Liver regeneration following partial hepatectomy is one of the few models in which it is possible to study cellular proliferation in the intact animal. Regeneration is an important component of recovery from toxic, metabolic, and immunologic injury to the liver and is important following liver transplantation. Despite the loss of two-thirds of the liver mass, metabolic and synthetic homeostasis is maintained. Glucose homeostasis is mediated by the induction of liver-specific immediate-early genes including those which encode gluconeogenic enzymes such as glucose-6- phosphatase and PEPCK. The basis for this induction in liver regeneration is not well understood, however, it is likely to involve the participation of growth-induced transcription factors including NF-kappaB and Stat3. We hypothesize that these factors exert their effects through cooperative interactions with constitutive liver-specific transcription factors. C/EBP proteins, which are expressed throughout liver regeneration and other hepatic factors such as HNF-l are logical candidate transcription factors for this type of complex regulation. It is likely that C/EBPalpha is important for the regulation of immediate-early genes necessary for glucose homeostasis including glucose-6-phosphatase and PEPCK since C/EBPalpha deficient mice are profoundly hypoglycemic at birth and do not demonstrate the normal induction of these mRNAs. We will examine the basis of activation of genes which are important for the maintenance of metabolic homeostasis using two approaches. (l) Potential target genes which are activated by C/EBPalpha during regeneration will be identified in C/EBPalpha deficient heterozygote mice which we hypothesize will manifest subtle changes in the level of expression of C/EBPalpha regulated genes in response to partial hepatectomy. Following identification of genes which are potential C/EBPalpha targets of activation, promoter regions of these genes will be examined in tissue culture systems to identify specific C/EBPalpha promoter elements and regulatory elements for other hepatic factors and growth-induced transcription factors which contribute to the activation of these genes. (2) We will determine the contribution of C/EBP proteins, HNF-1, and growth-induced factors to the activation of glucose-6-phosphatase a gene which we postulate is activated by C/EBPalpha during regeneration. We will isolate and sequence the promoter region and identify important regulatory elements for transcription factors which activate this gene in tissue culture systems. Defining the basis for activation of liver-specific immediate-early genes important for metabolic homeostasis will enhance our understanding of how the liver maintains its differentiated state during regeneration. The studies outlined in this proposal will be performed under the sponsorship of Dr. Rebecca Taub, who is an acknowledged expert in the field of liver regeneration and whose laboratory will provide an outstanding environment for the candidate's continued training and development as an independent investigator in hepatology.
| Mukherjee, D; Kaestner, K H; Kovalovich, K K et al. (2001) Fas-induced apoptosis in mouse hepatocytes is dependent on C/EBPbeta. Hepatology 33:1166-72 |
