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Cell proliferation, cell death and hepatocarcinogenesis
No full textThe carcinogenic process in the liver is a multistep process, characterised by an altered ratio between cell proliferation and cell death. In the last few years, we have undertaken studies aimed at determining the possible differences exhibited by two different types of cell proliferation, namely compensatory regeneration and direct hyperplasia at a molecular and cellular level. These two types of proliferative stimuli appear to play different roles in liver carcinogenesis. The scope of this article is to summarise the present knowledge about the differences in the expression of genes involved in the entry of liver cells into cell cycle, between liver regeneration following cell loss and/or cell death and direct hyperplasia induced by primary mitogens
ROLES OF HEPATOCYTE GROWTH-FACTOR AND TUMOR-NECROSIS-FACTOR-ALPHA ON LIVER-CELL PROLIFERATION IN RATS INDUCED BY LEAD NITRATE
No full text9-cis-retinoic acid is a direct hepatocyte mitogen in rats
No full textWe recently suggested that peroxisome proliferators (PP)-induced hepatocyte DNA synthesis may be mediated by a specific peroxisome proliferator activated receptor (PPAR). Heterodimers of the PPAR with the retinoid nuclear receptor, RXR, activate transcription after binding to DR1 response elements of the target genes. DR1 elements are also activated by RXR homodimers formed in the presence of 9-cis retinoic acid (9 cis RA) suggesting that PP and 9 cis RA might regulate an overlapping set of target genes. The present study was therefore designed to test whether 9-cis RA stimulates hepatocyte DNA synthesis. Male Wistar rats were given a single intragastric dose of 9-cis RA (10-100 mg/Kg) or all trans retinoic acid (RA)(200 mg/Kg and 100 mg/Kg), and levels of hepatocyte DNA synthesis after 24 hours were determined by BrdU immunohistochemistry. Effects of 9-cis RA and RA(10(-9)-10(-5)M) on hepatocyte DNA synthesis in primary culture were also examined. Over 10 fold increases in the levels of BrdU incorporation were noted 24 hours after a single dose of 9 cis RA at a dose of 60 and 100 mg/Kg. RA at a dose of 200 mg/Kg induced a 5-6 fold increases in BrdU labeling, while a dose of 100 mg/Kg had no significant effects. Since the RA effect only occurs at higher doses, it may be only after conversion to 9-cis RA. In primary culture of hepatocytes, neither 9-cis RA nor RA with or without EGF had stimulatory effects on hepatocyte DNA synthesis. This is the first report to demonstrate a potent stimulatory effect of 9-cis RA on DNA synthesis of rat hepatocytes in vivo. It is suggested that 9-cis RA exerts this effect through receptor mediated mechanisms similar to PP, both activating genes that regulate hepatocyte proliferation
Induction of cellular DNA synthesis in the pancreas and kidney of rats by 3,3',5-triiodo-L-thyronine (T3), 9-cis retinoic acid (9-cis RA) and peroxisome proliferators (PP).
No full textPossible roles of nonparenchymal cells in hepatocyte proliferation induced by lead nitrate and by tumor necrosis factor alpha
No full textA single intravenous injection of lead nitrate (LN) to rats induces liver cell proliferation without causing cell necrosis (direct hyperplasia), We suggested that liver cell proliferation in this model may be triggered by the induction of liver tumor necrosis factor alpha (TNF-alpha), Because administration of TNF-alpha in vivo has been shown to induce proliferation of both parenchymal and nonparenchymal cells of the Liver, we analyzed the temporal sequences of DNA synthesis in both cell populations following LN and recombinant TNF-alpha treatment by 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry. The patterns of cell proliferation induced by these agents were further compared with those induced by a single dose of nafenopin (NAF), a direct mitogen which does not induce liver TNF-alpha messenger RNA (mRNA), In male Wistar rats given a single dose of LN (100 mu mol/kg), BrdU incorporation of hepatocytes and nonparenchymal cells (Kupffer cells, endothelial cells and periportal nondescript cells) became evident 12 hours after the treatment; The labeling of all cell types reached a peak. after 38 hours and declined thereafter, Rats given a single intravenous injection of human recombinant TNF-alpha (46 mu g/rat) showed an increase of BrdU labeling in nonparenchymal cells after 24 hours, whereas the labeling of hepatocytes became evident at 36 hours, A single intragastric administration of NAF resulted in a rapid increase in the number of labeled hepatocytes with no substantial labeling of nonparenchymal cells, These results add further support to the notion that LN-induced liver cell proliferation is mediated by TNF-alpha, and suggest that different cell populations are involved in the initial proliferative response of the liver to mitogens, depending on the capacity of the mitogens to stimulate TNF-alpha production
Roles of growth factors and of tumor necrosis factor-alpha on liver cell proliferation induced in rats by lead nitrate
