase
FABP = fatty acid binding protein
ACS = acyl CoA synthetase
Figure 2. Overview of fatty acid degradation
ATP + CoA
AMP + PPi
palmitate
palmitoyl-CoA
Cytoplasm
ACS
CPT-I
[2]
[1]
CoA
palmitoyl-CoA
Intermembrane
Space
OUTER
MITOCHONDRIAL
MEMBRANE
carnitine
palmitoyl-carnitine
Figure 3 (top). Activation of palmitate to palmitoyl CoA
(step 4, Fig. 2) and conversion to palmitoyl carnitine
CPT-I
palmitoyl-CoA
Intermembrane Space
CoA
palmitoyl-carnitine
carnitine
CAT
[3]
INNER
MITOCHONDRIAL
MEMBRANE
CPT-II
Matrix
carnitine
palmitoyl-carnitine
[4]
palmitoyl-CoA
CoA
Figure 3 (bottom). Mitochondrial uptake via of palmitoylcarnitine via the carnitine-acylcarnitine translocase (CAT)
(step 5 in Fig. 2).
ATP + CoA AMP + PP
i
palmitate
Cytoplasm
palmitoyl-CoA
ACS
[1]
OUTER
MITOCHONDRIAL
MEMBRANE
CPT-I
[2]
CoA
palmitoyl-CoA
carnitine
Intermembrane
Space
palmitoyl-carnitine
CAT
[3]
INNER
MITOCHONDRIAL
MEMBRANE
CPT-II
Matrix
carnitine
palmitoyl-carnitine
[4]
palmitoyl-CoA
CoA
Palmitoylcarnitine
Carnitine
translocase
inner mitochondrial
membrane
matrix side
respiratory chain
Palmitoylcarnitine
2 ATP
3 ATP
Palmitoyl-CoA
FAD
oxidation
FADH2
H2O
hydration
recycle
6 times
oxidation
NAD+
Figure 4.
Processing and
-oxidation of
palmitoyl CoA
NADH
cleavage
CoA
CH3-(CH)12-C-S-CoA + Acetyl CoA
O
Citric
acid
cycle
2 CO2
OXIDATION OF ODD-CHAIN FATTY ACIDS
Final step of -oxidation produces:
propionyl CoA + acetyl CoA
propionyl CoA carboxylase: (biotin-dependent)
propionyl CoA + ATP + CO2 
methylmalonyl CoA + AMP + PPi
methylmalonyl CoA mutase:
(adenosyl cobalamin-dependent)
methylmalonyl CoA  succinyl CoA
Figure 5. Reactions in the metabolism of propionyl
CoA derived from odd-chain fatty acids
Fatty acid
-oxidation
MITOCHONDRION
oxidation to
CO2
Thiolase
2 Acetyl CoA
(excess
acetyl CoA)
Citric
acid
cycle
CoA
Acetoacetyl CoA
acetyl CoA
Figure 6. Ketone
HMG-CoA synthase
body formation
CoA
(ketogenesis) in liver
Hydroxymethylglutaryl CoA
mitochondria from
excess acetyl CoA
HMG-CoA-lyase
derived from the - acetyl CoA
oxidation of fatty
Acetoacetate
acids
NADH
(non-enzymatic)
-Hydroxybutyrate
dehydrogenase
Acetone
NAD+
-Hydroxybutyrate
KETONE BODY OXIDATION
high rates of lipolysis (e.g., long-term starvation or in
uncontrolled diabetes) produce sufficient ketones in the
blood to be effective as a fuel
ketones are the preferred fuel if glucose, ketones, fatty acids
all available in the blood
primary tissues: using ketones, when available, are brain,
muscle, kidney and intestine, but NOT the liver.
-Hydroxybutyrate + NAD+  acetoacetate + NADH
-hydroxybutyrate dehydrogenase in mitochondria;
reverse of ketogenesis
KETOACIDOSIS
Excessive build-up of ketone bodies results in ketosis eventually
leading to a fall in blood pH due to the acidic ketone bodies.
In diabetic patients the events that can lead to ketosis are:
 Relative or absolute (most common cause) deficiency of insulin
 Mobilization of free fatty acids (from adipose lipolysis)
 Increased delivery of free fatty acids to the liver
 Increased uptake and oxidation of free fatty acids by the liver
 Accelerated production of ketone bodies by the liver
Adipose
Tissue
X
Free fatty
acids
Liver
Ketone Bodies
Insulin
Pancreas
Figure 7. Mechanism for prevention of ketosis due to
excess ketone body production that can lead to ketoacidosis