Insight into molecular pathways of retinal metabolism, associated with vitellogenesis in zebrafish

Liraz Levi, Tamar Ziv, Arie Admon, Berta Levavi-Sivan, Esther Lubzens*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


Retinal is the main retinoid stored in oviparous eggs of fish, amphibians, and reptiles, reaching the oocytes in association with vitellogenins, the yolk precursor proteins. During early presegmentation stages of zebrafish embryos, retinal is metabolized to retinoic acid (RA), which regulates genes involved in cell proliferation, differentiation, and tissue function and is therefore essential for normal embryonic development. While synthesis of vitellogenin and its regulation by 17β-estradiol (E2) were extensively investigated, pathways for retinal synthesis remain obscure. We determined the expression pattern of 46 candidate genes, aiming at identifying enzymes associated with retinal synthesis, ascertaining whether they were regulated by E2, and finding pathways that could fulfill the demand for retinoids during vitellogenesis. Genes associated with retinal synthesis were upregulated in liver (rdh10, rdh13, sdr) and surprisingly also in intestine (rdh13) and ovary (rdh1, sdr), concomitantly with higher gene expression and synthesis of vitellogenins in liver but also in extrahepatic tissues, shown here for the first time. Vitellogenin synthesis in the ovary was regulated by E2. Gene expression studies suggest that elevated retinal synthesis in liver, intestine, and ovary also depends on cleavage of carotenoids (by Bcdo2 or Bmco1), but in the ovary it may also be contingent on higher uptake of retinol from the circulatory system (via Stra6) and retinol synthesis from retinyl esters (by Lpl). Decrease in oxidation (by Raldh2 or Raldh3) of retinal to RA and/or degradation of RA (by Cyp26a1) may also facilitate higher hepatic retinal levels. Together, these processes enable meeting the putative demands of retinal for binding to vitellogenins. Bioinformatic tools reveal multiple hormone response elements in the studied genes, suggesting complex and intricate regulation of these processes.

Original languageAmerican English
Pages (from-to)626-644
Number of pages19
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number6
StatePublished - Mar 2012


  • Carotenoids
  • Extrahepatic vitellogenin synthesis
  • Regulatory response elements
  • Retinoids


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