Metabolism
on-line - the virtual tutorial room
copyright © 2008 - 2015 David A Bender
Not an ounce of fat on her - and extreme emaciation in patient with advanced cancer
Not an ounce of fat on her - and extreme emaciation in patient with advanced cancer
Key points from this exercise:
The glycerol moiety of triacylglycerol arises from glycerol 3-phosphate, which is formed by reduction of the glycolytic intermediate dihydroxyacetone phosphate.
Fatty acids are bound to serum albumin in the bloodstream, and esterified with either carnitine or CoA in cells because free fatty acids will lyse cell membranes and precipitate insoluble calcium salts.
Fatty acids are activated for triacylglycerol synthesis by esterification with CoA. There is a cost equivalent to 2 x ATP for each mol of fatty acid esterified to form acyl CoA, because the reaction involves the hydrolysis of ATP to AMP and pyrophosphate.
The sequence of reactions in triacylglycerol synthesis is as follows:
A fatty acid from acyl CoA is esterified to carbon-1 of glycerol phosphate, forming 1-monoacylglycerol 3-phosphate (also known as lysophosphatidic acid). This is commonly a saturated fatty acid because glycerol 3-phosphate 1-acyltransferase has a higher affinity for, or activity towards, saturated rather than unsaturated fatty acids.
A fatty acid from acyl CoA is esterified to carbon-2 of 1-monoacylglycerol 3-phosphate, forming diacylglycerol 3-phosphate (also known as phosphatidic acid). This is commonly a polyunsaturated fatty acid. This is because lysophosphatidic acid 2-acyltransferase has a higher affinity for, or activity towards, polyunsaturated rather than saturated fatty acids.
Diacylglycerol 3-phosphate is hydrolysed to diacylglycerol, then a third fatty acid from fatty acyl CoA is esterified to carbon-3 of the glycerol, forming a triacylglycerol. This is commonly a saturated fatty acid. This is because diacylglycerol 3-acyltransferase has a higher affinity for, or activity towards, saturated rather than unsaturated fatty acids.
Diacylglycerol 3-phosphate (phosphatidic acid) is also the precursor of membrane and other phospholipids.
The enzyme that catalyses the esterification of 1-monoacylglycerol 3-phosphate, forming diacylglycerol 3-phosphate (lysophosphatidic acid 2-acyltransferase) is inactive in the adipose tissue of patients with congenital generalised lipodystrophy, but the liver enzyme is unaffected. Deficiency of the liver enzyme would almost certainly be lethal early in fetal development because of the severe impairment of phospholipid synthesis.
Patients with congenital generalised lipodystrophy have negligible reserves of subcutaneous and abdominal adipose tissue because adipose tissue is unable to esterify fatty acids to form triacylglycerol. They have hypertriglyceridaemia because triacylglycerol in chylomicrons and that exported from the liver in very low density lipoprotein cannot be used by adipose tissue for triacylglycerol synthesis, and fatty acids arising from lipoprotein lipase activity in the circulation are returned to the liver for re-esterification and re-export in very low density lipoprotein. There is also accumulation of triacylglycerol in droplets in the liver - hepatic steatosis. Patients appear very muscular partly because of the lack of adipose tissue over their muscles and partly due to increased uptake of fatty acids into muscle reserves of triacylglycerol, because of the high circulating concentration of triacylglycerol in chylomicrons and very low density lipoprotein.
In advanced cancer patients are hypermetabolic partly because of activation of hormone sensitive lipase in adipose tissue by a proteoglycan secreted by the tumour; this leads to release of non-esterified fatty acids that are re-esterified in the liver, at a cost of 2 x ATP per fatty acid (or 6 x ATP per mol of triacylglycerol).