Feedback regulation of bile acid synthesis in primary human hepatocytes: Evidence that CDCA is the strongest inhibitor
✍ Scribed by Ewa Ellis; Magnus Axelson; Anna Abrahamsson; Gösta Eggertsen; Anders Thörne,; Grzegorz Nowak; Bo-Göran Ericzon; Ingemar Björkhem;; Curt Einarsson
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- English
- Weight
- 979 KB
- Volume
- 38
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
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 pmol/L) significantly decreased formation of cholic acid (CA) to 44% +: 4% of controls and glycodeoxycholic acid (GDCA) decreased formation of CA to 67% f 11% of controls. Glycoursodeoxycholic acid (GUDCA; 100 pmol/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 pmol/L) markedly decreased cholesterol 7m hydroxylase (CYP7A1) mRNA levels to 2% f 1%, 2% 2 1%, and 29% f 11% of controls, respectively, whereas GUDCA had no effect. Addition of GDCA and GCDCA (100 pmol/L) significantly decreased sterol 12a-hydroxylase (CYP8B1) mRNA levels to 48% f 5% and 61% f. 4% of controls, respectively, whereas GCA and GUDCA had no effect. Addition of GCDCA and GDCA (100 pmol/L) significantly decreased sterol 27-hydroxylase (CYP27A1) mRNA levels to 59% f 3% and 60% f 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% f 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.