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Feedback regulation of bile acid synthesis in primary human hepatocytes: Evidence that CDCA is the strongest inhibitor
Author(s) -
Ellis Ewa,
Axelson Magnus,
Abrahamsson Anna,
Eggertsen Gösta,
Thörne, Anders,
Nowak Grzegorz,
Ericzon BoGöran,
Björkhem, Ingemar,
Einarsson Curt
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840380419
Subject(s) - bile acid , cyp8b1 , chenodeoxycholic acid , cholic acid , glycine , taurocholic acid , glycocholic acid , cholesterol 7 alpha hydroxylase , sterol , deoxycholic acid , biology , cyp27a1 , biochemistry , medicine , chemistry , amino acid , cholesterol
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. (Hepatology 2003;38:930‐938).