Format

Send to

Choose Destination
See comment in PubMed Commons below
Toxicol Sci. 2014 Oct;141(2):538-46. doi: 10.1093/toxsci/kfu151. Epub 2014 Jul 23.

Potency of individual bile acids to regulate bile acid synthesis and transport genes in primary human hepatocyte cultures.

Author information

1
University of Kansas Medical Center, Kansas City, Kansas 66160 Zunyi Medical College, Zunyi, China.
2
University of Kansas Medical Center, Kansas City, Kansas 66160 Upstate Medical University, Syracuse, New York 13210.
3
University of Kansas Medical Center, Kansas City, Kansas 66160.
4
CLINTEC.
5
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden University of Pittsburgh Medical Center, Pittsburgh, PA USA.
6
University of Kansas Medical Center, Kansas City, Kansas 66160 cdkcorvette@gmail.com.

Abstract

Bile acids (BAs) are known to regulate their own homeostasis, but the potency of individual bile acids is not known. This study examined the effects of cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) on expression of BA synthesis and transport genes in human primary hepatocyte cultures. Hepatocytes were treated with the individual BAs at 10, 30, and 100μM for 48 h, and RNA was extracted for real-time PCR analysis. For the classic pathway of BA synthesis, BAs except for UDCA markedly suppressed CYP7A1 (70-95%), the rate-limiting enzyme of bile acid synthesis, but only moderately (35%) down-regulated CYP8B1 at a high concentration of 100μM. BAs had minimal effects on mRNA of two enzymes of the alternative pathway of BA synthesis, namely CYP27A1 and CYP7B1. BAs increased the two major target genes of the farnesoid X receptor (FXR), namely the small heterodimer partner (SHP) by fourfold, and markedly induced fibroblast growth factor 19 (FGF19) over 100-fold. The BA uptake transporter Na(+)-taurocholate co-transporting polypeptide was unaffected, whereas the efflux transporter bile salt export pump was increased 15-fold and OSTα/β were increased 10-100-fold by BAs. The expression of the organic anion transporting polypeptide 1B3 (OATP1B3; sixfold), ATP-binding cassette (ABC) transporter G5 (ABCG5; sixfold), multidrug associated protein-2 (MRP2; twofold), and MRP3 (threefold) were also increased, albeit to lesser degrees. In general, CDCA was the most potent and effective BA in regulating these genes important for BA homeostasis, whereas DCA and CA were intermediate, LCA the least, and UDCA ineffective.

KEYWORDS:

BSEP; CYP7A1; FGF19; Human primary hepatocyte cultures; OSTα/β; bile acids

PMID:
25055961
PMCID:
PMC4271050
DOI:
10.1093/toxsci/kfu151
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments

    Supplemental Content

    Full text links

    Icon for Silverchair Information Systems Icon for PubMed Central
    Loading ...
    Support Center