Altered vitamin E status in Niemann-Pick type C disease

Ulatowski, Lynn; Parker, Robert S.; Davidson, Cristin; Yanjanin, Nicole M.; Kelley, Thomas J.; Corey, Deborah A.; Atkinson, Jeffrey; Porter, Forbes D.; Arai, Hiroyuki; Walkley, Steven U.; Manor, Danny

doi:10.1194/jlr.m015560

Cited by 34 publications

(45 citation statements)

References 86 publications

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“…At that point, NBD-␣-tocopherol co-localized with LysoTracker, a fluorescent reporter that selectively marks lysosomes, as we previously observed in fixed cells (Fig. 1A) (33,46). These observations support our previous findings that ␣-tocopherol is taken up through endocytosis (33) and extend these findings to live cells.…”

Section: Resultssupporting

confidence: 81%

“…Uptake of ␣-Tocopherol in Cultured Hepatocytes-To examine the uptake of ␣-tocopherol into hepatocytes with high spatial resolution, we utilized NBD-␣-tocopherol, a fluorescent analog that we have previously shown to be a reliable reporter of the vitamin's location in cells and when bound to TTP (19,30,31,33,(42)(43)(44)(45)(46). To examine the time course of vitamin E uptake, cells were incubated with the serum⅐NBD-␣-tocopherol complex at 4°C, and the unbound vitamin was washed with serumfree media and uptake initiated by switching the cells back to 37°C.…”

Section: Resultsmentioning

confidence: 99%

“…It is well established that secretion of ␣-tocopherol from hepatocytes is sensitive to disruption of lysosomal integrity (33,34,46,64,65), thereby implicating vesicular transport. Arai and co-workers (34) have shown that TTP-facilitated secretion of ␣-tocopherol from hepatocytes relies on a novel transport pathway that is independent of Golgi function and therefore uncoupled from the hepatic assembly and export of nascent lipoproteins.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Vitamin E and Phosphoinositides Regulate the Intracellular Localization of the Hepatic α-Tocopherol Transfer Protein

Chung¹,

Ghelfi

Atkinson

et al. 2016

Journal of Biological Chemistry

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␣-Tocopherol (vitamin E) is an essential nutrient for all vertebrates. From the eight naturally occurring members of the vitamin E family, ␣-tocopherol is the most biologically active species and is selectively retained in tissues. The hepatic ␣-tocopherol transfer protein (TTP) preferentially selects dietary ␣-tocopherol and facilitates its transport through the hepatocyte and its secretion to the circulation. In doing so, TTP regulates body-wide levels of ␣-tocopherol. The mechanisms by which TTP facilitates ␣-tocopherol trafficking in hepatocytes are poorly understood. We found that the intracellular localization of TTP in hepatocytes is dynamic and responds to the presence of ␣-tocopherol. In the absence of the vitamin, TTP is localized to perinuclear vesicles that harbor CD71, transferrin, and Rab8, markers of the recycling endosomes. Upon treatment with ␣-tocopherol, TTP-and ␣-tocopherol-containing vesicles translocate to the plasma membrane, prior to secretion of the vitamin to the exterior of the cells. The change in TTP localization is specific to ␣-tocopherol and is time-and dose-dependent. The aberrant intracellular localization patterns of lipid binding-defective TTP mutants highlight the importance of protein-lipid interaction in the transport of ␣-tocopherol. These findings provide the basis for a proposed mechanistic model that describes TTP-facilitated trafficking of ␣-tocopherol through hepatocytes.Vitamin E is a plant-derived lipid that was discovered as a dietary component vital for female fertility in rodents (1) and for neuronal health in humans (2). Eight vitamin E forms are synthesized by plants, differing in the degree of methylation of the chromanol ring and the saturation of the isoprenoid side chain (3). Of the eight naturally occurring forms of vitamin E, ␣-tocopherol exhibits the most potent biological activity in preventing deficiency-induced reproductive failure in rodents (4, 5). ␣-Tocopherol's efficacy in scavenging free radicals (i.e. functioning as an antioxidant) is thought to underlie its critical roles in health (6 -8), but additional redox-independent actions have been recently proposed (9).The major regulator of vitamin E status is the ␣-tocopherol transfer protein (TTP), 2 and mutations in the TTPA gene cause heritable vitamin E deficiency. In humans, mutations in the TTPA gene cause systemic vitamin E deficiency accompanied by neurological compromise, primarily spinocerebellar ataxia (10 -17). Patients afflicted with this disorder (ataxia with vitamin E deficiency; OMIM 277460) present with debilitating neurodegeneration, the severity of which depends on the specific mutation's effect on TTP's biochemical activity (18,19). Lifelong vitamin E supplementation can delay or reverse disease progression, especially when patients are treated in earlier stages (20,21). Disruption of the TtpA gene in mice recapitulated the human ataxia with vitamin E deficiency disorder (22).TTP is expressed at high levels in parenchymal cells of the liver (23, 24), but low level expression has b...

