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The Niemann-Pick C1 and caveolin-1 proteins interact to modulate efflux of low density lipoprotein-derived cholesterol from late endocytic compartments.

ABSTRACT: The Niemann-Pick C1 (NPC1) protein has a central role in regulating the efflux of lipoprotein-derived cholesterol from late endosomes/lysosomes and transport to other cellular compartments. Since the NPC1 protein has been shown to regulate the transport of cholesterol to cellular compartments enriched with the ubiquitous cholesterol-binding and transport protein caveolin-1, the present study was performed to determine whether the NPC1 and caveolin-1 proteins interact and function to modulate efflux of low density lipoprotein (LDL)-derived cholesterol from endocytic compartments. To perform these studies, normal human fibroblasts were grown in media with lipoprotein-deficient serum (LPDS) or media with LPDS supplemented with purified human LDL. The results indicated reciprocal co-immunoprecipitation and partial co-localization of the NPC1 and caveolin-1 proteins that was decreased when fibroblasts were grown in media with LDL. Consistent with interaction of the NPC1 and caveolin-1 proteins, a highly conserved caveolin-binding motif was identified within a cytoplasmic loop located adjacent to the sterol-sensing domain (SSD) of the NPC1 protein. To examine the functional relevance of this interaction, fibroblasts were transfected with caveolin-1 siRNA and found to accumulate increased amounts of LDL-derived cholesterol within late endosomes/ lysosomes. Together, this report presents novel results demonstrating that the NPC1 and caveolin-1 proteins interact to modulate efflux of LDL-derived cholesterol from late endocytic compartments.

SUBMITTER: Jelinek D

PROVIDER: S-EPMC4181540 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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The Niemann-Pick C1 and caveolin-1 proteins interact to modulate efflux of low density lipoprotein-derived cholesterol from late endocytic compartments.

Jelinek David D Heidenreich Randy A RA Orlando Robert A RA Garver William S WS

Journal of molecular biochemistry 20140201 1

The Niemann-Pick C1 (NPC1) protein has a central role in regulating the efflux of lipoprotein-derived cholesterol from late endosomes/lysosomes and transport to other cellular compartments. Since the NPC1 protein has been shown to regulate the transport of cholesterol to cellular compartments enriched with the ubiquitous cholesterol-binding and transport protein caveolin-1, the present study was performed to determine whether the NPC1 and caveolin-1 proteins interact and function to modulate eff ...[more]

PMID: 25285302

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Project description:OBJECTIVES:The aim of this study was to comprehensively evaluate the auditory phenotype in Niemann-Pick disease, type C1 (NPC1), to understand better the natural history of this complex, heterogeneous disorder, and to define further the baseline auditory deficits associated with NPC1 so that use of potentially ototoxic interventions (e.g., 2-hydroxypropyl-ß-cyclodextrin) may be more appropriately monitored and understood. DESIGN:Fifty patients with NPC1 ranging in age from 4 months to 21 years (mean = 9.3 years) enrolled in a natural history/observational study at the National Institutes of Health. The auditory test battery included, when possible, immittance audiometry, pure-tone and speech audiometry, otoacoustic emission testing, and a neurotologic auditory brainstem response study. Longitudinal data were collected on a subset of patients. RESULTS:Over half of the cohort exhibited hearing loss involving the high frequencies ranging from a slight to moderate degree, and 74% of patients presented with clinically significant hearing loss involving the frequencies most important to speech understanding (0.5, 1, 2, 4 kHz). Despite the heterogeneity of the sample, results among patients were sufficiently consistent to implicate retrocochlear dysfunction in the majority (66%) of individuals, with (22%) or without (44%) accompanying cochlear involvement. Some patients (10%) presented with a profile for auditory neuropathy spectrum disorder. The combination of cross-sectional and longitudinal data indicates these patients are at risk for a progressive decline in auditory function. CONCLUSIONS:This is the largest cohort of patients with NPC1 evaluated comprehensively for auditory dysfunction, and results implicate the pathological processes of NPC1 in the manifestation of hearing loss. Patients with NPC1 should be monitored audiologically throughout their lives, beginning at the time of diagnosis. Clinicians and researchers should be aware of this historically overlooked aspect of the phenotype.

Dataset Information

The Niemann-Pick C1 and caveolin-1 proteins interact to modulate efflux of low density lipoprotein-derived cholesterol from late endocytic compartments.

Publications

The Niemann-Pick C1 and caveolin-1 proteins interact to modulate efflux of low density lipoprotein-derived cholesterol from late endocytic compartments.

Similar Datasets

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