Adaptive regulation of hepatic bile salt transport: Effects of alloxan diabetes in the rat

Abstract

The hepatic transport of bile salts appears to be adaptively regulated by changes in the bile salt pool size and in the flux of bile salt through the liver. The maximum secretory rate of taurocholate increases or decreases when the bile salt pool size is modified by either oral feeding of cholate or taurocholate (up-regulation) or prolonged bile salt depletion through a biliary fistula (down-regulation), respectively. It is not known whether adaptive regulation of hepatic bile salt transport operates under conditions in which the bile salt pool size is modified by endogenous changes in bile acid metabolism. Because experimental diabetes mellitus is associated with alterations in the synthesis of bile acids and total bile salt pool size and composition in the rat, we examined the effects of diabetes mellitus induced by alloxan (5 mg/100 gm body weight, intravenously) and insulin treatment on hepatic bile salt transport and relate the changes to bile salt pool size variations. At 3 days after alloxan injection (DIAB-3 group) both taurocholate maximum secretory rate and pool size were significantly decreased, whereas they were restored to normal values after 6 days of diabetes (DIAB-6 group). Insulinopenic diabetes for 14 days (DIAB-14 group) and for 24 days (DIAB-24 group) resulted in a marked increase of basal bile salt secretory rate (secondary to an increased contribution of cholate conjugates) and an enhanced taurocholate maximum secretory rate compared with control rats (147% and 188% increase, respectively) and with a group (PHARM-control) that received alloxan but did not develop detectable glycosuria (224% and 286% increase, respectively). In contrast, sulfobromophthalein maximum secretory rate was not significantly modified in 14-day diabetic rats compared with control rats. In addition, diabetic rats demonstrated a significant reduction of the bile salt-independent fraction of bile flow. Insulin treatment (3 units/100 gm body wt/day) in diabetic rats from day 0 (alloxan injection) to day 14 (INS-14 group) and from day 14 to day 24 after alloxan administration (INS-24 group) normalized basal bile salt secretion, taurocholate maximum secretory rate and the bile salt-independent fraction of bile flow. Bile salt pool size was significantly greater in DIAB-14 and DIAB-24 groups than in the control group (172% and 216% greater, respectively) and the PHARM-control group (246% and 309% greater, respectively). Insulin treatment prevented, in the INS-14 group, and reversed, in the INS-24 group, the increase of bile salt pool. Cholestyramine administration (5% wt/wt in the diet) to diabetic rats from day 0 (alloxan injection) to day 14 (CHOL-14 group) and from day 14 to day 24 after alloxan administration (CHOL-24 group) prevented and reversed, respectively, bile salt pool and taurocholate maximum secretory rate increase without modifying the hyperglycemia. In conclusion, alloxan diabetes brings about marked changes in taurocholate maximum secretory rate, that appear to be selective, because sulfobromophthalein maximum secretory rate is unaltered. Both enhanced and decreased taurocholate maximum secretory rate appear to be primarily related to, and follow, parallel changes in bile salt (cholate) pool size induced by diabetes. Both insulin and cholestyramine can prevent and reverse the enhancement of taurocholate maximum secretory rate induced by diabetes. Thus changes in taurocholate maximum secretory rate in this experimental model probably represent an adaptive response to increased hepatic bile salt load, supporting the concept that bile salt pool size is an important factor in the down-regulation and up-regulation of hepatic bile salt transport. (Hepatology 1991;14:671-678.)