The role of lipophilic bile acids in the development of cirrhotic cardiomyopathy.

Marked hemodynamic changes occur in humans and experimental animals with cirrhotic liver disease. In the heart, basal contractility, responsiveness to beta-adrenoceptor activation, and excitation-contraction coupling (ECC) are negatively affected in models of cirrhosis and portal hypertension with portosystemic shunting (PVS), and comprise what has been called cirrhotic cardiomyopathy. These effects are accompanied by elevated circulating levels of bile acids. We investigated whether elevated bile acids act as a myocardial toxicant by exposing cardiac muscle in vitro to bile acids and compared these results with two models of cirrhotic cardiomyopathy with elevated bile acids: CCl4-induced cirrhosis and PVS. Cholic acid, a lipophilic bile acid, produced a decrease in basal cardiac contractility and responsiveness to beta-adrenoceptor activation, both of which appeared to result from altered ECC. beta-Adrenoceptor density and signaling were unaffected. Acutely, ursodeoxycholic acid, a more hydrophilic bile acid, had no effect. Cirrhosis produced a decrease in basal force, depressed beta-adrenoceptor responsiveness, and altered ECC similar to cholic acid. However, cirrhosis also altered beta-adrenoceptor signaling including decreases in cyclic AMP formation, expression of the stimulatory G protein, GS, and beta-adrenoceptor density. Displacement of lipophilic bile acids by chronic administration of ursodeoxycholic acid to rats during the development of cirrhotic cardiomyopathy produced by PVS produced attenuation of the effect on ECC. These results suggest a possible role for lipophilic bile acids in some, but not all of the myocardial consequences of chronic portal vein stenosis and CCl4-induced cirrhosis.

Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine.

BACKGROUND/AIMS: Adaptive changes in transporter expression in liver and kidney provide alternative excretory pathways for biliary constituents during cholestasis and may thus attenuate liver injury. Whether adaptive changes in ATP-binding cassette (ABC) transporter expression are stimulated by bile acids and their nuclear receptor FXR is unknown. METHODS: Hepatic, renal and intestinal ABC transporter expression was compared in cholic acid (CA)- and ursodeoxycholic acid (UDCA)-fed wild-type (FXR(+/+)) and FXR knock-out mice (FXR(-/-)). Expression was assessed by reverse transcription-polymerase chain reaction, immunoblotting and immunofluorescence microscopy. RESULTS: CA feeding stimulated hepatic Mrp2, Mrp3, Bsep and renal Mrp2 as well as intestinal Mrp2 and Mrp3 expression. Lack of Bsep induction by CA in FXR(-/-) was associated with disseminated hepatocyte necrosis which was not prevented by compensatory induction of Mrp2 and Mrp3. With the exception of Bsep, UDCA stimulated expression of hepatic, renal and intestinal ABC transporters independent of FXR without inducing liver toxicity. CONCLUSIONS: Toxic CA and non-toxic UDCA induce adaptive ABC transporter expression, independent of FXR with the exception of Bsep. Stimulation of hepatic Mrp3 as well as intestinal and renal Mrp2 by UDCA may contribute to its therapeutic effects by inducing alternative excretory routes for bile acids and other cholephiles.

Cholic acid aids absorption, biliary secretion, and phase transitions of cholesterol in murine cholelithogenesis.

Cholic acid is a critical component of the lithogenic diet in mice. To determine its pathogenetic roles, we fed chow or 1% cholesterol with or without 0.5% cholic acid to C57L/J male mice, which because of lith genes have 100% gallstone prevalence rates. After 1 yr on the diets, we measured bile flow, biliary lipid secretion rates, hepatic cholesterol and bile salt synthesis, and intestinal cholesterol absorption. After hepatic conjugation with taurine, cholate replaced most tauro-beta-muricholate in bile. Dietary cholic acid plus cholesterol increased bile flow and biliary lipid secretion rates and reduced cholesterol 7alpha-hydroxylase activity significantly mostly via deoxycholic acid, cholate's bacterial 7alpha-dehydroxylation product but did not downregulate cholesterol biosynthesis. Intestinal cholesterol absorption doubled, and biliary cholesterol crystallized as phase boundaries shifted. Feeding mice 1% cholesterol alone produced no lithogenic or homeostatic effects. We conclude that in mice cholic acid promotes biliary cholesterol hypersecretion and cholelithogenesis by enhancing intestinal absorption, hepatic bioavailability, and phase separation of cholesterol in bile.