No full textBACKGROUND: A single intravenous injection of lead nitrate to rats induces a synchronized wave of hepatocyte proliferation without accompanying liver cell necrosis. However, the mechanism of the mitogenic effect of lead nitrate is not known, and whether hepatocyte growth factor (HGF), transforming growth factor-alpha (TGF-alpha), and transforming growth factor-beta 1 (TGF-beta 1) play any role in it have not been investigated, These growth factors have indeed been shown to provide either positive or negative stimuli for liver cell regeneration after partial hepatectomy or liver cell necrosis. Moreover, there are reports showing that administration of non-necrogenic doses of tumor necrosis factor-alpha (TNF-alpha) to rats lead to an enhanced proliferation of hepatocytes and liver nonparenchymal cells, Lead is known to sensitize animals to lethal effects of bacterial lipopolysaccharides (LPS), suggesting that lead nitrate may modify the production of TNF-alpha in response to endogenous LPS of intestinal origin. An enhanced production of TNF-alpha could therefore be involved in the mitogenic action of lead nitrate. EXPERIMENTAL DESIGN: We investigated first whether a single intravenous dose of lead nitrate (100 mu mole/kg) to rats modifies the production of HGF, TGF-alpha, and TGF-beta 1, by examining the steady-state level of their mRNA in the liver by Northern blot analyses. The response of rats given lead nitrate to various doses of LPS was next evaluated to determine whether lead-treated rats have an enhanced sensitivity to LPS. Finally, the level of TNF-alpha mRNA was examined in the liver of rats at various time periods after a single injection of lead nitrate, RESULTS: No changes were observed in the liver levels of mRNAs for HGF, TGF-alpha, and TGF-beta 1 at various time intervals after a single injection of lead nitrate. All rats given only single injections of LPS up to 100 mu g survived. However, lead nitrate-treated rats tolerated LPS at dosages of only 6 mu g. The liver of control rats showed a single 1.6 kb TNF-alpha transcript, whereas 1.8-kb transcripts were seen at 1 hour after lead nitrate injection, and persisted for 12 hours. The 1.8 kb TNF-alpha transcript was also present in the spleen of control rats, and its expression was enhanced in lead nitrate-treated rats. CONCLUSIONS: Stimulation of hepatocyte proliferation induced by lead nitrate was not accompanied by changes in liver levels of HGF, TGF-alpha, or TGF-beta 1 mRNA, Lead nitrate, however, enhanced expression of TNF-alpha at a time preceding the onset of hepatocyte DNA synthesis, indicating that TNF-alpha may trigger the lead nitrate-induced proliferation of hepatocytes
Induction of cellular DNA synthesis in the pancreas and kidneys of rats by peroxisome proliferators, 9-cis retinoic acid, and 3,3',5-triiodo-L-thyronine
No full textWe recently suggested that peroxisome proliferators (PPs), 3,3',5-tri-iodo-L-thyronine (T-3), and 9-cis retinoic acid (9-cis RA) induce hepatocyte proliferation in rats through the activation of their nuclear receptors, PP-activated receptors, T-3 receptors, and retinoid X receptors. To test whether nuclear hormone receptor-mediated cell proliferation can be observed in organs other than liver, we examined the effects of these agents on the pancreas and kidneys of male Wistar rats using BrdUrd immunohistochemistry. A single s.c. injection of T-3 (2 mg/kg) and single intragastric administration of 9-cis RA (40 mg/kg) or 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio-(N-beta-hydroxyethyl) acetamide (200 mg/kg) induced a wave of DNA synthesis in the pancreatic acinar cells and in the proximal tubular epithelial cells of the kidneys, peaking after 24 h. No stimulation of DNA synthesis was observed in ductal or islet cells of the pancreas and in glomeruli of the kidneys. All-trans-retinoic acid, a ligand for retinoic acid receptor, at a dose (200 mg/kg) that induced hepatocyte proliferation, had no effects on fell proliferation of the pancreas and the kidneys. The results suggest that T-3, 9-cis RA, and PP activate genes that regulate cell proliferation in target cells through receptor-mediated pathways and initiate cellular DNA synthesis
Hepatocyte proliferation induced by a single dose of a peroxisome proliferator
No full textIn compensatory hyperplasia after partial hepatectomy or liver cell injury, hepatocyte proliferation is triggered by coordinated actions of growth factors such as hepatocyte growth factor and transforming growth factor-alpha and -beta. Initiation of hepatocyte DNA synthesis is preceded by tbe activation of the set of early growth response genes mediated by enhanced nuclear factor-kappa B binding to DNA. Using an experimental model to induce hepatocyte DNA synthesis in vivo by a single nose of a peroxisome proliferator, which does not induce liver cell necrosis (direct hyperplasia), we investigated whether peroxisome proliferator-induced hepatocyte proliferation involved an induction of known growth factors, an activation of early growth response genes, and nuclear factor-kappa B. A single intragastric administration of 250 mg/kg BR931 (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio-(N-beta-hydroxyethyl) acetamide) to male Wistar rats induced a wave of hepatocyte DNA synthesis starting after 12 hours and peaking at similar to 24 to 36 hours. The response was dose dependent. The treatment also induced the expression of the mRNA for the peroxisomal bifunctional enzyme, one of the peroxisome-related fatty acid beta-oxidation enzymes Pretreatment of rats with dexamethasone (2 mg/kg) inhibited both hepatocyte DNA synthesis and the induction of the peroxisomal bifunctional enzyme gene. Northern blot analyses of liver RNA during a period preceding the onset of DNA synthesis revealed no induction of hepatocyte growth factor, transforming growth factor-alpha, or tumor necrosis factor-alpha mRNAs. No induction of early growth response genes, liver regeneration factor-1, or c-myc was detected Furthermore, gel mobility shift assays showed no enhanced nuclear factor-kappa B binding to its DNA consensus sequence after BR931 treatment, whereas control studies demonstrated a distinct increase in binding after partial hepatectomy or lead nitrate treatment. Tbe results suggest that peroxisome-proliferator-induced hepatocyte proliferation may be triggered by signal transduction pathways different from those after partial hepatectomy and that the binding of peroxisome proliferators to their nuclear receptors may play a role in stimulation of DNA synthesis and peroxisome proliferation
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