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This Article Full Text Full Text (PDF) All Versions of this Article: 295/6/E1455    most recent 90527.2008v1 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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wang, F. Articles by Tikkanen, M. J. Search for Related Content PubMed PubMed Citation Articles by Wang, F. Articles by Tikkanen, M. J.

Role of lysosomal acid lipase in the intracellular metabolism of LDL-transported dehydroepiandrosterone-fatty acyl esters

¹Department of Medicine, Helsinki University Central Hospital, ²Institute of Biomedicine/Anatomy, ³Department of Organic Chemistry, ⁴Institute for Preventive Medicine, Nutrition and Cancer, Folkhälsan Research Center and Division of Clinical Chemistry, University of Helsinki, Helsinki, Finland

Submitted 21 June 2008 ; accepted in final form 14 September 2008

Dehydroepiandrosterone-fatty acyl esters (DHEA-FAE) belong to a unique family of naturally occurring hydrophobic steroid hormone derivatives that are transported in circulating lipoproteins and may act as a source of dehydroepiendrosterone (DHEA) and other biologically active steroid hormones in cells. Here, we studied the metabolic fate of low-density lipoprotein-associated [³H]DHEA-FAE ([³H]DHEA-FAE-LDL) and the possible role of lysosomal acid lipase (LAL) in the hydrolysis of DHEA-FAE in cultured human cells. When HeLa cells were incubated with [³H]DHEA-FAE-LDL, the accumulation of label in the cellular fraction increased with incubation time and could be inhibited by excess unlabeled LDL, suggesting LDL receptor or LDL receptor-related receptor-dependent uptake. During 48 h of chase, decreasing amounts of [³H]DHEA-FAE were found in the cellular fraction, while in the medium increasing amounts of unesterified [³H]DHEA and its two metabolites, [³H]-5-androstanedione (5-adione) and [³H]androstenedione (4-adione), appeared. As LDL-cholesteryl ester hydrolysis is dependent on LAL activity, we depleted LAL from HeLa cells using small interfering RNAs and compared the hydrolysis of [³H]DHEA-FAE-LDL and [³H]cholesteryl-FAE-LDL. The results demonstrated a more modest but significant reducing effect on the hydrolysis of [³H]DHEA-FAE compared with [³H]cholesteryl-FAE. Moreover, experiments in LAL-deficient human fibroblasts (Wolman disease patient cells) showed that [³H]DHEA-FAE hydrolysis was not completely dependent on LAL activity. In summary, LDL-transported [³H]DHEA-FAE entered cells via LDL receptor or LDL receptor-related receptor-mediated uptake, followed by intracellular hydrolysis and further metabolism into 5-adione and 4-adione that were excreted from cells. Although LAL contributed to the deesterification of DHEA-FAE, it was not solely responsible for the hydrolysis.

ribonucleic acid interference; chromatography; dehydroepiandrosterone