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ORIGINAL RESEARCH ARTICLE

Heme Regulates Exocrine Peptidase Precursor Genes in Zebrafish

Department of Zoology and Stephenson Research & Technology Center, University of Oklahoma, Norman, Oklahoma 73019

To whom requests for reprints should be addressed at ¹ Department of Zoology and Stephenson Research & Technology Center, University of Oklahoma, Norman, OK 73019. E-mail: hwang{at}ou.edu

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 (yqe^tp61) 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 (sau^tb223) larvae, carrying a mutation in the gene encoding -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.

Key Words: heme • zymogens • pancreas • porphyria • zebrafish