A common regulatory locus affects both HNF4/HNF1 alpha pathway activation and sensitivity to LPS-mediated apoptosis in rat hepatoma cells

Lipopolysaccharide (LPS) has been shown to protect certain cultured mammali an cells from undergoing programmed cell death (apoptosis) when exposed to tumor necrosis factor (TNF). However, LPS has also been reported to induce apoptosis in cultured endothelial cells, suggesting that apoptotic response mechanisms may be dependent upon cell type, In order to understand the inf luence of tissue-specific gene expression on apoptosis, we compared LPS-ind uced apoptosis in hepatoma cells with dedifferentiated hepatoma variant cel ls that have been selected for the loss of the liver-enriched HNF4/HNF1 alp ha transcriptional activation pathway. We report here that while human, rat and mouse hepatoma cell lines are resistant to LPS-mediated cell death, th e HNF4(-)/HNF1 alpha (-) rat hepatoma variant cells undergo rapid apoptosis (as determined by morphological analysis, DNA laddering and the TUNEL assa y) upon exposure to LPS, Genetic rescue experiments show that restoration o f the HNF4/HNF1 alpha pathway via chromosome transfer render the hepatoma v ariant cells resistant to LPS-mediated apoptosis, However, the introduction of HNF1 alpha alone failed to alter the apoptotic phenotype, suggesting th at the defect(s) in the hepatoma variant cells that influence apoptotic res ponses lies upstream of HNF4/HNF1 alpha expression. This study provides for the first time direct evidence of a common regulatory locus involved in ac tivation of hepatic gene expression and sensitivity to LPS-mediated apoptos is.