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

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 Glucose can can NOT be made from fatty acids FED FASTING

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

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

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

ADIPOSE VLDL Chylomicrons (liver) (intestine) Lipoprotein Lipase 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 Glycerol-3-phosphate NADH + H+ 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 Glycerol-3-phosphate Phosphatidate Triacylglycerol 2 Acyl-CoA CoA Acyl-CoA CoA + Pi

Triacylglycerol Storage

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 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

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

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