ALTERATION OF EXPRESSION OF LIVER-ENRICHED TRANSCRIPTION FACTORS IN THE TRANSITION BETWEEN GROWTH AND DIFFERENTIATION OF PRIMARY CULTURED RAT HEPATOCYTES
T. Mizuguchi et al., ALTERATION OF EXPRESSION OF LIVER-ENRICHED TRANSCRIPTION FACTORS IN THE TRANSITION BETWEEN GROWTH AND DIFFERENTIATION OF PRIMARY CULTURED RAT HEPATOCYTES, Journal of cellular physiology, 174(3), 1998, pp. 273-284
In the present study, we showed the role of the liver-enriched transcr
iption factors in the transition during which proliferating hepatocyte
s become quiescent. We used primary rat hepatocytes cultured in modifi
ed L-15 medium. The cells proliferated and, after the addition of 2% d
imethyl sulfoxide (DMSO) from day 4, they stopped growing and graduall
y differentiated. During hepatic proliferation, expression of hepatocy
te nuclear factors (HNF)1 alpha, HNF4, C/EBP alpha, and C/EBP beta mRN
As was depressed, whereas that of HNF3 alpha and HNF3 beta transcripts
was enhanced. After the addition of DMSO, the expression of HNF1 alph
a, HNF3 gamma, and HNF4 returned to the level in isolated cells and HN
F1 beta mRNA expression gradually increased. However, expression of C/
EBP alpha and C/EBP beta mRNAs was partially recovered. The mitoinhibi
tory agents, IL-1 beta, IL-6, TGF-beta, and activin A, were examined t
o determine whether they could induce differentiation of proliferating
hepatocytes as shown in cells treated with DMSO. Although these facto
rs inhibited cell growth, the cells did not differentiate. The express
ion pattern of HNF3 gamma mRNA was quite different in the cells cultur
ed with DMSO and those cultured with cytokines. Therefore, hepatic dif
ferentiation requires not only inhibition of DNA synthesis but also in
duction of appropriate transcription factors. Thus; expression of HNF3
gamma, C/EBP alpha, and C/EBP beta may be necessary for hepatocytes t
o acquire highly differentiated functions in addition to coexpression
of certain amounts of transcripts of HNF1 alpha, HNF1 beta, HNF3 alpha
, HNF3 beta, and HNF4 as well as suppression of C/EBP delta. (C) 1998
Wiley-Liss, Inc.