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

Abstract

Levi L, Ziv T, Admon A, Levavi-Sivan B, Lubzens E. Insight into molecular pathways of retinal metabolism, associated with vitellogenesis in zebrafish. Am J Physiol Endocrinol Metab 302: E626 -E644, 2012. First published December 28, 2011; doi:10.1152/ajpendo.00310.2011Retinal 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 17␤-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 E 2. 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. extrahepatic vitellogenin synthesis; regulatory response elements; retinoids; carotenoids RETINAL IS THE PREDOMINANT RETINOID in eggs and oocytes of marine fish and some freshwater fish species and may constitute almost the entire pool of retinoids in these eggs. In oviparous eggs of nonmammalian vertebrates such as teleosts, amphibians, and birds, maternally derived retinal is bound via a Schiff-base linkage to vitellogenins (Vtgs) (15, 32, 62, 63, 64, 72 reviewed in 50). The retinal in fish oocytes and eggs consists of several isomers, whereas the all-trans form is the most abundant in zebrafish embryos (15,44). The use of the all-trans isomer of retinal for major retinoid storage is unique to reptiles, anamniotic vertebrates (teleosts and amphibians), and eggs of ascidian (33,34). This is in contrast to higher vertebrates (birds and mammals), where retinol is the...

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