Heme Regulates Exocrine Peptidase Precursor Genes in Zebrafish
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Date
2007-10-01Author
Han Wang
Qingchun Zhou
Jason W. Kesinger
Chad Norris
Cammi Valdez
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Abstract
We previously determined that yquem harbors a mutation in the gene encoding uroporphyrinogen decarboxylase (UROD), the fifth enzyme in heme biosynthesis, and established zebrafish yquem (yqetp61) as a vertebrate model for human hepatoery-thropoietic porphyria (HEP). Here we report that six exocrine peptidase precursor genes, carboxypeptidase A, trypsin precursor, trypsin like, chymotrypsinogen B1, chymotrypsinogen 1-like, and elastase 2 like, are downregulated in yquem/urod (−/−), identified initially by microarray analysis of yquem/urod zebrafish and, subsequently, confirmed by in situ hybridization. We then determined downregulation of these six zymogens specifically in the exocrine pancreas of sauternes (sautb223) larvae, carrying a mutation in the gene encoding δ-amino-levulinate synthase (ALAS2), the first enzyme in heme biosynthesis. We also found that ptf1a, a transcription factor regulating exocrine zymogens, is downregulated in both yquem/urod (−/−) and sau/alas2 (−/−) larvae. Further, hemin treatment rescues expression of ptf1a and these six zymogens in both yquem/urod (−/−) and sauternes/alas2 (−/−) larvae. Thus, it appears that heme deficiency downregulates ptf1a, which, in turn, leads to downregulation of exocrine zymogens. Our findings provide a better understanding of heme deficiency pathogenesis and enhance our ability to diagnose and treat patients with porphyria or pancreatic diseases.
Citation
Wang, H., Zhou, Q., Kesinger, J. W., Norris, C., & Valdez, C. (2007). Heme Regulates Exocrine Peptidase Precursor Genes in Zebrafish. Experimental Biology and Medicine, 232(9), 1170-1180. doi: 10.3181/0703-rm-77