RESUMEN
Retinoic acid (RA) has been found to regulate hypothalamic function, but precisely where it acts is unknown. This study shows expression of retinaldehyde dehydrogenase (RALDH) enzymes in tanycytes that line the third ventricle in an area overlapping with the site of hypothalamic neural stem cells. The influence of RA was examined on the proliferation of progenitors lining the third ventricle using organotypic slice cultures. As has been shown in other regions of neurogenesis, RA was found to inhibit proliferation. Investigations of the dynamics of RALDH1 expression in the rat hypothalamus have shown that this enzyme is in tanycytes under photoperiodic control with highest levels during long versus short days. In parallel to this shift in RA synthesis, cell proliferation in the third ventricle was found to be lowest during long days when RA was highest, implying that RALDH1 synthesized RA may regulate neural stem cell proliferation. A second RA synthesizing enzyme, RALDH2 was also present in tanycytes lining the third ventricle. In contrast to RALDH1, RALDH2 showed little change with photoperiodicity, but surprisingly the protein was present in the apparent absence of mRNA transcript and it is hypothesized that the endocytic tanycytes may take this enzyme up from the cerebrospinal fluid (CSF).
Asunto(s)
Proliferación Celular/efectos de los fármacos , Hipotálamo/citología , Hipotálamo/enzimología , Fotoperiodo , Retinal-Deshidrogenasa/biosíntesis , Tretinoina/farmacología , Familia de Aldehído Deshidrogenasa 1 , Animales , Western Blotting , Células Cultivadas , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Inmunohistoquímica , Hibridación in Situ , Isoenzimas/biosíntesis , Masculino , Ratones , Ratones Endogámicos C57BL , Células-Madre Neurales/efectos de los fármacos , Técnicas de Cultivo de Órganos , Reacción en Cadena de la Polimerasa , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Retinal-Deshidrogenasa/líquido cefalorraquídeo , Tercer Ventrículo/citología , Tercer Ventrículo/efectos de los fármacos , Tercer Ventrículo/metabolismo , Tretinoina/análisisRESUMEN
Retinoic acid (RA) constitutes the major active ingredient of vitamin A and is required for various biological processes. The tissue RA level is maintained through a cascade of metabolic reactions where retinal dehydrogenases (RALDHs) catalyze the terminal reaction of RA biosynthesis from retinal, a rate-limiting step. We showed that dietary supplement of cholesterol enhanced the expression of RALDH1 and 2 genes and the cellular RA content in vital organs such as brain, kidney, liver and heart. Consistently, the cholesterol-lowering agent (pravastatin sodium) downregulated the expression of RALDH1 and 2 genes in several organs especially the liver and in cultured liver cells. Further, cholesterol metabolites, predominantly the oxysterols, the natural ligands for liver X receptor (LXR), induced these genes via upregulation of sterol regulatory element binding protein-1c (SREBP-1c) that bound to the regulatory regions of these genes. Knockdown of LXRalpha/beta or SREBP-1c downregulated the expression of RALDH genes, which could be rescued by re-expressing SREBP-1c, suggesting SREBP-1c as a direct positive regulator for these genes. This study uncovered a novel crosstalk between cholesterol and RA biosynthesis.