title: Potency of individual bile acids to regulate bile acid synthesis and transport genes in primary human hepatocyte cultures.
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.
authors: University of Kansas Medical Center, Kansas City, Kansas 66160 Zunyi Medical College, Zunyi, China.
authors: Jie
authors: J
authors: Liu
authors: University of Kansas Medical Center, Kansas City, Kansas 66160 Upstate Medical University, Syracuse, New York 13210.
authors: Hong
authors: H
authors: Lu
authors: University of Kansas Medical Center, Kansas City, Kansas 66160 Zunyi Medical College, Zunyi, China.
authors: Yuan-Fu
authors: YF
authors: Lu
authors: University of Kansas Medical Center, Kansas City, Kansas 66160 Upstate Medical University, Syracuse, New York 13210.
authors: Xiaohong
authors: X
authors: Lei
authors: University of Kansas Medical Center, Kansas City, Kansas 66160.
authors: Julia Yue
authors: JY
authors: Cui
authors: CLINTEC.
authors: Ewa
authors: E
authors: Ellis
authors: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden University of Pittsburgh Medical Center, Pittsburgh, PA USA.
authors: Stephen C
authors: SC
authors: Strom
authors: University of Kansas Medical Center, Kansas City, Kansas 66160 cdkcorvette@gmail.com.
authors: Curtis D
authors: CD
authors: Klaassen
mesh_terms: D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D001647:Bile Acids and Salts; D026901:Membrane Transport Proteins; D012333:RNA, Messenger
keywords: BSEP; CYP7A1; FGF19; Human primary hepatocyte cultures; OSTα/β; bile acids