Fasting long-chain fatty acid oxidation

The inhibition of CPT I by either POCA or MeTDGA caused a decrease in [ l4C]palmitate oxidation. MeTDGA effectively inhibited palmitate oxidation in kidney cortex slices [98], diaphragm [98], heart [99] and hepatocytes [ 100] from fasted rats. POCA produced an almost complete suppression of long-chain fatty acid oxidation in the perfused rat heart from either fed or fasted animals [101]. POCA also inhibited hepatocyte oxidation of oleate up to 85% with maximal effects of POCA observed at concentrations as low as 1 /xM... 

In both long-chain fatty add oxidation disorders (LCFAOD) and medium-chain fatty acid oxidation disorders (MCAD), emergency management of acute illness and the avoidance of prolonged fasting are key treatment strategies. 

When a long-chain fatty acid has finally been degraded to the C4 compound, butyrate (in the activated form), the next oxidation cycle in the 3-position produces acetoacetate—or more correctly, acetoacetyl-CoA. The reaction is reversible as many others are when acetyl-CoA is available in superabundance (e.g. during fasting, which causes the mobilization of fat reserves or in diabetes, where due to pathologically elevated production of acetyl-CoA not all of it is used up), then acetoacetyl-CoA is formed from 2 acetyl-CoA. ... 

One of the most frequent defects of fatty acid oxidation is deficiency of a mitochondrial acyl-CoA dehydrogenase.50 If the long-chain-specific enzyme is lacking, the rate of P oxidation of such substrates as octanoate is much less than normal and afflicted individuals excrete in their urine hexanedioic (adipic), octanedioic, and decanedioic acids, all products of co oxidation.54 Much more common is the lack of the mitochondrial medium-chain acyl-CoA dehydrogenase. Again, dicarboxylic acids, which are presumably generated by 0) oxidation in the peroxisomes, are present in blood and urine. Patients must avoid fasting and may benefit from extra carnitine. 

The very long-chain acyl-coenzyme A dehydrogenase (VLCAD) enzyme has substrate specificity for long-chain acyl-CoAs of 10-20 carbons. VLCAD is the main enzyme for acyl-CoAs of this chain length, and there is very little other enzyme activity. Therefore, mutations that completely abolish residual activity will result in a near complete block of fatty acid oxidation flux and can cause symptoms outside of fasting, often in the neonatal period. The majority of mutations of patients identified with VLCAD on newborn screening are mild and leave residual activity. These patients are still at risk for intermittent symptoms at times of increased fatty... 

Fatty acid oxidation disorders and ketone metabolism disorders often present with intermittent symptoms triggered by prolonged fasting. Avoidance of fasting is a key component of treatment, and its practical application requires continued education of parents to maintain vigilance. Symptoms of cardiac and skeletal muscle pose important problans particularly in patients with long-chain disorders, for which current treatment is only partially effective. 

McGarry et al. (1971) showed that, unlike oleate, octanoate was oxidized to ketone bodies at similar rates in livers from fasted and diabetic rats. Furthermore, studies with isolated mitochondria are consistent with a limitation of fatty acid oxidation at the transferase step (Fritz and Marquis, 1965). Carnitine acyltransferase I is probably as important as transferase II. The physiolgocial significance of the transferase step becomes more apparent when one considers that the majority of the free fatty acids circulating in the plasma during starvation are of the long-chain variety. Their oxidation to CO2 or to ketone bodies within the mitochondria ultimately depends on passage of the acylcarnitine across the inner mitochondrial membrane. 

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