期刊
PHYSIOLOGICAL GENOMICS
卷 24, 期 2, 页码 133-143出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/physiolgenomics.00156.2005
关键词
diabetes; beta-cell; pancreas; exenatide; glucagon-like peptide-1; islet; regeneration
资金
- NIDDK NIH HHS [U01-DK-56947, R01-DK-062965, P30-DK-50306, F32 DK060273, K12-DK-063682-02, F32-DK-60273] Funding Source: Medline
After partial pancreatectomy (Ppx), substantial regeneration of the endocrine and exocrine pancreatic compartments has been shown in adult rodents. Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor agonist that augments endocrine beta-cell mass by stimulating neogenesis, proliferation, and cell survival. After Ppx, treatment with Ex-4 ameliorates hyperglycemia by stimulating beta-cell mass recovery. We utilized a cDNA microarray approach to identify genes differentially regulated during pancreatic regeneration after Ppx and/or Ex-4 administration. The pancreatic remnant after Ppx showed a large number of differentially regulated genes. In contrast, Ex-4 treatment resulted in a smaller number of differentially regulated genes. Of note, a common subset of genes regulated by Ex-4 and after Ppx was identified, including three members of the mitogenic Reg gene family, Reg2, -3 gamma, and -3 beta, as well as fragilis, a gene that maintains pluripotency during germ cell specification, and Serpin b1a, a member of an intracellular protease inhibitor family involved in cell survival. These observations were confirmed by real-time PCR. We determined that Reg3 beta protein is also induced in the acinar pancreas after Ppx, suggesting a novel role for this factor in pancreatic growth or response to injury. Finally, comparison of transcription factor-binding sites present in the proximal promoters of these genes identified potential common transcription factors that may regulate these genes. Chromatin immunoprecipitation analyses confirmed Reg3 gamma as a novel transcriptional target of Foxa2 (HNF3 beta). Our data suggest molecular pathways that may regulate pancreatic growth and offer a unique set of candidate genes to target in the development of therapies aimed at improving pancreatic growth and function.
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