NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets

Hum Mol Genet. 2003 Nov 15;12(22):2981-91. doi: 10.1093/hmg/ddg321. Epub 2003 Sep 23.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3-Hydroxysteroid Dehydrogenases
  • Alleles
  • Animals
  • Biomarkers
  • Blotting, Western
  • COS Cells
  • Chlorocebus aethiops
  • Cholesterol / biosynthesis*
  • Codon, Nonsense
  • Endoplasmic Reticulum / enzymology
  • Endoplasmic Reticulum / metabolism*
  • Fluorescent Antibody Technique, Direct
  • Golgi Apparatus / metabolism*
  • Green Fluorescent Proteins
  • HeLa Cells
  • Humans
  • Hydroxysteroid Dehydrogenases / metabolism*
  • Lipid Metabolism*
  • Luminescent Proteins / metabolism
  • Mice
  • Microscopy, Confocal
  • Models, Biological
  • Protein Transport
  • Recombinant Fusion Proteins / metabolism
  • Subcellular Fractions / metabolism

Substances

  • Biomarkers
  • Codon, Nonsense
  • Luminescent Proteins
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins
  • Cholesterol
  • 3-Hydroxysteroid Dehydrogenases
  • Hydroxysteroid Dehydrogenases
  • Nsdhl protein, human