CHANGES IN G-PROTEIN EXPRESSION ACCOUNT FOR IMPAIRED MODULATION OF HEPATIC CAMP FORMATION AFTER BDL

The regulation of cAMP synthesis by hormones and bile acids is altered in isolated hamster hepatocytes 2 days after bile duct ligation (BDL) [Y. Matsuzaki, B. Bouscarel, M. Le, S. Ceryak, T. W. Gettys, J. Shoda , and H. Fromm. Am. J. Physiol. 273 (Gastrointest. Liver Physiol. 36): G164-G174, 1997]. Therefore, studies were undertaken to elucidate the mechanism(s) responsible for this impaired modulation of cAMP formati on. Hepatocytes were isolated 48 h after either a sham operation or BD L. Both preparations were equally devoid of cholangiocyte contaminatio n. Although the basal cAMP level was not affected after BDL, the abili ty of glucagon to maximally stimulate cAMP synthesis was decreased by similar to 40%. This decreased glucagon effect after BDL was not due t o alteration of the total glucagon receptor expression. However, this effect was associated with a parallel 50% decreased expression of the small stimulatory G protein alpha-subunit (G(s) alpha(S)). The express ion of either the large subunit (G(s) alpha(L)) or the common beta-sub unit remained unchanged. The expression of G(i) alpha(2) and G(i) alph a(3) was also decreased by 25 and 46%, respectively, and was associate d with the failure of ANG II to inhibit stimulated cAMP formation. The refore, alterations of the expression of G(s) alpha(S) and G(i) alpha are, at least in part, responsible for the attenuated hormonal regulat ion of cAMP synthesis. Because cAMP has been reported to stimulate bot h bile acid uptake and secretion, impairment of cAMP synthesis and bil e acid uptake may represent an initial hepatocellular defense mechanis m during cholestasis.