TRIGLYCERIDES AND FATTY ACIDS 85 



molecules of ketone bodies, as compared with 1.0 molecules for butyric acid. 

 Although Witter et al}^ reported this relationship for caproic acid and sorbic 

 acid (CH3-CH:CH-CH:CH-C00H) when these acids were incubated 

 with liver slices, Deuel and co-workers have found that a 1 : 1 ratio obtains 

 in vivo in the exogenous ketonuria of rats after the feeding of caproic 

 acid^^"'-^ or of sorbic acid.-- This might suggest that the direct formation 

 of acetoacetate was the most important change occurring in vivo, but that 

 the synthesis of acetoacetate may obtain in tissues in which the end- 

 products cannot be removed and in which the substrate remains in the 

 tissue for a long enough period to allow an equilibrium to be reached. 



Although the jS-oxidation-acetic acid condensation theory does satis- 

 factorily explain how the long-chain acids may have a greater ketogenic 

 activity than the short-chain acids, as well as how acetic acid gives rise to 

 ketone bodies, it does not necessarily completely invalidate the multiple 

 alternate oxidation theory. It is possible that the formation of a poly- 

 ketone is the first step in the oxidation of a long-chain fatty acid; this is 

 followed by an explosion to yield a number of acetate fragments simultane- 

 ously. On the other hand, the theory of Knoop and of Dakin, which sug- 

 gests that the oxidation of fatty acids occurs in a stepwise fashion on the 

 iS-carbon, is not completely ruled out. 



The oxidation and resynthesis of fatty acid may be occurring simul- 

 taneously. This somewhat complicates the explanation of the mechanism 

 of oxidation. In studies carried out on C^Mabeled palmitic acid in which 

 the isotope had been introduced into either carboxyl position, the fifth 

 carbon or the eleventh carbon, Chaikoff and co-workers^^ found that C^^ 

 was recovered only in the carboxyl and carbonyl carbons of acetoacetate. 

 This would suggest that the oxidation of long-chain fatty acids involves the 

 progressive cleavage of the chain into 2C units. The following sequence 

 of results is described : 



1. Oxidation of the |S-carbon of the fatty acid of Cn length. 



2. Cleavage of the molecule between the a- and /3-carbon, yielding a 

 C„_2 residue and a 2C unit which immediately enters into the 2C metabolic 

 pool in the liver. 



3. Random condensation of 2C units from the pool to give rise to aceto- 

 acetate. 



4. Oxidation of the fifth carbon of the original Cn chain, now the jS- 

 carbon of the Cn-2 fragment. Two separate processes {A and B) can now 



" R. F. Witter, E. H. Newcomb, and E. Stotz, /. Biol. Chem., 185, 537-548 (1950). 

 " I. L. Chaikoff, D. S. Goldman, G. W. Brown, Jr., W. G. Dauben, and M. Gee, 

 J. Biol. Chem., 190, 229-240 (1951). 



