| The elongation of a fatty acid chain beyond 16-carbon length requires another set of enzymes
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| Palmitate released from fatty acid synthase becomes a substrate for the synthesis of longer-chain fatty acids, with the exception of certain essential fatty acids (see below). Chain elongation occurs by the addition of further 2-carbon fragments derived from malonyl-CoA (Fig. 15.5). This process occurs on the endoplasmic reticulum by the action of yet another multienzyme complex, fatty acid elongase. The reactions occurring during chain elongation are similar to those involved in fatty acid synthesis, except that the fatty acid is attached to CoA, rather than to the ACP.
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| The substrates for the cytosolic fatty acid elongase include saturated fatty acids with a chain length from 10-carbon upwards, and also unsaturated fatty acids. Very-long-chain (22-24-carbon) fatty acids are produced in the brain, and elongation of stearoyl-CoA (C18) in the brain increases rapidly during myelination, producing fatty acids required for the synthesis of sphingolipids.
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| Fatty acids can also be elongated in the mitochondria, where a still different system is used: it is NADH-dependent and uses acetyl-CoA as a source of 2-carbon fragments. It is simply the reverse of β-oxidation (see Chapter 13) and the substrates for chain elongation are short- and medium-chain fatty acids containing fewer than 16 carbon atoms.
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| LIPID ABNORMALITIES IN ALCOHOLISM |
| A 36-year-old woman attending a well-woman clinic was found to have serum concentrations of triglyceride 73.0 mmol/L (6388 mg/dL) and cholesterol 13 mmol/L (503 mg/dL). After some initial prevarication she admitted to drinking three bottles of vodka and six bottles of wine per week. When she discontinued alcohol, her triglyceride concentrations decreased to 2 mmol/L (175 mg/dL) and her cholesterol concentration decreased to 5.0 mmol/L (193 mg/dL). Three years later, the woman presented again with an enlarged liver and return of the lipid abnormality. Liver biopsy indicated alcoholic liver disease with steatosis or infiltration of the liver cells with fat. |
| Comment. In alcoholic individuals, the metabolism of alcohol produces increased amounts of reduced hepatic nicotinamide adenine dinucleotide (NADH+). Increased NADH + H+/NAD+ ratios inhibit the oxidation of fatty acids. Fatty acids reaching the liver either from dietary sources or by mobilization from adipose tissue are therefore re-esterified with glycerol to form triglycerides. In the initial stages of alcoholism, these are packaged with apolipoproteins and exported as very-low-density lipoproteins (VLDL). Increased concentrations of VLDL, and hence of serum triglycerides, are often present in the early stages of alcoholic liver disease. As the liver disease progresses, there is a failure to produce the apolipoproteins and export the fat as VLDL; accumulation of triglycerides in the liver cells thus ensues. |
| During fasting and starvation, elongation of fatty acids is greatly reduced.
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