Heme regulates exocrine peptidase precursor genes in zebrafish.
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.
Wang
Han
H
Department of Zoology and Stephenson Research & Technology Center, University of Oklahoma, Norman, Oklahoma 73019, USA. hwang@ou.edu
Zhou
Qingchun
Q
Kesinger
Jason W
JW
Norris
Chad
C
Valdez
Cammi
C
D000624:5-Aminolevulinate Synthetase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017931:DNA Primers / Q000378:metabolism; D015536:Down-Regulation; D004625:Embryo, Nonmammalian / Q000201:enzymology; D004792:Enzyme Precursors / Q000235:genetics* / Q000378:metabolism; D006418:Heme / Q000172:deficiency / Q000378:metabolism*; D006427:Hemin / Q000378:metabolism / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D046790:Pancreas, Exocrine / Q000201:enzymology* / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; D004792:Enzyme Precursors; D014157:Transcription Factors; C062602:transcription factor PTF1; D006418:Heme; D006427:Hemin; D000624:5-Aminolevulinate Synthetase; D010447:Peptide Hydrolases