Download Triacylglycerol Metabolism Gone Bad: A major cause of disease

Propionate metabolism
Some amino acids
Propionyl-CoA
Odd chain fatty acids
CO2
D-methylmalonyl-CoA
Coenzyme B12
deoxyadenosine
Vitamin B12
Requires
biotin
L-methylmalonyl-CoA
Requires
Coenzyme B12
Succinyl-CoA
Propionic acid metabolism
• Oxidation of an odd chain fatty acid results
in the production of one propionyl-CoA.
• The conversion of propionyl-CoA to
succinyl-CoA requires vitamin B12.
• Vitamin B12 deficiency can lead to
permanent neurological problems due to a
build up of metabolites of methylmalonate.
• Vitamin B12 deficiency can also lead to
pernicious anemia (covered later in the
course).
LIVER
Glucose
Ketone bodies
Glucose
Fatty acids
Glycerol
VLDL
TCA cycle
FED FASTING
Glucose can
can NOT be made
from fatty acids
Roles of Various Tissues in TG metabolism:
MUSCLE
Glucose
Glucose
Fatty acids Ketone bodies
Acetyl-CoA
Lactate
(anaerobic)
TCA cycle
(aerobic)
Not possible
FED FASTING
PPAR
• Fibrates (lipid lowering drugs) upregulate PPAR.
– Increase synthesis of muscle and liver genes
involved in fatty acid uptake and oxidation.
• Study Problem:
When fasting, mice that lack the PPAR gene,
–
–
–
–
become hypoketonemic.
become hypoglycemic.
have elevated plasma levels of free fatty acids.
have elevated VLDL
Explain each of the above observations in terms
of the relevant biochemical pathways
BRAIN
Fatty acids
Glucose
Glucose
Ketone bodies
Acetyl-CoA
TCA cycle
FED FASTING
Not
metabolized
ADIPOSE
VLDL
(liver)
Lipoprotein
Lipase
Chylomicrons
(intestine)
Fatty acids
Fatty acids
Triacylglycerol
Glucose
Glycerol
FED FASTING
Triacylglycerol Storage
• Fatty acids are released from triacylglycerol in VLDL
and chylomicrons by the action of Lipoprotein lipase.
– L.P. lipase is an extracellular enzyme, located on the
endothelial wall. It is teathered to heparin.
– L.P. Lipase is made in adipocytes (as well as other cells).
Insulin stimulates the secretion of L.P. Lipase.
• The fatty acids that are generated are taken up by
nearby cells or transported as a complex with serum
albumin
Triacylglycerol Storage
• Glycerol-3-phosphate is required for
triacylglycerol synthesis.
H2C-OH
|
HOCH O
|
|
H2C-O-P-O ||
O-
H2C-OH
|
O=C O
|
|
H2C-O-P-O ||
O-
Dihydroxyacetone Phosphate
NADH + H+
Glycerol-3-phosphate
NAD+
Glycerol-3-phosphate dehydrogenase
Triacylglycerol Storage
• In adipose, glucose metabolism is required for
the synthesis of triacylglycerol.
• Glucose is taken up via the GLUT-4 transporter
• Glucose uptake is increased by insulin
(mobilization of GLUT-4)
Triacylglycerol Storage
• Fatty acids must be activated to Acyl-CoA
Fatty acid + CoA + ATP
Acyl-CoA + AMP + PPi
Fatty acyl-CoA synthetase
PPi + H2O
2 Pi
Pyrophosphatase
Triacylglycerol Storage
• Addition of 3 Acyl groups from Acyl-CoA
to Glycerol-3-phosphate
O
||
O H2C - O - C - R1
||
|
R2 - C - O - CH
|
H2C - O - C - R3
||
O
H2C-OH
|
HO-CH O |
|
H2 C-O-P-O ||
O-
Glycerol-3-phosphate
2 Acyl-CoA
Phosphatidate
CoA
Acyl-CoA
Triacylglycerol
CoA + Pi
Triacylglycerol Storage
Capillary
Adipocyte
+
Insulin
GLUT-4
Glucose
CM or
VLDL
+
To liver
& kidney
Lipoprotein
lipase
Glycerol
+
3 Fatty acid
Glucose
Glycerol-3-phosphate
H2O P1 + 3 CoA
Triacylglycerol
Triacylglycerol
3 Acyl-CoA
3 AMP + 3 PPi
Acyl CoA
Synthetase
3 ATP + 3 CoA
3 Fatty acid
Fatty acid mobilization
Adipocyte
Insulin
-
Triacylglycerol
Adipose triacylglycerol lipase
Fatty acid
Hormone sensitive lipase
Insulin
Catecholamines
(from adipose
tissue neuroins)
1,2-Diacylglycerol
+
Hormone sensitive lipase
Fatty acid
2-Monoacylglycerol
Monoglycerol lipase
Glycerol
Fatty acid
Blood
Fatty acid mobilization
• The rate controling step is the hydroysis of
triacylglycerol by hormone sensitive lipase to
form 2-monoacylglycerol. Other unregulated
lipases release the remaining fatty acid.
• Fatty acids and glycerol are released into the
blood.
• Fatty acids are transported bound to albumin
Fatty acid mobilization
Regulation of hormone sensitive lipase
• Perilipin and hormone sensitive lipase interact when
phosphorylated. Their interaction is necessary for triacylglycerol
mobilization.
• Regualtion is primarily via dephosphorylation catalyzed by
insulin-stiulated phosphatases
• Phosphorylation inactivates. It is catalyzed by PKA that is
stimulated by epinepherine and norepinepherine produced by
nerves that inervate adipose tissue.
Fatty acid mobilization
•Another regulated lipase, adipose triacylglycerol lipase,
also participates in triacylglycerol mobilization.
•Adipose triacylglycerol lipase hydrolyzes fatty acid
from the 1-position.
•Transcription of the adipose triacylglycerol lipase gene is
Repressed by insulin.
Fatty acid mobilization
Catecholamines
Insulin
ATP
+
Adenylate
cyclase
AMP
Pi
+
Phosphodiesterase
ppi
H2O
cAMP
Triacylglyerol droplet
P
+
Triacylglyerol droplet
P
Protein kinase A
ATP
ADP
P
ATG
L
ATG
L
P
P
HSL
P
P
Pi
H2O
P
P
HSL
HSL
P
HSL
Phosphatases
+
P
P
P
ATG
L
P
Starved State
(accelerated lipolysis)
Fed State
(minimal lipolysis)
Insulin
HSL
ATG
L
P
Hormone sensitive
Lipase
Adipose triacylglycerol
lipase
Fatty acid mobilization
• Insulin decreases triacylglycerol mobilization
– Insulin inactivates hormone sensitive lipase
– Insulin represses adipose triacylglycerol lipase
synthesis
• Insulin stimulates triacylglycerol synthesis for
storage
– glucose uptake increased by GLUT
– fatty acid uptake increased by L.P Lipase action
Fatty acid mobilization
• Adipose under normal conditions has no
glycerol kinase.
• Since glycerol can not be recycled, the
resynthesis of triacylglycerol is inhibited during
fatty acid mobilization
VLDL
(liver)
Chylomicrons
(intestine)
Control by
Hormone sensitive lipase
Insulin  mobilization
L.P.Lipase
Fatty acids
Fatty acids
Triacylglycerol
Glucose
Glycerol
Control by
GLUT-4 & L.P.Lipase
Insulin  uptake
FED FASTING
Albumin