Human Molecular Genetics Advance Access originally published online on September 23, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 22 2981-2991
DOI: 10.1093/hmg/ddg321
© 2003 Oxford University Press
NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets
1Center for Molecular and Human Genetics, Columbus Children's Research Institute, Columbus, OH 43205, USA and 2Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
Received July 15, 2003; Revised August 29, 2003; Accepted September 11, 2003
NSDHL, for NAD(P)H steroid dehydrogenase-like, encodes a sterol dehydrogenase or decarboxylase involved in the sequential removal of two C-4 methyl groups in post-squalene cholesterol biosynthesis. Mutations in this gene are associated with human CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects), an X-linked, male lethal disorder, as well as the mouse mutations bare patches and striated. In the present study, we have investigated the subcellular localization of tagged proteins encoded by wild-type and selected mutant murine Nsdhl alleles using confocal microscopy. In addition to an ER localization commonly found for enzymes of post-squalene cholesterol biosynthesis, we have identified a novel association of NSDHL with lipid droplets, which are endoplasmic reticulum (ER)-derived cytoplasmic structures that contain a neutral lipid core. We further demonstrate that trafficking through the Golgi is necessary for ER membrane localization of the protein and propose a model for the association of NSDHL with lipid droplets. The dual localization of NSDHL within ER membranes and on the surface of lipid droplets may provide another mechanism for regulation of the levels and sites of accumulation of intracellular cholesterol.
* To whom correspondence should be addressed at: Columbus Children's Research Institute, 700 Children's Drive, Room W403, Columbus, OH 43205, USA. Tel: +1 6147222848/9; Fax: +1 6147222817; Email: hermang{at}pediatrics.ohio-state.edu
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