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Hepatology. 2003 Oct;38(4):930-8.

Feedback regulation of bile acid synthesis in primary human hepatocytes: evidence that CDCA is the strongest inhibitor.

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  • 1Division of Gastroenterology and Hepatology, Department of Medicine, Huddinge University Hospital, SE-141 86 Stockholm, Sweden. ewa.ellis@medhs.ki.se

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.

PMID:
14512880
[PubMed - indexed for MEDLINE]
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