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Propionate metabolism
Propionyl-CoA
Some amino acids
Odd chain fatty acids
D-methylmalonyl-CoA
L-methylmalonyl-CoA
Succinyl-CoAVitamin B12
deoxyadenosine
CO2
Requires biotin
RequiresCoenzyme B12
Coenzyme B12
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
Fatty acids
Ketone bodies
VLDL
Glycerol
Glucose
FED FASTING
Glucose can can NOT be made
from fatty acids
TCA cycle
Roles of Various Tissues in TG metabolism:
MUSCLE
Fatty acids Ketone bodiesGlucose
FED FASTING
Acetyl-CoA
TCA cycle (aerobic)
Lactate(anaerobic)
Glucose
Not possible
• 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
PPAR
ADIPOSE
Glucose
Fatty acids Fatty acids
Triacylglycerol
Glycerol
FED FASTING
VLDL Chylomicrons(liver) (intestine)
Lipoprotein Lipase
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.
Dihydroxyacetone Phosphate Glycerol-3-phosphate
NADH + H+ NAD+
Glycerol-3-phosphate dehydrogenase
H2C-OH |O=C O | | H2C-O-P-O -
|| O -
H2C-OH |HOCH O | | H2C-O-P-O -
|| O -
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
Glycerol-3-phosphate Phosphatidate Triacylglycerol
2 Acyl-CoA CoA Acyl-CoA CoA + Pi
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 -
Triacylglycerol Storage
Adipocyte Capillary
CM or VLDL
Glycerol +
3 Fatty acid
To liver & kidney
3 Fatty acid
3 Acyl-CoA
Glucose Glucose
Glycerol-3-phosphate
3 AMP + 3 PPi 3 ATP + 3 CoA
H2O P1 + 3 CoA
Triacylglycerol +
Insulin +
GLUT-4
Lipoprotein lipase
Acyl CoA Synthetase
Triacylglycerol
Insulin -
-
+
Insulin
Catecholamines (from adipose
tissue neuroins)
Triacylglycerol
2-Monoacylglycerol
Glycerol
Fatty acid
Fatty acid
Fatty acid
1,2-Diacylglycerol
Adipocyte
Hormone sensitive lipase
Adipose triacylglycerol lipase
Hormone sensitive lipase
Monoglycerol lipase
Blood
Fatty acid mobilization
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 mobilizationRegulation 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
Fed State (minimal lipolysis)
Starved State (accelerated lipolysis)
P
P
P
P
HSL
HSL
Triacylglyerol droplet
P
P
P
P
P
P
P
P
ATGL ATG
L
HSL
P
HSL
P
Triacylglyerol droplet
Insulin Catecholamines
+
ATGL
ATP ADP
Hormone sensitive Lipase Adipose triacylglycerol lipase
HSL
ATGL P
cAMP
+
ATP
ppi
Pi H2O
+
Pi H2O
+
Insulin
Phosphodiesterase
AMP
Phosphatases
Protein kinase A
Adenylate cyclase
-
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