Characterization of Growth-Differentiation Factor 15, a Transforming Growth Factor β Superfamily Member Induced following Liver Injury

We have identified a new murine transforming growth factor beta superfamily member, growth-differentiation factor 15 (Gdf15), that is expressed at highest levels in adult liver. As determined by Northern analysis, the expression of Gdf15 in liver was rapidly and dramatically up-regulated following various surgical and chemical treatments that cause acute liver injury and regeneration. In situ hybridization analysis revealed distinct patterns of Gdf15 mRNA localization that appeared to reflect the known patterns of hepatocyte injury in each experimental treatment. In addition, treatment of two hepatocyte-like cell lines with either carbon tetrachloride or heat shock induced Gdf15 mRNA expression, indicating that direct cellular injury can induce Gdf15 expression in the absence of other cell types, such as inflammatory cells. In order to investigate the potential functions of Gdf15, we created Gdf15 null mice by gene targeting. Homozygous null mice were viable and fertile. Despite the dramatic regulation of Gdf15 expression observed in the partial-hepatectomy and carbon tetrachloride injury models, we found no differences in the injury responses between homozygous null mutants and wild-type mice. Our findings suggest either that Gdf15 does not have a regulatory role in liver injury and regeneration or that Gdf15 function within the liver is redundant with that of other signaling molecules.