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Vitamin E and Phosphoinositides Regulate the Intracellular Localization of the Hepatic α-Tocopherol Transfer Protein

Chung¹,

Ghelfi

Atkinson

et al. 2016

Journal of Biological Chemistry

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“…1G, middle panel). NPC1 protein levels are reduced by approximately 70% in the knockdown cells used in this study (50). While this amount of NPC1 expression was sufficient to substantially reduce SREBP-1 processing following LDL loading similarly to the results seen in parent cells with physiological NPC1 protein levels, SREBP-1 pro- …”

Section: Resultsmentioning

confidence: 73%

“…Human lung epithelial A549 cells (ATCC catalog number CCL-185) and Chinese hamster ovary (CHO) cells (ATCC catalog PTA9816) were grown in Ham's F12 and minimal essential medium (MEM)-alpha media, respectively, supplemented with 10% fetal bovine serum (FBS). Immortalized human hepatocyte cells (ATCC catalog number CRL-11233) stably expressing noncoding shRNA or NPC1 shRNA (denoted "shControl" or "shNPC1," respectively) were grown in Dulbecco's minimal essential media (DME) supplemented with puromycin (10 g/ml) and 10% FBS (50). A549 and shNPC1 cells with stable expression of a FLAG-tagged RID␣ transgene are described in references 15 and 16.…”

Section: Methodsmentioning

confidence: 99%

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

Cianciola

Chung

Manor

et al. 2017

J Virol

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Human adenoviruses (Ads) generally cause mild self-limiting infections but can lead to serious disease and even be fatal in high-risk individuals, underscoring the importance of understanding how the virus counteracts host defense mechanisms. This study had two goals. First, we wished to determine the molecular basis of cholesterol homeostatic responses induced by the early region 3 membrane protein RID␣ via its direct interaction with the sterol-binding protein ORP1L, a member of the evolutionarily conserved family of oxysterol-binding protein (OSBP)-related proteins (ORPs). Second, we wished to determine how this interaction regulates innate immunity to adenovirus. ORP1L is known to form highly dynamic contacts with endoplasmic reticulum-resident VAP proteins that regulate late endosome function under regulation of Rab7-GTP. Our studies have demonstrated that ORP1L-VAP complexes also support transport of LDL-derived cholesterol from endosomes to the endoplasmic reticulum, where it was converted to cholesteryl esters stored in lipid droplets when ORP1L was bound to RID␣. The virally induced mechanism counteracted defects in the predominant cholesterol transport pathway regulated by the late endosomal membrane protein Niemann-Pick disease type C protein 1 (NPC1) arising during early stages of viral infection. However, unlike NPC1, RID␣ did not reconstitute transport to endoplasmic reticulum pools that regulate SREBP transcription factors. RID␣-induced lipid trafficking also attenuated proinflammatory signaling by Toll-like receptor 4, which has a central role in Ad pathogenesis and is known to be tightly regulated by cholesterol-rich "lipid rafts." Collectively, these data show that RID␣ utilizes ORP1L in a way that is distinct from its normal function in uninfected cells to fine-tune lipid raft cholesterol that regulates innate immunity to adenovirus in endosomes.IMPORTANCE Early region 3 proteins encoded by human adenoviruses that attenuate immune-mediated pathology have been a particularly rich source of information regarding intracellular protein trafficking. Our studies with the early region 3-encoded RID␣ protein also provided fundamental new information regarding mechanisms of nonvesicular lipid transport and the flow of molecular information at membrane contacts between different organelles. We describe a new pathway that delivers cholesterol from endosomes to the endoplasmic reticulum, where it is esterified and stored in lipid droplets. Although lipid droplets are attracting renewed interest from the standpoint of normal physiology and human diseases, including those resulting from viral infections, experimental model systems for evaluating how and why they accumulate are still limited. Our studies also revealed an intriguing relationship between lipid droplets and innate immunity that may represent a new paradigm for viruses utilizing these organelles.KEYWORDS adenoviruses, cholesterol, endocytic pathway, endoplasmic reticulum, lipid droplet

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Sterol uptake by the NPC system in eukaryotes: a Saccharomyces cerevisiae perspective

et al. 2021

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Sterols are an essential component of membranes in all eukaryotic cells and the precursor of multiple indispensable cellular metabolites. After endocytotic uptake, sterols are integrated into the lysosomal membrane by the Niemann-Pick type C (NPC) system before redistribution to other membranes. The process is driven by two proteins that, together, compose the NPC system: the lysosomal sterol shuttle protein NPC2 and the membrane protein NPC1 (named NCR1 in fungi), which integrates sterols into the lysosomal membrane. The Saccharomyces cerevisiae NPC system provides a compelling model to study the molecular mechanism of sterol integration into membranes and sterol homeostasis. This review summarizes recent advances in the field, and by interpreting available structural data, we propose a unifying conceptual model for sterol loading, transfer and transport by NPC proteins.

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Altered vitamin E status in Niemann-Pick type C disease

Cited by 34 publications

References 86 publications

Vitamin E and Phosphoinositides Regulate the Intracellular Localization of the Hepatic α-Tocopherol Transfer Protein

Vitamin E and Phosphoinositides Regulate the Intracellular Localization of the Hepatic α-Tocopherol Transfer Protein

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

Sterol uptake by the NPC system in eukaryotes: a Saccharomyces cerevisiae perspective

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