title: Increase of deoxycholate in supersaturated bile of patients with cholesterol gallstone disease and its correlation with de novo syntheses of cholesterol and bile acids in liver, gallbladder emptying, and small intestinal transit.
abstract: A total of 100 nonobese and normolipidemic subjects (29 control subjects, 49 patients with cholesterol stones [CSs], and 22 patients with brown pigment stones) were studied to elucidate the pathogenetic contributions of deoxycholate (DC) to supersaturated bile formation with special reference to de novo syntheses of cholesterol and bile acids in the liver. A higher proportion of DC was observed in gallbladder bile from patients with CSs (CSs; 21.7 +/- 1.4%, mean +/- SEM, vs. control subjects; 10.2 +/- 0.9%). Cholesterol saturation in bile was elevated parallel to the increase of DC (r = .48; P = .0002), irrespective of the existence of stones. In a comparison between the 52 subjects with increased DC in bile (> 10% of biliary bile acids) and the 20 subjects without the increase (< 10%), the molar percentage of cholesterol in bile was significantly higher in the former (9.4 +/- 0.5%) than in the latter (6.7 +/- 0.4%) (P < .001). Consistent with the decrease in steady-state level of low-density lipoprotein (LDL) receptor-messenger RNA (mRNA), the catalytic activity and mRNA level of microsomal hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for de novo cholesterol synthesis, were significantly lower in the former (2.9 +/- 0.3 pmol/min/mg protein) than in the latter (5.1 +/- 0.6) (P < .0001). Biliary molar percentage of bile acids was significantly lower in the former (69.8 +/- 1.1%) than in the latter (75.2 +/- 1.5%) (P < .01). However, contrary to expectations, the catalytic activity and mRNA level of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme for bile acid synthesis, were significantly higher in the former (5.8 +/- 0.4 pmol/min/mg protein) than in the latter (3.7 +/- 0.6) (P < .01). The magnitude of the impaired gallbladder emptying (control subjects; 78.4 +/- 4% vs. CSs; 58 +/- 3%; P < .0005) together with the prolonged small intestinal transit (control subjects; 126 +/- 9 minutes vs. CSs; 198 +/- 9 minutes; P < .01) correlated significantly with the increased percentage of DC in bile. It is concluded that in cholesterol gallstone disease an increase of DC in bile, linked to an impaired gallbladder emptying together with a prolonged small intestinal transit, may play a significant role in downregulating de novo cholesterol synthesis but not bile acid synthesis in the liver.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Gastroenterology, University of Tsukuba, Ibaraki, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Shoda
authors.forename: B F
authors.initials: BF
authors.lastname: He
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: T
authors.initials: T
authors.lastname: Osuga
authors.forename: S
authors.initials: S
authors.lastname: Yamamori
authors.forename: H
authors.initials: H
authors.lastname: Miyazaki
authors.forename: J
authors.initials: J
authors.lastname: Sjövall
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism; D001769:Blood / Q000378:metabolism; D002769:Cholelithiasis / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000378:metabolism*; D005260:Female; D005704:Gallbladder / Q000378:metabolism*; D005772:Gastrointestinal Transit; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000235:genetics
chemical_list: D001647:Bile Acids and Salts; D015345:Oligonucleotide Probes; D003840:Deoxycholic Acid; D002784:Cholesterol