Specific endocrine and hormonal receptor changes associated with liver regeneration in adult rats.

Abstract

Partial removal of the adult rat liver-a procedure that stimulates liver regeneration-causes arterial levels of insulin and thyroxin to fall and glucagon levels to rise. These changes are correlated with the quantity of liver tissue excised and not solely with nonspecific operative manipulations or with blood glucose levels. During regeneration (about 24 hr postoperatively), hepatic plasma membranes become partially resistant to binding glucagon; this change is specific because it is not detected in laparotomized controls and insulin binding is not significantly altered. It remains to be proven whether any one or more of these specific endocrine changes are causally related to the initiation of hepatic proliferation.The phenomenon of liver regeneration in adult rats has been investigated for many years in attempts to understand processes that control mammalian cell proliferation. After partial removal of the liver (partial hepatectomy), the remaining tissue undergoes metabolic changes which culminate in the initiation of hepatocyte DNA synthesis and mitosis about 14 and 24 hr later, respectively, and which continue until the initial cellular mass is restored (1).It has been proposed that hepatocyte proliferation is controlled by blood-borne factors, the levels of which appear to be regulated by the available liver mass (2). Indirect in vvo evidence suggests that hormones may be involved (3-8). Recently, it has been reported that in adult rats, peripheral venous perfusions of glucagon and thyroxin-but not insulinstimulate partial hepatocellular growth similar to the hyperplasia induced by partial hepatectomy (9). However, a growth regulatory role for pancreatic hormones is controversial (10-13); moreover, neither glucagon nor thyroxin appear to be specific hepatotrophic mitogens (14).A conceptual attempt to unify these apparently unrelated findings was discussed elsewhere (15, 16) and was based upon in vitro growth control studies using chemically defined medium and quiescent monolayer cultures (17) of differentiated fetal rat hepatocytes (18-21). Direct evidence from these studies suggested that many serum (22) and conditioning factors (17) contributed to the growth response, including insulin and thyroxin, which partially stimulated the initiation of DNA synthesis, and glucagon, which partially inhibited this process.These findings suggested that the in vivo induction of liver regeneration by partial hepatectomy might be accompanied by specific alterations in plasma levels of these hormones as well as in the liver's capacity for hormonal responsiveness.Accordingly, we began approaching these problems by measuring plasma levels of insulin, glucagon, and thyroxin in partially hepatectomized rats and by measuring the capacity of plasma membranes derived from regenerating liver to bind peptide hormones. Measurements were performed during the period that precedes maximal DNA replication rates (0-24 hr) because regulatory changes initiating growth would be expected to occur during this time (1). MATERIALS AND...

Augmenter of liver regeneration: Its place in the universe of hepatic growth factors

“…The emergence of insulin and the demonstration by Short and Lieberman (45) that hormone cocktails could drive r~sting livers into mitosis prompted a flurry of hormoneregulatory hypotheses to explain hepatic regeneration (45)(46)(47), supported by claims that glucagon was synergistic with insulin (48). However, the hypothesis was undermined by the inability to confirm a glucagon effect in the canine Eck fistula model (11,34) or in selective evisceration experiments in dogs (43,44), and by failure with the Eck fistula during the next 15 yr to add more hormones to the list ofhepatotrophic molecules with the possible exception of the weakly hepatotrophic thyroxin (T 3) (18).…”

“…Without this context introduced by Jacob and Monod (80), it is impossible to envision how the long list of factors (many nonspecific) that can promote or initiate mitotic activity of hepatocytes in tissue culture (46,(81)(82)(83)(84) could result in coherent growth or regeneration responses. A regulatory role also has been suggested for insulin (85,86).…”

Small-for-size liver transplanted into larger recipient: A model of hepatic regeneration

“…The identifiable hallmarks of classic posthepatectomy regeneration that also were seen after transplantation included an early increase in ODe, followed by increased thymidine incorporation, DNA synthesis and mitoses. The typical hormone changes that follow PH were present as well, including the falls in systemic blood insulin (8,9) and androgen (11) and elevations of glucagon (8,9,29) and estrogen (13). The circulating sex hormone changes were congruent with simultaneous measurements of hepatic nuclear and cytosolic binding sites for androgens and estrogens (9-12, 29, 30).…”

Growth control of differentiated fetal rat hepatocytes in primary monolayer culture. IX. Specific inhibition of DNA synthesis initiation by very low density lipoprotein and possible significance to the problem of liver regeneration.

“…7). Moreover, these kinetic changes could have been predicted partly from the rapid elevation of serum glucagon occurring after partial hepatectomy (27,29) because hyperglucagonemic states suppress hepatic VLDL production (8). However, growth regulation by glucagon is probably complex (6,27), and other factors, including prostaglandin-El, heparin production by mast cells, and alpha~-fetoprotein, also may be involved with suppression of hepatic VLDL production (27,28).…”

“…Operations were performed under ether anesthesia between 0900 and 1200 h as previously described (29).…”