Liver cells retain the capacity to proliferate in response to hepatic injury or loss of mass as a result of viral infection, drug hepatotoxicity, ischemic injury, metabolic diseases and following liver transplantation. Although many of the events that are important for liver cell proliferation in compensatory liver growth models including the rodent partial hepatectomy model have been extensively characterized, the molecular basis for liver cell proliferation in response to direct mitogenic stimulation by peroxisome proliferators (Pps) is not well understood. Single dose PP-administration in the rat results in primary mitogenic stimulation of hepatocyte DNA synthesis that requires the expression of the nuclear hormone receptor protein PPARalpha, and is comparable in magnitude to that seen in compensatory hepatic growth models. A single dose PP-hepatic growth model has been adapted to the mouse in order to examine differences in the growth response in genetically targeted strains. The significant changes in liver mass and NP cell activation observed in single dose PP-treated mice have established the utility of this experimental for the examination of signaling pathways that are important for stimulating liver cell growth by these compounds. Previous investigators have arrived at conflicting conclusions regarding the importance of the TNF-alpha. IL-6 cytokine activation pathway for PP-induced liver growth stimulation. The contribution of cytokine signaling pathways to PP-stimulated hepatic growth will be addressed through the following specific aims: (1) Characterize the basis for the observed increase in liver mass following single dose PP- administration in the mouse model. (2) Examine the potential contributions of IL-6 signaling pathways to PP-stimulated hepatic growth. (3)Assess the importance of PPARalpha function for hepatic growth by examining the regenerative response to partial hepatectomy in mice that do not express the PPARalpha gene. A detailed understanding of the basis for liver cell proliferation by peroxisome proliferator activation pathways may be useful for future development of therapies that will augment the regenerative capacity of the liver in a variety of clinical situations.
