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J. Biol. Chem., Vol. 279, Issue 47, 48654-48662, November 19, 2004

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Secretion of Sterols and the NPC2 Protein from Primary Astrocytes^*

Aino-Liisa Mutka, Sari Lusa, Matts D. Linder, Eija Jokitalo, Outi Kopra, Matti Jauhiainen, and Elina Ikonen¶

From the Institute of Biotechnology, University of Helsinki, Viikinkaari 9, 00014 University of Helsinki and National Public Health Institute, Biomedicum Helsinki, Haartmaninkatu 8, 00251 Helsinki, Finland

Astrocytes secrete cholesterol in lipoprotein particles. Here we show that primary murine embryonic astrocytes secrete endogenously synthesized cholesterol but also the cholesterol precursors desmosterol and lathosterol. In astrocyte membranes, desmosterol and cholesterol were the predominant sterols. Astrocytes derived from Niemann-Pick type C lipidosis (NPC1^–/–) mice displayed late endosomal cholesterol deposits, but the secretion of biosynthetic sterols from the cells was not inhibited. Both wild-type and NPC1^–/– astrocytes secreted the NPC2 protein. Size-exclusion chromatography combined with electron microscopy showed that the majority of sterols were secreted separately from NPC2 in heterogeneous spherical particles with an average diameter of 20 nm. These data suggest that NPC2 and the majority of sterols secreted from astrocytes are not released together and that the secretion of neither sterols nor NPC2 requires NPC1 function. In addition, the findings reveal a complexity of sterol species in astrocytes and bring up the possibility that some of the effects assigned to astrocyte cholesterol may be attributed to its penultimate precursors.

Received for publication, May 13, 2004 , and in revised form, August 25, 2004.

^* This study was supported by Academy of Finland Grants 48905 and 49987, the Ara Parseghian Medical Research Foundation, the Sigrid Juselius Foundation, and the Helsinki Biomedical Graduate School. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 358-9-191-59423; Fax: 358-9-191-59366; E-mail: elina.ikonen{at}helsinki.fi.

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