title: Hepatocyte nuclear factor 6 activates the transcription of CYP3A4 in hepatocyte-like cells differentiated from human induced pluripotent stem cells.
abstract: Human induced pluripotent stem cells (iPSCs) are a valuable source of hepatocytes for applications in drug metabolism studies. However, the current protocols for generating iPSC-derived hepatocyte-like cells (iPSHCs) are still very inefficient, and iPSHCs do not have sufficient hepatocyte-specific features, which include expression of a series of hepatocyte-specific genes, such as those encoding cytochrome P450 (CYP). In this study, we investigated whether introduction of human hepatocyte nuclear factor 6 (HNF6) could modulate the expression of CYP3A4 and other CYP genes in iPSHCs as well as in HepG2 cells, a fetal liver cell line (HFL cells), and in hepatocytes. CYP3A4 mRNA could be detected in iPSHCs, but the expression level was very low compared with those in HepG2 cells and hepatocytes. However, the CYP3A4 mRNA levels markedly increased on introduction of HNF6 and reached one-tenth of those in hepatocytes. We also found that HNF6 introduction increased CYP3A4 gene transcription in HFL cells and HepG2 cells, which have features similar to those of fetal hepatocyte-like cells; however, it did not affect CYP3A4 mRNA expression in hepatocytes. These results suggest that HNF6 plays an important role in the gene regulation of CYP3A4 during development from the fetal period to the postnatal period.
authors.affiliation: Department of Environmental and Health Science, Tohoku Pharmaceutical University, Sendai, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Shogo
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Numata
authors.forename: Masayo
authors.initials: M
authors.lastname: Narita
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kumagai
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kondo
authors.forename: Tamihide
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohmori
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nagata
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D056945:Hep G2 Cells; D051559:Hepatocyte Nuclear Factor 6 / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D012333:RNA, Messenger / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D051559:Hepatocyte Nuclear Factor 6; D012333:RNA, Messenger; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human