ZFIN ID: ZDB-PUB-071001-15
Heme regulates exocrine peptidase precursor genes in zebrafish
Wang, H., Zhou, Q., Kesinger, J.W., Norris, C., and Valdez, C.
Date: 2007
Source: Experimental Biology and Medicine   232(9): 1170-1180 (Journal)
Registered Authors: Wang, Han
Keywords: heme, zymogens, pancreas, porphyria, zebrafish
Microarrays: GEO:GSE8651
MeSH Terms:
  • 5-Aminolevulinate Synthetase/genetics
  • 5-Aminolevulinate Synthetase/metabolism
  • Animals
  • DNA Primers/metabolism
  • Down-Regulation
  • Embryo, Nonmammalian/enzymology
  • Enzyme Precursors/genetics*
  • Enzyme Precursors/metabolism
  • Heme/deficiency
  • Heme/metabolism*
  • Hemin/metabolism
  • Hemin/pharmacology
  • Oligonucleotide Array Sequence Analysis
  • Pancreas, Exocrine/enzymology*
  • Pancreas, Exocrine/metabolism
  • Peptide Hydrolases/genetics*
  • Peptide Hydrolases/metabolism
  • Phylogeny
  • Transcription Factors/genetics
  • Transcription Factors/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish/metabolism
PubMed: 17895525 Full text @ Exp. Biol. Med.
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 delta-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.