δ-tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders

Miao Xu, Ke Liu, Manju Swaroop, Forbes D. Porter, Rohini Sidhu, Sally Finkes, Daniel S. Ory, Juan J. Marugan, Jingbo Xiao, Noel Southall, William J. Pavan, Cristin Davidson, Steven U. Walkley, Alan T. Remaley, Ulrich Baxa, Wei Sun, John C. McKew, Christopher P. Austin, Wei Zheng

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that δ-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a δ-tocopherol-induced intracellular Ca2+ response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that δ-tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases.

Original languageEnglish (US)
Pages (from-to)39349-39360
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number47
DOIs
StatePublished - Nov 16 2012

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Tocopherols
Wolman Disease
Cholesterol
Lipids
Exocytosis
Type A Niemann-Pick Disease
Mucopolysaccharidosis III
Fibroblasts
Type C Niemann-Pick Disease
Lysosomal Storage Diseases
Sterol Esterase
Phenotype
Lysosomes
Ceroid
Gene encoding
Mutation
Pharmaceutical Preparations
Genes
Proteins
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

δ-tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders. / Xu, Miao; Liu, Ke; Swaroop, Manju; Porter, Forbes D.; Sidhu, Rohini; Finkes, Sally; Ory, Daniel S.; Marugan, Juan J.; Xiao, Jingbo; Southall, Noel; Pavan, William J.; Davidson, Cristin; Walkley, Steven U.; Remaley, Alan T.; Baxa, Ulrich; Sun, Wei; McKew, John C.; Austin, Christopher P.; Zheng, Wei.

In: Journal of Biological Chemistry, Vol. 287, No. 47, 16.11.2012, p. 39349-39360.

Research output: Contribution to journalArticle

Xu, M, Liu, K, Swaroop, M, Porter, FD, Sidhu, R, Finkes, S, Ory, DS, Marugan, JJ, Xiao, J, Southall, N, Pavan, WJ, Davidson, C, Walkley, SU, Remaley, AT, Baxa, U, Sun, W, McKew, JC, Austin, CP & Zheng, W 2012, 'δ-tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders', Journal of Biological Chemistry, vol. 287, no. 47, pp. 39349-39360. https://doi.org/10.1074/jbc.M112.357707
Xu, Miao ; Liu, Ke ; Swaroop, Manju ; Porter, Forbes D. ; Sidhu, Rohini ; Finkes, Sally ; Ory, Daniel S. ; Marugan, Juan J. ; Xiao, Jingbo ; Southall, Noel ; Pavan, William J. ; Davidson, Cristin ; Walkley, Steven U. ; Remaley, Alan T. ; Baxa, Ulrich ; Sun, Wei ; McKew, John C. ; Austin, Christopher P. ; Zheng, Wei. / δ-tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 47. pp. 39349-39360.
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AU - Liu, Ke

AU - Swaroop, Manju

AU - Porter, Forbes D.

AU - Sidhu, Rohini

AU - Finkes, Sally

AU - Ory, Daniel S.

AU - Marugan, Juan J.

AU - Xiao, Jingbo

AU - Southall, Noel

AU - Pavan, William J.

AU - Davidson, Cristin

AU - Walkley, Steven U.

AU - Remaley, Alan T.

AU - Baxa, Ulrich

AU - Sun, Wei

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N2 - Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that δ-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a δ-tocopherol-induced intracellular Ca2+ response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that δ-tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases.

AB - Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that δ-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a δ-tocopherol-induced intracellular Ca2+ response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that δ-tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases.

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