Induction of Fatty Liver in Rats

Abstract

The administration of a purified diet supplemented with 1 % orotic acid induces in rats a rapid accumulation of lipids in the liver [290]. Such an effect is species specific and does not seem to occur in humans. The deposition of triglycerides in the liver, accompanied by a decrease in the concentration of plasma lipids, is a common and characteristic feature of fatty liver induced by various drugs. The earliest biochemical change [291,292] detected in rats given orotic acid is an increase in the pool of uridine nucleotides paralleled by a concomitant reduction of the level of adenine nucleotides and the oxidized and reduced forms of NAD.The fatty infiltration of the liver which accompanies the ingestion of orotic acid does not seem to be accompanied by serious pathological disturbances [293] and is readily reversible, unlike the development of fatty liver induced by a choline deficient diet. Supplementation of the orotic acid diet with adenine essentially modifies the effect of orotic acid [294]. Since PRPP is required for both the synthesis of purines and the metabolism of orotic acid, the decrease in the pool of adenine nucleotides is caused [295,296] by an inhibition of purine synthesis de novo due to extensive depletion of PRPP during the conversion of orotic acid to UMP. After the disappearance of orotic acid from the liver of animals previously fed a diet containing orotic acid, stimulation of the synthesis of adenine nucleotides occurred.Fatty liver developed in rats fed a diet containing orotic acid is characterized by the deposition of droplets of triglycerides in the tubules of the endoplasmic reticulum [297,298]. The reticulum breaks down into individual vesicles which contain lipid droplets 0.24).5 J.tm in diameter which accumulate the apolipoproteins of low and very low density lipoproteins. The liver otherwise appears to be functionally normal, unlike that of animals receiving other lipotrophic agents. The administration of orotic acid has a specific effect on lipoprotein synthesis without overall inhibition of protein synthesis. The effect is selective for hepatic but not intestinal {3-lipoprotein production and triglyceride transport [299).Plasma {3-lipoprotein concentration in rats receiving orotic acid falls to less than 1 % of normal and rebounds to normal level within 48 hours following withdrawal of orotic acid [300]. When perfused in situ, the livers from orotic acid fed rats released a-lipoprotein, albumin, and other plasma proteins but no detectable {3-lipoprotein. They also released smaller amounts of cholesterol and phospholipids than normal livers and no triglycerides, although they contained ten times the normal amount of triglycerides [300]. Since {3-lipoprotein has a specific role in the normal transport of triglycerides, the fatty liver produced by orotic acid appears to result from the inhibition of synthesis or release of hepatic {3-lipoprotein.Plasma contains an apoprotein which combines with lipids in the liver to form plasma lipoproteins [301]. Rats treated with orotic acid di...