REVERSAL OF OROTIC ACID-INDUCED FATTY LIVER IN RATS BY CLOFIBRATE

  • 1 January 1977
    • journal article
    • research article
    • Vol. 36  (2) , 215-231
Abstract
The addition of 1% orotic acid to a sucrose-enriched semipurified diet resulted in markedly fatty liver when fed to rats for 7 to 22 days. Light microscopy revealed lipid droplets, mostly small, distributed throughout the cytoplasm of all hepatocytes. EM showed that all the endoplasmic reticulum (ER) was broken into vesicles. Within the interior (cisterna) of each vesicle 1 or more lipid droplets were present. Morphologic signs of normal lipid transport (ER to Golgi apparatus to space of Disse) disappeared: the Golgi elements were flattened and lacked very low density lipoproteins particles; the Golgi-derived secretory vacuoles were not present. Biochemical analyses showed an increase in hepatic triacylglycerol levels, to approximately 8 times the levels of sucrose-fed controls by the 7th day, 18 times by the 15th day and 25 times by the 22nd day. Heaptic cholesterol levels increased 2- to 4-fold. Serum triacylglycerol levels fell markedly; serum cholesterol levels were reduced. Immunoelectrophoretic determinations showed that the apoprotein B component of plasma lipoproteins was practically absent at 7 days and increased slightly at 22 days. Reversal of an orotic acid-induced fatty liver was achieved by adding ethyl chlorophenoxyisobutyrate, a lipolytic drug, (clofibrate or CPIB) to the diet. By 8 to 16 days the ER of the hepatocytes returned to its usual parallel configuration and lipid droplets were not seen within its cisternae. Morphologic features of normal lipid transport reappeared. GERL [Golgi Endoplasmic Reticulum Lysosome System] became prominent, distended with small particles, interpreted as lipid undergoing degradation. Lipid-containing residual bodies are common. Peroxisomes are more numerous than in hepatocytes of control rats. Liver triacylglycerol levels approach sucrose-fed control levels and serum triacylglycerol levels returned to chow-fed control levels. Hepatic cholesterol levels were similar to those of sucrose-fed and chow-fed controls, whereas serum cholesterol levels were lower. Serum apoprotein B levels returned to chow-fed control levels. A sequence of events terminating in the lipid removal from the hepatocytes is suggested by observation of morphologic changes following chlorophenoxyisobutyrate administration. This appears to involve lipid transport into the cytosol where it accumulates as large spheres. Extensive smooth ER accumulations appear. The cytosol lipid then disappears as the rough ER develops. Peroxisomes and mitochondria are prominent during the reversal process.