Vitamin D depletion retards the normal regeneration process after partial hepatectomy in the rat.

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the hormone of the vitamin D3 (D3) endocrine system, has been shown to influence malignant and normal cell proliferation/differentiation, while insulin (I) is known to be essential for liver growth. To investigate the influence of D3 on liver regeneration, the effect of the D status was studied in D-depleted rats (D-) pretreated with: G1, placebo (D-, hypocalcemic); G2, oral calcium only (D-, normocalcemic); G3, D3; and G4, 1,25-(OH)2D3. Two thirds hepatectomy (HX) or sham operation was performed, and regeneration was studied for 3 weeks. I response to glucose challenge and the hepatic I receptor were also studied. Cell volume, DNA, and RNA were not affected by pretreatment. After HX, the pattern of [3H]thymidine incorporation into DNA (P less than 0.003) and the cell labeling index (P less than 0.0001) were highly influenced by pretreatment and suggestive of an earlier appearance of the S phase of the cell cycle in the 1,25-(OH)2D3-treated compared to the D- hypocalcemic group. Furthermore, the mitotic index revealed a significant effect of pretreatment (P less than 0.01), with peak mitosis 24 h after HX in D3-treated and 1,25-(OH)2D3-treated rats compared to 30-36 h after HX in the D- groups. Liver weight restitution was impaired in D- rats (P less than 0.009) and is illustrated by the estimated time required to achieve 70% recovery of the resected liver mass, which was found to be 186 and 300 h in G1 and G2, and 154 and 107 h in G3 and G4. G1 rats had significantly higher glucose concentrations (fasting as well as after glucose injection) and reduced I secretion when challenged with glucose (P less than 0.001); they also had an upregulation in hepatic I receptor number (P less than 0.005) compared to calcium or D3-treated rats, while 1,25-(OH)2D3 led to a liver I receptor number similar to that found in hypocalcemic D- rats; the affinity of the I receptor was, however, only slightly changed by pretreatment (P less than 0.08). Our data indicate that in D depletion, hypocalcemia retards DNA synthesis and liver mass recovery, while normocalcemia contributes to DNA synthesis, but fails to sustain mitosis and compensatory liver growth to a level comparable to that found after D3 and/or 1,25-(OH)2D3 repletion. The observation that both D3 and 1,25-(OH)2D3 significantly promoted normal liver recovery after partial HX illustrates the role of the D endocrine system in normal cell physiology in vivo.