BIOSYNTHESIS OF CHOLESTEROL 383 



that these amino acids form cholesterol. Zabin and Bloch'^^ were able to 

 establish the fact that the isopropyl residue of isovaleric acid is more 

 rapidly converted to acetone bodies by rat liver slices, and is less rapidly 

 oxidized to CO2, than is the two-carbon moiety. It was later reported^^^ 

 that the cholesterol isolated after the feeding of isovalerate-4,4'-C^^, 

 1-C^^ had the same isotope distribution as that synthesized from acetate. 

 It was suggested that all the carbon atoms of the isopropyl group are 

 utilized for cholesterol synthesis, as well as for that of the acetyl groups and 

 fatty acids. 



c. Acetoacetate. Since acetoacetate was shown to be converted to 

 cholesterol by liver shces,'^^ it was believed that acetoacetate might be an 

 intermediate in cholesterol synthesis. The efficiency of pyruvate, ^^^ and 

 the hmited capacity of isovaleric acid,^^'*'^^'' as carbon sources for cholesterol, 

 have been attributed to the conversion of these acids to acetoacetate. 

 Moreover, since the incorporation of C^'^-CaCOs into cholesterol is greatly 

 increased in the presence of isovalerate, the possibility exists that aceto- 

 acetate or a similar four-carbon compound is formed in vivo from the iso- 

 propyl group of isovaleric acid by a C3 + Ci condensation ; this C4-com- 

 pound is believed to be an intermediate in the transformation of isovalerate 

 into cholesterol. Zabin and Bloch^^* interpreted their data obtained with 

 butyric acid-l-C^^, 3-C^^ as supporting evidence that acetoacetate is an 

 intermediate in the utilization of butyrate for sterol synthesis. These re- 

 sults were consistent with the earlier data of Little and Bloch,^^^ which in- 

 dicated that a C4 compound is formed from C2 units in the course of choles- 

 terol synthesis. According to CurraUj^"" who investigated the synthesis of 

 cholesterol from ethyl-3-C ^^-acetoacetate by rat liver slices, neither acetic 

 acid nor acetone is an intermediate in this synthesis. However, the exact 

 role of acetoacetate remains uncertain, in view of the findings of Blecher^^^ 

 that the C'' in cholesterol formed from 1->C'^- or 4-C^*-acetoacetate is in- 

 distinguishable from that produced by acetate. Fisher and Vars^"' like- 

 wise observed an increase of 20 to 25% in total cholesterol in the circulating 

 blood six hours after the infusion of acetoacetate into the portal vein. 



133 1. Zabin and K. Bloch, J. Biol. Chem., 185, 117-129 (1950). 



19* I. Zabin and K. Bloch, /. Biol. Chem., 192, 267-273 (1951). 



"5 R. O. Brady and S. Gurin, /. Biol. Chem., 189, 371-377 (1951). 



"6 J. L. Rabinowitz and S. Gurin, /. Biol. Chem., 208, 307-313 (1954). 



1" I. Zabin and K. Bloch, J. Biol. Chem., 185, 131-138 (1950). 



198 1. Zabin and K. Bloch, J. Biol. Chem., 192, 261-266 (1951). 



"9 H. N. Little and K. Bloch, J. Biol. Chem., 183, 33-46 (1950). 



^^ G. L. Curran, J. Biol. Chem., 191, 775-782 (1951). 



201 M. Blecher, Federation Proc, 13, 184 (1954). 



"^^ B. Fisher and H. M. Vars, Federation Proc, 12, 202-203 (1953). 



