Studies of Biochemical Changes in Subcellular Particles of Rat Liver and Their Relationship to a New Hypothesis Regarding the Pathogenesis of Carbon Tetrachloride Fat Accumulation*

Recent work in our laboratory, carried out in collaboration with Dr. M. C. Schotz, has led to the formulation of a simple hypothesis regarding the pathogenesis of carbon tetrachloride fat accumulation. This hypothesis consists essentially of an extension of the work of Byers and Friedman (1) to the carbon tetrachloride-poisoned liver. These workers have recently shown that the liver is constantly secreting large quantities of triglycerides into the plasma. According to our hypothesis, the formation of triglycerides by the liver is not interfered with in the carbon tetrachloride-poisoned animal, but the hepatic triglyceride secretory mechanism is inhibited or destroyed. As a result, triglycerides accumulate in the liver. Two preliminary aspects of the problem had previously been clarified. It was first observed that carbon tetrachloride reached its peak concentration in the liver of the rat within 1 to 2 hours after force feeding of the hepatotoxin (2). This observation established a basic frame of reference for all subsequent studies. It was next shown (3) that hepatic content of triglycerides was elevated 34% within 1 hour and 195a/, within 3 hours after carbon tetrachloride poisoning. This observation indicated that a serious derangement of hepatic lipid metabolism occurred coincident with the arrival of the toxic compound in the liver. After establishment of these two preliminary points, the”%ypothesis stated above was developed from two main considerations. The first of these was a systematic study of changes in biochemical properties of subcellular fractions obtained from livers of rats poisoned with carbon tetrachloride. A series of investigations (4, 5) had previously led to the tentative conclusion that the hepatic parenchymal cell mitochondria were probably not the primary loci for the attack by carbon tetrachloride. An extension of these studies has eliminated the mitochondria from serious consideration as possible primary targets. Study of some microsomal enzymes, on the other hand, indicated that pathological changes occur in the endoplasmic reticulum as early as 2 hours after carbon tetrachloride poisoning. The observation that carbon tetrachloride feeding results in patho-