Hormonal Influences on Liver Lipid Partition,Carbohydrate and Electrolyte Metabolism in the Rat

Abstract

Comment and Summary

The experiments presented here represent and attempt to obtain data on the comparative influences of short-term hormonal overdosage or endocrine insufficiencies upon electrolyte, carbohydrate, and lipid metabolism followed concurrently in the animal. The major purpose of these studies was to secure information on the metabolic patterns of the two latter foodstuffs which would enable an evaluation of the endocrine influences upon potassium of the endocrine influences upon potassium content and distribution in tissues. It is generally agreed that hormones modify the rates of metabolic reactions. It was our intent in Exp. I (Table I and Fig. 1) to obtain data concerning a number of constituents of liver and plasma in intact, adrenalectomized, and adrenalectomized-alloxanized which would allow a comparative evaluation of the metabolic status of the latter two types of animals with that of the intact rat. The two endocrine-deficient kinds of animals which were used in this comparative study were considered desirable for our purposes since it is well known that certain adrenocortical hormones and insulin have similar resultant influences upon certain phases of carbohydrate metabolism (glycogen formation) and are dissimilar in their resultant influences on other phases of carbohydrate metabolism (gulcose oxidation). There is also increasing evidence that adrenocortical hormones and insulin are antagonistic in their fatty acids to the liver and the mobilization of depot fat. It is apparent therefore that caution must be used in relating the level of tissue constituents to the effects of a specific hormone on intermediary metabolism or the absence of a gland in that the observed effects may be due to “unrestrained” influences of an antagonistic hormone(s). Examination of the data in Experiment I within this context suggests that in the adrenalectomized rat carbohydrate oxidation, and lipogenesis or neutral fat mobilization was greater than in the intact rat. As stated above, this might be interpreted as the resultant influence of lack of adrenocortical hormones or the unopposed activity of insulin. Parallel inspection of the data of the adrenalectomized-alloxanized group suggests that glucose oxidation in the adrenalectomized group was proceeding under the unopposed action of insulin since in the former group the evidence suggests an amelioration of this metabolic status during the condition of dual-glandular insufficiencies (adrenal and insulin). However, it is equally evident that the status of the metabolism of fat as evidenced by the levels of neutral fat and phospholipid in the liver was not altered in the absence of insulin and adrenal hormones from that found in the absence of adrenal gland secretions alone. Thus the changes in the levels of the various lipids in the two groups from those found in the controls of Experiment I mus be due mainly to absence of the hormonal influences of the adrenal gland. A more detailed interpretation of the liver lipid changes must necessarily be tentative in view of the uncertaintics regarding the metabolic interrelationships of the lipid fractions in the liver. It has been reported that in the depancreatized dog there is a marked increase in the turnover of liver phospholipids when exogenous insulin is withdrawn (22) . Since the liver phospholipids probably are not involved in fat transport (23) , the increased turnover suggested that some of the liver phospholipids participate in fat catabolism. In teh present experiments the decrease in liver phospholipids observed in the animals with glandular deficiencies suggests an elevated level of fat metabolism. The increase in neutral fat could be due either to mobilization of fat from depots or an increased rate of synthesis in response to the elevated level of fat metabolism.

Information concerning the effect of epinephrine on lipid metabolism is very meagre. Cori and Cori (24) deduced from their data that fat is the fuel for the increased metabolism due to epinephrine. An increase in liver phospholipids and fatty acids 2-3 hours after subcutaneous injection of epinephrine in rabbits was reported by Pollack (25) . There is increasing evidence however that insulin affects several phases of lipid metabolism. A marked reduction in the phospholipids of blood and liver in depancreatized dogs maintained with insulin was reported (26) (27) . A depression in lipogenesis in the alloxan-diabetic rat (28) and an increase inhepatic lipogenesis in the normal rabbit fed a high carbohydrate diet given insulin injection has been reported (29) . In general the evidence reported in the literature indicates that insulin's influence upon lipid metabolism is related through the effects of this hormone on glucose utilization. The data presented in Experiment II (Fig. 2) show that significant changes in the fractions of liver lipids followed the injection of insulin and epinephrine. However, the present data does not permit a definitive interpretation of a specific effect of either epinephrine or insulin on these lipid fractions because of the evidence recently reported that in the intact animal each of these hormones stimulated the secretion of the other hormone (30-32) ; the known effects which both of these hormones exert upon carbohydrate utilization and oxidation; and the increasing evidence of an influence of the latter processes upon lipid metabolism. A particularly puzzling aspects of the findings in this experiment is that in the shift in the liver lipid pattern from that in the intact untreated animal is essentially the same found in the adrenalectomized, the adrenalectomized-alloxanized rats, and the intact rat which received injections of epinephrine or insulin. It would appear that the same changes in fat metabolism in the liver occurred in all 4 types of experimental animals. Further investigation of the effects of insulin and epinephrine with the purpose of delimiting their specific actions on liver lipid metabolism is presented in the succeeding paper.

The data of Fig 3 show clearly that administration of intravenous glucose affected the level of the liver lipid fractions. Also the results show that the endocrine status of the animals exerted a definite influence on the effects of the glucose administration upon the liver fractions. In the adrenalectomized group the increase in total lipid content was accounted for by the increased neutral fat fraction alone. In the intact and the adrenalectomized-alloxanized groups the changes in the neutral fat and the phospholipid fractions were in opposite directions following the glucose infusions. It is noteworthy that the liver glycogen content of the intact and adrenalectomized rats was significantly increased after the glucose (Table III) and in both these groups the neutral fat content was increased. The evidence presented is suggestive that in the absence of insulin and adrenal gland secretions there was a decrease in the level of fat metabolism following the glucose infusion. Furthermore, the data presented in Table III is suggestive that carbohydrate utilization was apparently proceeding at an extremely slow rate in the adrenalectomized-alloxanized group.

There are several general aspects of the liver lipid data obtained in these experiments which deserve special comment. First, significant changes in the level of the lipid constituents can occur with much greater rapidity (30-60 minutes) than is generally recognized. Thus, it appears that fat metabolism is as responsive to the changing metabolic requirements of the organism as is carbohydrate metabolism. Secondly, the changes in the levels of phospholipid and neutral fat were always in opposite directions. When changes occurred in the cholesterol fractions, they parralleled those for the phospholipids. These interrelationships are probably a reflection of the functions of these constituents in fat metabolism. Neutral fat being the form in which fat is mobilized and transported, and the phospholipid and cholesterol esters constituents involved in some stages of fat catabolism in the liver. Thirdly, it is apparent from the present data that the level of total fat in the liver is not a dependable criterion in studies on the influence of hormone deficiency or excess on fat metabolism in the liver. Some of the shifts in lipid pattern reported here occurred without any change being evident in total lipid values. The total lipid values found in the various experimental groups reported here appeared to be the resultant of opposing changes in the different fractions, and whether the values were the same, greater, or less than the respective controls was due to the quantitative rather than the qualitative nature of the changes in the level of the lipid constituents. Finally, it should be emphasized that the level of the various lipids found in these experiments are all within the so-called normal range for the rat. Thus, the significant changes are not due to grossly abnormal conditions but rather represent “normal” shifts in the pathways of metabolism in response to changes in the hormonal pattern of the organism.