The specific focus of this project is on genes that play a role in both growth and metabolism in the liver, with a major emphasis on insulin-like growth factor binding protein-1 (IGFBP-1). Expression of IGFBP-1 is highly upregulated during liver growth in regeneration and development. Its expression is also upregulated during fasting and downregulated by high insulin levels. IGFBP-1 can cause upregulation of glucose levels with a proposed mechanism based on its inhibition of serum IGF function. In preliminary studies, the applicant demonstrates that increased transcription of the IGFBP-1 gene during liver regeneration is mediated in part by interleukin-6 (IL-6) a critical cytokine in the regenerative response.
Aim 1 will examine whether IL-6 activation of IGFBP-1 transcription is mediated through STAT-3 co-activation of HNF-1 transcription of the IGFBP-1 promoter and identify the mechanism by which IL-6 blocks insulin-mediated repression of IGFBP-1 promoter expression. Experiments are also proposed to identify the mechanism by which IL-6 upregulation of AP-1 activity mediates increased IGFBP-1 gene expression. IGFBP-1 null or knockout mice have been created and they display defects in glucose regulation and abnormal liver regeneration and repair.
Aim 2 will examine the ability of IGFBP-1 null livers to regenerate and repair and explore mechanistic defects after partial hepatectomy, acute and chronic carbon tetrachloride (CCl4) mediated liver injury and FAS mediated liver injury. The applicant will assess basic parameters of glucose metabolism in IGFBP-1 null mice and determine the basis for any abnormalities.
