The effect of cholesterol‐lowering agents on hepatic and plasma cholesterol in Niemann‐Pick disease type C

Patterson, Marc C.; Bisceglie, Adrian M. Di; Higgins, James J.; Abel, Robert; Schiffmann, Raphael; Parker, Clarissa C.; Argoff, Charles E.; Grewal, Rajbala; Yu, Kaifu; Pentchev, P. G.; Ro, Brady; Barton, Norman W.

doi:10.1212/wnl.43.1_part_1.61

Cited by 95 publications

(56 citation statements)

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“…Although the lipid profiles of NPC-deficient patients have been reported previously to be normal (1,42), the only data in the literature are for total plasma cholesterol levels (43). With the help of the Ara Parseghian Medical Research Foundation, we obtained the fasting lipid profiles of 21 NPC1 Ϫ/Ϫ patients ( Table I).…”

Section: Hdl Levels Are Low In Npc1mentioning

confidence: 99%

Impaired ABCA1-dependent Lipid Efflux and Hypoalphalipoproteinemia in Human Niemann-Pick type C Disease

Choi

Karten

Chan

et al. 2003

Journal of Biological Chemistry

130

119

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The cholesterol trafficking defect in Niemann-Pick type C (NPC) disease leads to impaired regulation of cholesterol esterification, cholesterol synthesis, and low density lipoprotein receptor activity. The ATP-binding cassette transporter A1 (ABCA1), which mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, is also regulated by cell cholesterol content. To determine whether the Niemann-Pick C1 protein alters the expression and activity of ABCA1, we determined the ability of apolipoprotein A-I (apoA-I) to deplete pools of cellular cholesterol and phospholipids in human fibroblasts derived from NPC1 and NPC1؉/؊ cells but showed low levels at base line and in response to cholesterol loading in NPC1 ؊/؊ cells. Consistent with impaired ABCA1-dependent lipid mobilization to apoA-I for HDL particle formation, we demonstrate for the first time decreased plasma HDL-cholesterol levels in 17 of 21 (81%) NPC1 ؊/؊ subjects studied. These results indicate that the cholesterol trafficking defect in NPC disease results in reduced activity of ABCA1, which we suggest is responsible for the low HDL-cholesterol in the majority of NPC subjects and partially responsible for the overaccumulation of cellular lipids in this disorder.

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Section: Hdl Levels Are Low In Npc1mentioning

confidence: 99%

Impaired ABCA1-dependent Lipid Efflux and Hypoalphalipoproteinemia in Human Niemann-Pick type C Disease

Choi

Karten

Chan

et al. 2003

Journal of Biological Chemistry

130

119

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“…In plants, a connection between membrane sterol composition and cell polarity has not been reported previously. However, several sterols structurally related to cholesterol are present in plants, sitosterol being the most abundant (Patterson et al, 1993). Campesterol, the next abundant sterol, is a precursor of brassinosteroids, which are involved in the control of plant growth and development (Altmann, 1998;Clouse and Feldmann, 1999).…”

Section: Introductionmentioning

confidence: 99%

Cell Polarity and PIN Protein Positioning in Arabidopsis Require STEROL METHYLTRANSFERASE1 Function

et al. 2003

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Plants have many polarized cell types, but relatively little is known about the mechanisms that establish polarity. The orc mutant was identified originally by defects in root patterning, and positional cloning revealed that the affected gene encodes STEROL METHYLTRANSFERASE1, which is required for the appropriate synthesis and composition of major membrane sterols. smt1 orc mutants displayed several conspicuous cell polarity defects. Columella root cap cells revealed perturbed polar positioning of different organelles, and in the smt1 orc root epidermis, polar initiation of root hairs was more randomized. Polar auxin transport and expression of the auxin reporter DR5 -␤ -glucuronidase were aberrant in smt1 orc . Patterning defects in smt1 orc resembled those observed in mutants of the PIN gene family of putative auxin efflux transporters. Consistently, the membrane localization of the PIN1 and PIN3 proteins was disturbed in smt1 orc , whereas polar positioning of the influx carrier AUX1 appeared normal. Our results suggest that balanced sterol composition is a major requirement for cell polarity and auxin efflux in Arabidopsis.

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“…The early work of Pentchev and others showed that NPC-diseased cells are laden with LDL-derived free unesterified cholesterol and other lipids in their lysosomes, which was thought to be the direct cause of NPC disease pathology (2)(3)(4). Therapeutic interventions aimed at limiting the biosynthesis and/or uptake of cholesterol and other lipids have been quite effective in reducing the hyperaccumulation phenotype; however, such approaches have not been successful in significantly decreasing NPC disease progression in various human and animal disease models (5)(6)(7)(8). Accordingly, the true functional role of NPC1 has been controversial and is, perhaps, unknown (9).…”

mentioning

confidence: 99%

Niemann-Pick C1 Functions in Regulating Lysosomal Amine Content

Kaufmann

Krise

2008

Journal of Biological Chemistry

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Mutations in the late endosomal/lysosomal membrane protein Niemann-Pick C1 (NPC1) are known to cause a generalized block in retrograde vesicle-mediated transport, resulting in the hyper-accumulation of multiple lysosomal cargos. An important, yet often overlooked, category of lysosomal cargo includes the vast array of small molecular weight amine-containing molecules that are substrates for ion trapping in the highly acidic organelle lumen. We show here that the introduction of aminecontaining molecules in lysosomes can significantly stimulate NPC1-mediated late endosome/lysosome fusion, and subsequently the secretion of lysosomal cargo. To illustrate the physiological importance of this NPC1-mediated transport pathway, we show that NPC1-deficient cells are more susceptible to the toxic effects of a lysosomotropic polyamine metabolite 3-aminopropanal. Moreover, NPC fibroblasts are shown to have higher levels of polyamine oxidase, an enzyme involved in the formation of 3-aminopropanal. Collectively, these findings provide strong support for a novel functional role for NPC1 and may also provide clues toward understanding NPC disease progression.

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The effect of cholesterol‐lowering agents on hepatic and plasma cholesterol in Niemann‐Pick disease type C

Cited by 95 publications

References 0 publications

Impaired ABCA1-dependent Lipid Efflux and Hypoalphalipoproteinemia in Human Niemann-Pick type C Disease

Impaired ABCA1-dependent Lipid Efflux and Hypoalphalipoproteinemia in Human Niemann-Pick type C Disease

Cell Polarity and PIN Protein Positioning in Arabidopsis Require STEROL METHYLTRANSFERASE1 Function

Niemann-Pick C1 Functions in Regulating Lysosomal Amine Content

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