Inductions By Hormones Added Singly, Simultaneously Or Sequentially: What Cultured Hepatocytes Can Tell Us About Metabolic Regulation In The Whole Animal

Abstract

The culture of liver parenchymal cells from adult rats offers many investigative opportunities not previously available. It is now possible to study hepatocytes in the absence of organismic signals, or in the presence of a defined spectrum of such signals added singly, simultaneously or sequentially. While one cannot expect such cells to perform every liver cell function at once (4), it is possible to study and characterize many biochemical activities which are known to occur in the whole animal (such as the inductions of ODC and TAT activities, and the stimulation of increases in the level of cAMP), and other biochemical activities (such as the “permissive” effect of glucocorticoids on AIB transport which could only be inferred from whole animal data (6, 41) in retrospect). Homeostatic regulation in the whole animal is orchestrated by sequential biochemical reactions many of which are, in turn, modulated by sequential hormone actions. For example, it is well known that corticosterone levels oscillate in the rat (13). Furthermore, it can be inferred from the considerable literature (8, 11, 34, 35) on glucocorticoid “permissive” effects, including the present report, that the oscillation of corticosterone is intimately involved with maintaining a relatively constant level of blood glucose by potentiating the effect of various non-steroid hormones such as glucagon. However, the data discussed in this paper demonstrate that the “permissive” effects of natural steroids (i.e., hydrocortisone and corticosterone) on the glucagon induction of amino acid transport are relatively short-lived in the absence of steroid. Thus, the maximum effect of glucagon in vivo might be expected to occur at or shortly following an episodic corticosterone peak (42), whereas the minimum glucagon effect would occur when corticosteroid levels are low. In fact, this may be the case in the report by Baril and Potter (41) where the oscillation of amino acid transport in vivo was abolished by adrenalectomy. Additionally, we have obtained evidence that the “permissive” effect on AIB transport plateaus much more rapidly in cells pre-treated with dexamethasone and then with glucagon (sequential) than in cells simultaneously exposed to dexamethasone and glucagon. Thus, the nature of the oscillation of glucocorticoid in vivo may regulate not only the potential level of glucagon induced activity but also the time required to reach the maximally-induced level. The question of how hormones interact, as well as how they act, is of fundamental importance to the understanding of animal physiology. The simplicity with which adult rat liver parenchymal cells in primary monolayer culture can be employed to study the effects of exposure to single, simultaneous and sequential hormonal additions ranks these cells as the principal model for such investigations.