Yasutoshi Muto

Hepatocyte growth factor, a potent mitogen for mature hepatocytes in vitro, seems to function as a hepatotrophic factor for liver regeneration. We examined the mitogenic effect of hepatocyte growth factor on mouse liver in vivo. The labeling index of hepatocytes was markedly increased when recombinant human hepatocyte growth factor was injected intravenously into mice subjected to 30% hepatectomy (control, 1.7% +/- 0.1%; 1 microgram hepatocyte growth factor, 6.4% +/- 1.3%; 5 micrograms hepatocyte growth factor, 18.3% +/- 0.2%) and into mice administered carbon tetrachloride (control, 12.7% +/- 1.0%; 1 microgram hepatocyte growth factor, 26.3% +/- 2.8%) or alpha-naphthylisothiocyanate (control, 0.4% +/- 0.1%; 1 microgram hepatocyte growth factor, 3.8% +/- 1.1%; 5 micrograms hepatocyte growth factor, 14.2% +/- 2.0%). In addition, weights of the remnant livers in mice given hepatocyte growth factor 60 hr after 30% hepatectomy were significantly greater than those of untreated control mice (control, 0.93 +/- 0.04 gm; 5 micrograms hepatocyte growth factor, 1.06 +/- 0.04 gm). Hepatocyte growth factor prevented any marked increase in the serum levels of liver enzymes and bilirubin when it was administered to mice also treated with alpha-naphthylisothiocyanate (control: ALT, 394 +/- 278 IU/L; lactate dehydrogenase, 2,644 +/- 1,109 IU/L; bilirubin, 9.6 +/- 2.6 mg/dl; and 5 micrograms hepatocyte growth factor: ALT, 135 +/- 7.9 IU/L; lactate dehydrogenase, 1,672 +/- 626 IU/L; bilirubin, 1.0 +/- 0.8 mg/dl). Our findings show that intravenously injected hepatocyte growth factor stimulates the growth of hepatocytes in mouse liver and protects the integrity of hepatocytes in vivo against hepatitis caused by hepatotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract Retinol circulates in rat plasma bound to a specific protein, retinol-binding protein (RBP). A radioimmunoassay for rat RBP was developed with a double antibody precipitation technique. The immunoassay accurately measures RBP in amounts of 0.5 to 3 ng per assay tube. There was no significant difference in the immunoreactivity of apo-RBP as compared to holo-RBP. Using this assay, a study was conducted to examine the effects of vitamin A depletion and deficiency, and of repletion, on the level of serum RBP, in order to explore the role of nutritional vitamin A status in the regulation of RBP metabolism. Weanling rats were divided into five groups, each fed a vitamin A-deficient diet with or without supplements as follows: Group 1, control: supplemented with vitamin A; Group 2, pair-fed control: supplemented with vitamin A but with food intake matched to that of the deficient rats; Group 3, deficient: no vitamin A supplementation; Groups 4 and 5, retinoic acid: supplemented, after the initial depletion period, with a modest daily dose (14 or 28 µg) of retinoic acid. The rats were studied for 75 days. In the deficient group the serum vitamin A levels decreased gradually during the first 25 to 30 days of the study, to levels of about 2 µg/100 ml. Serum RBP levels also declined during the induction of vitamin A deficiency, with a time course similar to that seen for vitamin A, but with a lag of about 3 days (from 50 ± 4 µg per ml on Day 3 to 20 ± 2 µg per ml at Day 27, and then more slowly to 13 ± 2 µg per ml at Day 75). After 3 to 4 weeks most of the circulating RBP was present as the apoprotein, not containing a molecule of bound retinol. The results obtained with the retinoic acid-fed rats, who continued to grow normally, were identical with those of the deficient rats. In contrast both the pair-fed and ad libitum control groups exhibited no major changes in either serum vitamin A or RBP, throughout the entire study. Liver homogenates were immunoreactive, and generated immunoassay curves which were indistinguishable from those obtained with pure rat RBP. The level of immunoreactive RBP in the livers of deficient rats was 4 times (p l 0.001) that in the livers of control rats. When vitamin A was administered orally to deficient rats on Day 53, a very rapid increase in serum RBP level, from a mean of 14 to 56 µg per ml, was seen within 5 hours (the first time interval sampled). These findings suggest that vitamin A deficiency primarily interferes in some way with the secretion, rather than with the synthesis, of RBP by the liver, and that the deficient liver contains a pool of previously formed apo-RBP which can be released rapidly into the serum, as holo-RBP, when vitamin A becomes available.

Retinoid is a collective term which indicates vitamin A (retinol) and its derivatives. Retinoid has a variety of functions such as growth promotion, maintenance of reproduction and dark adaptation. Retinoid also regulates cell differentiation and tissue morphogenesis. Sinceabnormality in the differentiation induces cellular atypia and that of the morphogenesis induces structural atypia, retinoid has important effects which inhibit carcinogenesis.