Background/aims: To specify roles of HNF 4 alpha in mouse liver development, we have analyzed the ex vivo morphogenetic potential of HNF4 alpha-null embryonic hepatic cells.
Methods: Using mice with floxed or deficiency alleles of HNF4 alpha, hepatic cells lacking this transcription factor were explanted into primary culture and derived into cell lines.
Results: Contrary to behavior in vivo where HNF4 alpha-null liver cells fail to show normal polarity and epithelialization, e18.5 hepatic cells in primary culture from mutant embryos show restoration of apical expression of tight junction protein-1 and of transcripts for E-cadherin. Clones of control and HNF4 alpha-null cell lines were indistinguishable, even when differentiation of bile canalicular formation was induced. HNF4 alpha-null and control cell lines showed similar potential to colonize livers of the murine ALB-uPA/SCID model of liver regeneration, but null cells formed only bile ducts and not clusters of hepatocytes. Finally, analysis of mutant embryonic livers revealed a transcriptional signature consistent with a stress response, which could underlie the morphogenetic defects observed in vivo.
Conclusions: We conclude that the lack of epithelialization characteristic of the HNF4 alpha-null embryonic liver is due, at least in part, to non-cell autonomous defects, and that null cells do not suffer intrinsic defects in polarization.
Background/aims: To specify roles of HNF 4 alpha in mouse liver development, we have analyzed the ex vivo morphogenetic potential of HNF4 alpha-null embryonic hepatic cells.
Methods: Using mice with floxed or deficiency alleles of HNF4 alpha, hepatic cells lacking this transcription factor were explanted into primary culture and derived into cell lines.
Results: Contrary to behavior in vivo where HNF4 alpha-null liver cells fail to show normal polarity and epithelialization, e18.
Cholesterol 7 alpha-hydroxylase (Cyp7a1) plays a central role in the regulation of bile acid and cholesterol metabolism, and transcription of the gene is controlled by bile acids and hormones acting through a complex interaction with a number of potential steroid-hormone-binding sites. Transcriptional activity of the human CYP7A1 gene promoter transfected into HepG2 cells was decreased in a concentration-dependent manner by co-transfection with an expression vector for peroxisome-proliferator-activated receptor-alpha (PPAR alpha). This effect was augmented by 9-cis-retinoic acid receptor-alpha (RXR alpha) and activators of PPAR alpha to give a maximum inhibition of approx.
