D. Goupil et al., HEPATIC EXPRESSION OF REGENERATION MARKER GENES FOLLOWING PARTIAL-HEPATECTOMY IN THE RAT - INFLUENCE OF 1,25-DIHYDROXYVITAMIN D-3 IN HYPOCALCEMIA, Journal of hepatology, 26(3), 1997, pp. 659-668
Background/Aims: Vitamin D (D) depletion is a common feature of chroni
c liver diseases, In past years, disturbances in calcium metabolism in
volving inadequate D and parathyroid hormone status have been reported
to significantly impair the hepatic regeneration process following pa
rtial hepatectomy in the rat, The purpose of this study was to investi
gate how hypocalcemia and D deficiency affect specific cell markers of
hepatic compensatory growth. Methods: Steady-state mRNA levels of gen
e markers of the regeneration process were investigated following 2/3
partial hepatectomy, The response of hypocalcemic D-depleted rats was
compared to that of animals whose calcium status had been normalized b
y repletion with the active D hormone 1,25-dihydroxyvitamin D-3 (1,25(
OH)(2)D-3). Results: The transcript for the major hepatic mitogen HGF
increased in both groups after partial liver resection but the increas
e was significantly lower as well as delayed in livers obtained from c
alcium deficient rats in the prereplicative phase of the regeneration
process, TGF alpha mRNA levels were also found to be significantly low
er in calcium deficient rats at all time-points following partial hepa
tectomy, while the relative behavior of the tandem TGF alpha-EGFR indi
cated an early dominant effect in normocalcemic 1,25(OH)(2)D-3-replete
d animals, HGF-c-met mRNA levels also indicated that the 1,25(OH)(2)D-
3-repleted animals reacted more promptly to the regeneration stimuli,
Indeed, while relative (1,25(OH)(2)D-3/D-Ca- ratio) maximum mRNA level
s were observed 12 h following liver resection in 1,25(OH)(2)D-3-treat
ed animals, relative peak levels were only apparent 24 h post-surgery
in hypocalcemic rats, Maximum cyclin D-1 (a marker of the G1 phase of
the cell cycle) mRNA occurred between 8-18 h after partial hepatectomy
in 1,25(OH)(2)D-3-repleted animals to return to base-line value there
after, but in hypocalcemic rats the transcript levels remained signifi
cantly below 1,25(OH)(2)D-3-repleted animals during the prereplicative
period with increases above initial values between 12-24 h post-surge
ry, Both cyclin A (an S phase marker) transcripts (1.8 and 2.9 kb) wer
e influenced by the regeneration process, The transcripts significantl
y and sharply increased in hypocalcemia between 30-36 h following part
ial hepatectomy to decrease thereafter, while the increase was observe
d between 24-30 h, acid at 48 h (1.8 kb) in 1,25(OH)(2)D-3-repleted an
imals. Liver weight recovery was also found to be decreased in D-deple
ted rats over the 48 h period of observation, Conclusions: Our data fu
rther confirm the presence of an impaired regeneration process in hypo
calcemia of D deficiency which seems to be associated with gene marker
s indicating an inefficient transit across the G1 phase of the cell cy
cle.