Liver regeneration after two thirds partial hepatectomy (PH) is an orchestrated hyperplastic growth process requiring coordinated expression of many genes. The synchronous progression of 95% of the remnant hepatocytes through the cell cycle provides an in vivo model for examining the influence of bile acids on the molecular regulation of hepatocyte replication and growth. In this study, we examined the effects of endogenous deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) on messenger RNA (mRNA) expression and growth rate during liver regeneration. Rats were fed diets containing no addition, 0.4% DCA, UDCA, or both for 14 days; they then underwent 70% PH and were maintained on the diets for an additional 14 days. mRNA transcript levels for a variety of cell cycle-regulated genes were examined post-PH by Northern blot analysis. Bile acid concentrations were determined in liver, isolated nuclei, and plasma by gas chromatography and mass spectrometry. The results indicated that the addition of DCA and UDCA to the diet markedly shifted the bile-acid compositions of liver and plasma. In addition, DCA dramatically altered the abundance of many transcripts post-PH, whereas coadministration of UDCA suppressed the effect. DCA feeding significantly inhibited liver growth through day 3; however, by day 8, it induced an approximately 20% increase in mass compared with controls, UDCA-fed, or combination-fed animals. UDCA was concentrated greater than 20-fold in nuclei compared with whole liver in controls and DCA-fed animals and greater than 2-fold with UDCA feeding. These data suggest that bile acids may have a key role in liver regeneration, which is significantly altered by modulation of the bile-acid pool.
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Supported in part by grants from the National Institutes of Health and Ciba-Geigy Corporation, Pharmaceuticals Division, Summit, NJ.