This Article Full Text Full Text (PDF) Supplemental Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zikova, M. Articles by Bartunek, P. Search for Related Content PubMed PubMed Citation Articles by Zikova, M. Articles by Bartunek, P.

DISP3, a Sterol-Sensing Domain-Containing Protein that Links Thyroid Hormone Action and Cholesterol Metabolism

Departments of Cell Differentiation (M.Z., A.C., P.B.) and Molecular Virology (P.P.), Institute of Molecular Genetics AS CR v.v.i., and Department of Neurohumoral Regulation (Z.B.), Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic

Address all correspondence and requests for reprints to: Petr Bartunek, Ph.D., Department of Cell Differentiation, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. E-mail: bartunek{at}img.cas.cz.

In the body, the brain is the most cholesterol-rich organ. Despite this, remarkably little is known about the mechanisms in the brain that regulate cholesterol homeostasis. Due to the blood-brain barrier, plasma lipoproteins are unable to traverse, and instead cholesterol must be synthesized de novo from within the central nervous system. Thyroid hormone receptors, activated in response to thyroid hormone (T₃), are known to modulate the level of serum cholesterol via complex regulatory pathways. By screening for T₃-regulated genes we have identified Disp3, a sterol-sensing domain-containing protein that is related to the Dispatched family of proteins. Analysis by RT-PCR and immunohistochemistry demonstrated that DISP3 is predominately expressed in specific cell types of the brain, retina, and testis. Using the model of hyperthyroidism in vivo, we observed the modulation of Disp3 expression in the retina. Furthermore, in vitro analysis of Disp3 expression in cells treated with T₃ revealed both positive and negative regulation. DISP3 localizes within the endoplasmic reticulum and was further found to colocalize with cholesterol. Ectopic expression of DISP3 in fibroblasts resulted in elevated cholesterol levels combined with an altered cholesterol distribution. Given that DISP3 is highly expressed in Purkinje cells, hippocampal neurons, and retinal ganglion cells and that its overexpression results in increased cholesterol levels, it is tempting to postulate that DISP3 may contribute to cholesterol homeostasis in neural cell types. Taken together, we propose that DISP3 represents a new molecular link between thyroid hormone and cholesterol metabolism.

NURSA Molecule Pages Link:

Ligands:   Thyroid hormone