1. Propionate metabolism
Some amino acids
Propionyl-CoA
Odd chain fatty acids
CO2
Requires
biotin
D-methylmalonyl-CoA
Coenzyme B12
L-methylmalonyl-CoA
Requires
Coenzyme B12
deoxyadenosine
Succinyl-CoA
Vitamin B12

2. 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).

3. LIVER Glucose Ketone bodies Glucose Fatty acids Glycerol VLDL
TCA cycle
Glucose can
can NOT be made
from fatty acids
FED FASTING

4. Roles of Various Tissues in TG metabolism: MUSCLE
Glucose
Fatty acids
Ketone bodies
Glucose
Acetyl-CoA
Lactate
(anaerobic)
TCA cycle
(aerobic)
FED FASTING
Not possible

5. PPAR Study Problem: When fasting, mice that lack the PPAR gene,
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

6. BRAIN Fatty acids Glucose Glucose Ketone bodies Not metabolized
Acetyl-CoA
TCA cycle
FED FASTING

7. ADIPOSE VLDL Chylomicrons (liver) (intestine) Lipoprotein Lipase
Fatty acids
Fatty acids
Triacylglycerol
Glucose
Glycerol
FED FASTING

8. 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

9. 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 Glycerol-3-phosphate
NADH + H NAD+
Glycerol-3-phosphate dehydrogenase

10. 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)

11. Triacylglycerol Storage
Fatty acids must be activated to Acyl-CoA
Fatty acid + CoA + ATP Acyl-CoA + AMP + PPi
Fatty acyl-CoA synthetase
PPi + H2O Pi
Pyrophosphatase

12. 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

13. Triacylglycerol Storage

14. Fatty acid mobilization

15. 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

16. 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.

17. 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.

18. Fatty acid mobilization

19. 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

20. 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

21. Hormone sensitive lipase Insulin  mobilization
Control by
Hormone sensitive lipase
Insulin  mobilization
VLDL Chylomicrons
(liver) (intestine)
L.P.Lipase
Albumin
Fatty acids
Fatty acids
Triacylglycerol
Glucose
Glycerol
Control by
GLUT-4 & L.P.Lipase
Insulin  uptake
FED FASTING