Multivariate Gene Expression Profiling Reveals Common Expression Patterns Associated to Acute Phase Reaction, Lipid Metabolism and Proliferation in Regenerating Livers With and Without Activation of Hepatic Progenitor Cells (Oval Cells)

Under certain conditions, when the proliferative capacity of hepatocytes is severely impaired, liver regeneration can be accomplished by hepatic progenitor cells (oval cells). So far, only few factors have been identified to be uniquely regulated during oval cell activation. Using macroarray analysis of 1,176 spotted genes in a rat model of oval cell proliferation (AAF treatment and partial hepatectomy), we identified 11 differentially expressed genes compared to appropriate control models (AAF treatment and sham operation or AAF treatment alone). Three genes could be characterized as acute phase proteins (insulin-like growth factor binding protein 1, heat shock protein 60, alpha 1-proteinase inhibitor), and four down-regulated genes as enzymes involved in lipid metabolism (cytochrome P450 2C23, cytochrome P450 2C11, fatty acid acyl-CoA synthetase 2, 11-beta-hydroxysteroid dehydrogenase), and one enzyme involved in regulation of cellular pH (carbonic anhydrase III). Remaining group of three up-regulated genes could be linked to cell proliferation: thymidine kinase 1, essential for DNA replication, and two novel candidate genes (jun-D and ADP-ribosylation factor 4, ARF–4) associated to activation/proliferation of oval cells. However, comparison with normal liver regeneration (partial hepatectomy alone) revealed a high concordance of expression patterns, indicating overlapping expression patterns of acute phase reaction and metabolic adaptation. Induction of jun-D and ARF–4 expression was anticipated after PH without AAF treatment, and may represent newly identified transcriptional mechanisms activated both in oval cell-dependent and -independent liver regeneration.

Key words

arrays - oval cells - partial hepatectomy