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J Lipid Res. 2017 Apr;58(4):695-708. doi: 10.1194/jlr.M072140. Epub 2017 Feb 13.

Histone deacetylase inhibitors correct the cholesterol storage defect in most Niemann-Pick C1 mutant cells.

Author information

1
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065; and Department of Chemical Physiology and Cell and Molecular Biology.
2
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037.
3
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037 frmaxfie@med.cornell.edu webalch@scripps.edu.
4
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065; and Department of Chemical Physiology and Cell and Molecular Biology, frmaxfie@med.cornell.edu webalch@scripps.edu.

Erratum in

Abstract

Niemann-Pick C (NPC) disease is an autosomal recessive disorder that leads to excessive storage of cholesterol and other lipids in late endosomes and lysosomes. The large majority of NPC disease is caused by mutations in NPC1, a large polytopic membrane protein that functions in late endosomes. There are many disease-associated mutations in NPC1, and most patients are compound heterozygotes. The most common mutation, NPC1I1061T, has been shown to cause endoplasmic reticulum-associated degradation of the NPC1 protein. Treatment of patient-derived NPC1I1061T fibroblasts with histone deacetylase inhibitors (HDACis) vorinostat or panobinostat increases expression of the mutant NPC1 protein and leads to correction of the cholesterol storage. Here, we show that several other human NPC1 mutant fibroblast cell lines can also be corrected by vorinostat or panobinostat and that treatment with vorinostat extends the lifetime of the NPC1I1061T protein. To test effects of HDACi on a large number of NPC1 mutants, we engineered a U2OS cell line to suppress NPC1 expression by shRNA and then transiently transfected these cells with 60 different NPC1 mutant constructs. The mutant NPC1 did not significantly reduce cholesterol accumulation, but approximately 85% of the mutants showed reduced cholesterol accumulation when treated with vorinostat or panobinostat.

KEYWORDS:

NPC1; cellular cholesterol; cholesterol trafficking; drug therapy; inborn errors of metabolism; lipid transport

PMID:
28193631
PMCID:
PMC5392745
DOI:
10.1194/jlr.M072140
[Indexed for MEDLINE]
Free PMC Article

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