Selective ablation of retinoid X receptor alpha in hepatocytes impairs their lifespan and regenerative capacity

Retinoid X receptors (RXRs) are involved in a number of signaling pathways as heterodimeric partners of numerous nuclear receptors. Hepatocytes expres s high levels of the RXR alpha isotype, as well as several of its putative heterodimeric partners. Germ-line disruption (knockout) of RXR alpha has be en shown to be lethal in utero, thus precluding analysis of its function at later life stages. Hepatocyte-specific disruption of RXRa during liver org anogenesis has recently revealed that the presence of hepatocytes is not ma ndatory for the mouse, at least under normal mouse facility conditions, eve n though a number of metabolic events are impaired [Wan, Y.-J., et al. (200 0) Mel. Cell. Biol. 20, 4436-4444]. However, it is unknown whether RXR alph a plays a role in the control of hepatocyte proliferation and lifespan. Her e, we report a detailed analysis of the liver of mice in which RXR alpha wa s selectively ablated in adult hepatocytes by using the tamoxifen-inducible chimeric Cre recombinase system. Our results show that the lifespan of adu lt hepatocytes lacking RXR alpha is shorter than that of their wild-type co unterparts, whereas proliferative hepatocytes of regenerating liver exhibit an even shorter lifespan. These lifespan shortenings are accompanied by in creased polyploidy and multinuclearity. We conclude that RXR alpha plays im portant cell-autonomous function(s) in the mechanism(s) involved in the lif espan of hepatocytes and liver regeneration.