Biliary lipid synthesis and secretion in gallstone patients before and during treatment with chenodeoxycholic acid.
The interrelationships between biliary lipid secretion and the hepatic activities of the rate-limiting enzymes for bile acid and cholesterol synthesis have not been investigated in patients with gallstones before and during desaturation therapy. Liver biopsies for enzyme assays and biliary lipid secretion measurements were performed in 12 patients with gallstones before chenodeoxycholic acid therapy and in nine of these patients at 9 months of therapy. Six nongallstone control patients underwent only the lipid secretion measurements. In the patients with gallstones before treatment, all of whom had saturated bile, increased cholesterol secretion correlated directly with increased HMGCoAR activity, whereas bile acid and phospholipid secretion rates were significantly lower than in controls. During desaturation in response to chenodeoxycholic acid, biliary cholesterol and phospholipid secretion rates decreased significantly, and bile acid secretion was unchanged. Concomitantly, both HMGCoAR and cholesterol 7alpha-hydroxylase activities decreased significantly, but the correlation between HMGCoAR and cholesterol secretion was lost. Furthermore, no correlation was found between cholesterol 7alpha-hydroxylase activity and bile acid secretion during therapy. Enzyme assays were performed on single liver samples obtained at the same time of day but 48 hr before the lipid secretion measurements. That correlations between data obtained under these conditions are valid remains to be proved. In conclusion, the mechanism of biliary cholesterol saturation in patients with gallstones probably is related primarily to increased hepatic cholesterol synthesis, whereas desaturation during chenodeoxycholic acid therapy involves altered relationships among hepatic enzyme activities and biliary lipid secretions.
D001647:Bile Acids and Salts / Q000096:biosynthesis; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism*; D002635:Chenodeoxycholic Acid / Q000494:pharmacology* / Q000627:therapeutic use*; D002769:Cholelithiasis / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008297:Male; D008875:Middle Aged
D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase