68 CHOLINE 



mental cirrhosis. Droplets of stainable lipid appear in the hepatic cells 

 surrounding the central veins within 24 hours after rats are placed on a diet 

 low in choline and in its precursors. Large intracytoplasmic masses of fat 

 are formed from smaller droplets during the first week, and the paren- 

 chymal cells are expanded to twice the original size. The fat content cf the 

 liver in this stage may be increased ten times, but it rapidly disappears if 

 choline is administered to the rat. If the choline-deficient diet is continued 

 for 1 to 2 months, distended cell walls rupture and large fatty masses, 

 called lipodiastemata, form by fusion of several cells. These and the fatty 

 liver cells compress the sinusoids in the center of lobules where the intra- 

 vascular pressure is lowest, with resulting interference with the oxygen 

 supply. The partial anoxia is believed by Hartroft to be an important factor 

 in the ensuing atrophy and regression of liver cells which are followed by 

 disappearance of the fat and by the growth of fibrous tissue. 



The rapidity and extent of the increase in liver lipids in choline deficiency 

 as well as their removal following administration of choline suggest strongly 

 that the effectiveness of choline as a lipotropic agent depends on some func- 

 tion of choline-containing phospholipids in fat metabolism. Definite evi- 

 dence of an influence of choline on phospholipid activity in the form of 

 data on the turnover of P^'- has been presented, but the correlation of the 

 appearance or disappearance of liver fat with changes in lecithin levels is 

 not at all satisfactory. The accelerating effect of aminoethanol and of its 

 mono- and dimethyl derivatives in certain aspects of phospholipid activity 

 together with the lipotropic activity of betaine and methionine indicate 

 that the maintenance of choline in one or another of its combined forms is 

 a complex function of considerable importance. Actually, the choline re- 

 quirement in weanling male rats given an adequate supply of protein was 

 found by Griffith and Mulford^* to be 2 and 5.5 mg. of choline chloride per 

 day for the prevention of renal lesions and of fatty livers, respectively. 

 The nature of the compounds sharing the lipotropic activity of choline is 

 indicated in Section V, p. 45. 



The quantity and nature of the dietary fat influences the fatty liver but 

 is not the determining factor because accumulation of liver lipids occurs on 

 low choline diets that are low in fat.^^ • ^° Barrett et al}^ fed deuterium-labeled 

 fatty acids and were unable to demonstrate the presence of the isotope in 

 the liver fat. There appears little question but that the bulk of the excess 

 fat in a fatty liver of this type is formed in the liver from carbohydrate. 

 Nevertheless, Channon and Wilkinson"*- found variations due to the nature 



38 W. H. Griffith and D. J. Mulford, J. Am. Chem. Soc. 63, 929 (1941). 



39 C. H. Best and M. E. Huntsman, J. Physiol . (London) 83, 255 (1935). 

 " W. H. Griffith, J. Biol. Chem. 132, 639 (1940). 



" H. M. Barrett, C. H. Best, and J. H. Ridout, J. Physiol. {London) 93, 367 (1938). 

 ^2 H. J. Channon and H. Wilkinson, Biochem. J. 30, 1033 (1936). 



