HEPATOCYTE PROLIFERATION INDUCED BY A SINGLE-DOSE OF A PEROXISOME PROLIFERATOR

In compensatory hyperplasia after partial hepatectomy or liver cell in jury, hepatocyte proliferation is triggered by coordinated actions of growth factors such as hepatocyte growth factor and transforming growt h factor-alpha and -beta. Initiation of hepatocyte DNA synthesis is pr eceded by tbe activation of the set of early growth response genes med iated by enhanced nuclear factor-kappa B binding to DNA. Using an expe rimental model to induce hepatocyte DNA synthesis in vivo by a single nose of a peroxisome proliferator, which does not induce liver cell ne crosis (direct hyperplasia), we investigated whether peroxisome prolif erator-induced hepatocyte proliferation involved an induction of known growth factors, an activation of early growth response genes, and nuc lear factor-kappa B. A single intragastric administration of 250 mg/kg BR931 -xylidino)-2-pyrimidinylthio-(N-beta-hydroxyethyl) acetamide) t o 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-re lated fatty acid beta-oxidation enzymes Pretreatment of rats with dexa methasone (2 mg/kg) inhibited both hepatocyte DNA synthesis and the in duction of the peroxisomal bifunctional enzyme gene. Northern blot ana lyses of liver RNA during a period preceding the onset of DNA synthesi s revealed no induction of hepatocyte growth factor, transforming grow th factor-alpha, or tumor necrosis factor-alpha mRNAs. No induction of early growth response genes, liver regeneration factor-1, or c-myc wa s detected Furthermore, gel mobility shift assays showed no enhanced n uclear factor-kappa B binding to its DNA consensus sequence after BR93 1 treatment, whereas control studies demonstrated a distinct increase in binding after partial hepatectomy or lead nitrate treatment. Tbe re sults suggest that peroxisome-proliferator-induced hepatocyte prolifer ation may be triggered by signal transduction pathways different from those after partial hepatectomy and that the binding of peroxisome pro liferators to their nuclear receptors may play a role in stimulation o f DNA synthesis and peroxisome proliferation.