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 μmol/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 μmol/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 μmol/L) markedly decreased cholesterol 7α-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 μmol/L) significantly decreased sterol 12α-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 μmol/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. (H epatology 2003;38:930-938.)
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