title: Feedback regulation of bile acid synthesis in primary human hepatocytes: evidence that CDCA is the strongest inhibitor.
abstract: Primary human hepatocytes were used to elucidate the effect of individual bile acids on bile acid formation in human liver. Hepatocytes were treated with free as well as glycine-conjugated bile acids. Bile acid formation and messenger RNA (mRNA) levels of key enzymes and the nuclear receptor short heterodimer partner (SHP) were measured after 24 hours. Glycochenodeoxycholic acid (GCDCA; 100 micromol/L) significantly decreased formation of cholic acid (CA) to 44% +/- 4% of controls and glycodeoxycholic acid (GDCA) decreased formation of CA to 67% +/- 11% of controls. Glycoursodeoxycholic acid (GUDCA; 100 micromol/L) had no effect. GDCA or glycocholic acid (GCA) had no significant effect on chenodeoxycholic acid (CDCA) synthesis. Free bile acids had a similar effect as glycine-conjugated bile acids. Addition of GCDCA, GDCA, and GCA (100 micromol/L) markedly decreased cholesterol 7alpha-hydroxylase (CYP7A1) mRNA levels to 2% +/- 1%, 2% +/- 1%, and 29% +/- 11% of controls, respectively, whereas GUDCA had no effect. Addition of GDCA and GCDCA (100 micromol/L) significantly decreased sterol 12alpha-hydroxylase (CYP8B1) mRNA levels to 48% +/- 5% and 61% +/- 4% of controls, respectively, whereas GCA and GUDCA had no effect. Addition of GCDCA and GDCA (100 micromol/L) significantly decreased sterol 27-hydroxylase (CYP27A1) mRNA levels to 59% +/- 3% and 60% +/- 7% of controls, respectively, whereas GUDCA and GCA had no significant effect. Addition of both GCDCA and GDCA markedly increased the mRNA levels of SHP to 298% +/- 43% and 273% +/- 30% of controls, respectively. In conclusion, glycine-conjugated and free bile acids suppress bile acid synthesis and mRNA levels of CYP7A1 in the order CDCA > DCA > CA > UDCA. mRNA levels of CYP8B1 and CYP27A1 are suppressed to a much lower degree than CYP7A1.
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000494:pharmacology*; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D053493:Cholestanetriol 26-Monooxygenase; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D005246:Feedback; D005260:Female; D006000:Glycocholic Acid / Q000494:pharmacology; D006002:Glycodeoxycholic Acid / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D002635:Chenodeoxycholic Acid; D006002:Glycodeoxycholic Acid; C024033:glycoursodeoxycholic acid; D014580:Ursodeoxycholic Acid; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D013253:Steroid 12-alpha-Hydroxylase; D006000:Glycocholic Acid