Propionate metabolism Propionyl-CoA Some amino acids Odd chain fatty acids D-methylmalonyl-CoA L-methylmalonyl-CoA Succinyl-CoA Vitamin B12 deoxyadenosine.

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

BRAIN

Fatty acids

Ketone bodiesGlucose

FED FASTING

Acetyl-CoA

TCA cycle

Glucose

Not metabolized

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 -


• 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)


• 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


• 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 -


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


• 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.


•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.


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

-


• 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


• Adipose under normal conditions has no glycerol kinase.

• Since glycerol can not be recycled, the resynthesis of triacylglycerol is inhibited during fatty acid mobilization

Glucose

Fatty acids Fatty acids

Triacylglycerol

Glycerol

FED FASTING

VLDL Chylomicrons(liver) (intestine)

L.P.Lipase

Control byHormone sensitive lipase

Insulin mobilization

Control by GLUT-4 & L.P.Lipase

Insulin uptake

Albumin

Propionate metabolism Propionyl-CoA Some amino acids Odd chain fatty acids D-methylmalonyl-CoA L-methylmalonyl-CoA Succinyl-CoA Vitamin B12 deoxyadenosine.

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