Metabolism
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Not an ounce of fat on her - and extreme emaciation in patient with advanced cancer
TGL is a 20 year old woman; she appears to be very muscular, with little or no subcutaneous adipose tissue and under-developed breasts. Over the last few years her abdomen has become more protuberant, and her liver is palpably enlarged. Blood tests revealed significant fasting hypertriglyceridaemia (plasma concentration of triacylglycerol 450 - 520 mmol /L on various occasions compared with a desirable range < 1.7 mmol /L). CAT scanning shows that she has very little subcutaneous or intra-abdominal adipose tissue.
She was
born at term after an unremarkable pregnancy, but even at birth she appeared
abnormally muscular, with very little subcutaneous adipose tissue. Her younger
brother is similarly affected, as are two distant cousins.
What conclusions can you draw from her pedigree?
This is almost certainly a genetic condition, with an autosomal recessive pattern of inheritance.
If isolated adipocytes are incubated with fatty acids, they only synthesise triacylglycerol if they are also provided with glucose.
What is the most likely metabolite of glucose that will be the source of glycerol for triacylglycerol synthesis?
The most likely source of glycerol will be glycerol 3-phosphate, which arises as a result of the reduction of dihydroxyacetone phosphate, an intermediate in glycolysis.
How do you think fatty acids are "activated" in order to be esterified to glycerol 3-phosphate?
Remember that fatty acids are never in free solution in cells; they are always esterified to either CoA or carnitine. Fatty acyl carnitine is formed only to transport fatty acids into the mitochondrion for beta-oxidation (see the exercise on Muscle weakness, heart failure and profound hypoglycaemia in a young girl).
This means that fatty acids are activated for triacylglycerol synthesis by esterification with CoA.
Why is it important that fatty acids are not in free solution in the cell?
They would lyse membranes - soap is a mixture of sodium salts of fatty acids. They would also form insoluble precipitates with calcium ions.
If non-esterified fatty acids were in free solution in the bloodstream they would lyse red cell membranes and risk blocking blood vessels with precipitated calcium salts (as well as causing severe disturbance to plasma calcium ion concentrations.
How are non-esterified fatty acids transported in the bloodstream?
Non-esterified fatty acids are transported bound to serum albumin, which has a high affinity binding site for fatty acids.
How do you think the reaction of acyl CoA synthase is maintained as a unidirectional reaction?
One of the products of the reaction is pyrophosphate (PPi). Pyrophosphate is rapidly hydrolysed by pyrophosphatase, yielding two mol of inorganic phosphate. This means that one of the products of the reaction is unavailable to undergo the back reaction.
In order to investigate TGL's condition, biopsies of her (almost negligible) subcutaneous adipose tissue and liver were take, and were incubated with [14C]palmitate (C16:0) and [14C]linoleate (C18:2 n-6), together with glucose and insulin. Similar incubations were set up using adipose tissue and liver biopsy samples from a control subject. Esterified lipids were separated by high pressure liquid chromatography, and the radioactivity in each fraction was measured. The results were as follows (in dpm per mg DNA in the tissue samples ± sd for three replicate incubations):
| tissue | 1-monoacylglycerol phosphate
(lysophosphatidic acid) |
1,2-diacylglycerol phosphate (phosphatidic acid) |
phospholipids |
1,2-diacylglycerol |
triacylglycerol |
|
| control subject | hepatocytes | 1105 ± 65 |
2098 ± 87 |
2125 ± 120 |
2105 ± 95 |
15523 ± 150 |
| adipocytes | 1098 ± 70 |
2112 ± 90 |
420 ± 61 |
2126 ± 87 |
14952 ± 170 |
|
| TGL | hepatocytes | 1050 ± 75 |
2105 ± 115 |
2200 ± 110 |
2098 ± 120 |
14625 ± 262 |
| adipocytes | 1025 ± 80 |
122 ± 95 |
135 ± 75 |
120 ± 69 |
120 ± 50 |