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 acidsKetone 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
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 H 2 C-OH | O=C O | | H 2 C-O-P-O - || O - H 2 C-OH | HOCH O | | H 2 C-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 + H 2 O 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
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.