EFFECTS OF MALONATE ON LIPID METABOLISM 149 



tumor), 30 mM malonate inhibits 8-73% (van Vals and Emmelot, 1957); 

 and in rat liver extracts containing mitochondria, 10 mM malonate in- 

 hibits 51% (Iliffe and Myant, 1964). 



These divergent observations are difficult to explain satisfactorily and 

 one must conclude that the final effects of malonate must depend on many 

 factors. In cellular preparations malonate may alter the levels of ATP, 

 NAD(P)H, and coenzyme A, as well as divert the metabolism of acetyl- 

 CoA by its inhibition of the cycle. In nonmitochondrial soluble enzyme 

 systems these actions would be minimized or absent, and the most important 

 factors might be the facilitation of fatty acid synthesis through the forma- 

 tion of malonyl-CoA or direct effects on the enzymes involved, although 

 there is no evidence for such direct affects at present. When malonate is 

 itself incorporated into fatty acids, as in several examples above and in 

 spinach chloroplasts, where malonate incorporation occurs at about half 

 the rate for acetate (Mudd and McManus, 1964), additional complications 

 must be considered. Since the incorporation of acetate- 1-C^* into lipid in 

 chloroplasts is reduced 71% by 0.67 mM malonate (Mudd and McManus, 

 1962), it would appear that malonate also inhibits some step or steps in the 

 pathway. The compartmentalization of the pools of acetyl-CoA, malonyl- 

 CoA, acetoacetate, and the various enzymes and cofactors within the cell 

 must be borne in mind in trying to explain certain differential affects of 

 malonate. 



Effects on the Metabolism of Fats, Phospholipids, and Sterols 



Several observations on total lipid response to malonate are interesting 

 even though it is impossible to assign a mechanism. In rat liver homogenates 

 incubated with palmitate-1-C^*, the lipids other than phosphohpids increase 

 22% in the presence of 10 mM malonate compared to controls (Jedeikin 

 and Weinhouse, 1954). Whether this is direct utilization of palmitate or 

 lipid synthesis with the C^^Og formed from palmitate is difficult to say. 

 Malonate at 50 mM also increases the total lipid content of potato tuber 

 slices some 230% (Table 1-19) (Romberger and Norton, 1961) and this 

 could be due mainly to an increased synthesis of fatty acids. On the other 

 hand, lipid synthesis from glucose-C^* in human placenta is depressed 75% 

 by 20 mM malonate (Hosoya et al, 1960). These results again show that 

 the action of malonate on lipid metabolism is quite variable. It will be more 

 profitable to turn to the synthesis of particular lipid fractions. 



Injections of malonate lead to elevation of the free and esterified cho- 

 lesterol in the liver, kidney, and blood of the rat (see tabulation) (Mook- 

 erjea and Sadhu, 1955). Injections of 800 mg/kg of sodium malonate were 

 made daily for 3-4 weeks, some toxic effects being noted, and the animals 

 then sacrificed. Simultaneously, the blood glucose rose from 92 mg% to 

 196 mg% and the blood acetoacetate from 0.8 mg% to 3.6 mg%. Kidney 



