NPC1 and NPC2 Regulate Cellular Cholesterol Homeostasis through Generation of Low Density Lipoprotein Cholesterol-derived Oxysterols

Frolov, Andrey; Zielinski, Sarah E.; Crowley, Jan R.; Dudley-Rucker, Nicole; Schaffer, Jean E.; Ory, Daniel S.

doi:10.1074/jbc.m302588200

Cited by 192 publications

(204 citation statements)

References 49 publications

Supporting

Mentioning

182

Contrasting

Order By: Relevance

“…7, which is published as supporting information on the PNAS web site). However, despite deficiency of endogenous oxysterol ligands (13), NPC1 mutants respond appropriately to exogenous LXR ligand activation. To extend these findings to an in vivo model of NPC1 disease, we investigated whether treatment of npc1 Ϫ/Ϫ mice with T0901317 can promote LXR target gene expression in brain tissue and thereby ameliorate disease progression.…”

Section: T0901317 and Allo Therapy Improves Function And Survival Inmentioning

confidence: 99%

“…NPC1 mutant cells also fail to appropriately use lipoprotein cholesterol for synthesis of 25-hydroxycholesterol and 27-hydroxycholesterol (13). These oxysterols reduce cellular cholesterol levels by suppressing sterol regulatory element-binding protein-dependent gene expression and by transcriptional activation of liver X receptor (LXR)-dependent pathways that promote cellular cholesterol efflux and catabolism (15,16).…”

mentioning

confidence: 99%

“…These oxysterols reduce cellular cholesterol levels by suppressing sterol regulatory element-binding protein-dependent gene expression and by transcriptional activation of liver X receptor (LXR)-dependent pathways that promote cellular cholesterol efflux and catabolism (15,16). Moreover, treatment of human NPC1 fibroblasts with 25-hydroxycholesterol or 27-hydroxycholesterol corrects sterol homeostatic defects and mobilizes cholesterol from the aberrant lysosomal compartment (13).…”

mentioning

confidence: 99%

“…Concomitant with the lipid accumulation, brains of NPC1 mice exhibit microglial activation and infiltration and expression of proinflammatory mediators (10-12). Recent studies in chimeric NPC mice indicate that Purkinje cells undergo cell-autonomous neurodegeneration, suggesting that inflammation is not the initiating factor in Purkinje cell death, but rather a consequence of cell degeneration (12).The lipid trafficking defects in NPC1 disease also affect cellular utilization of lipoprotein cholesterol (13,14). In the npc1 Ϫ/Ϫ mice, disruption of the NPC1-mediated cholesterol trafficking has a profound effect on neurosteroidogenesis, resulting in substantially less pregnenolone and allopregnanolone (ALLO) in the brains of npc1 Ϫ/Ϫ mice as compared with WT mice (14).…”

mentioning

confidence: 99%

“…The lipid trafficking defects in NPC1 disease also affect cellular utilization of lipoprotein cholesterol (13,14). In the npc1 Ϫ/Ϫ mice, disruption of the NPC1-mediated cholesterol trafficking has a profound effect on neurosteroidogenesis, resulting in substantially less pregnenolone and allopregnanolone (ALLO) in the brains of npc1 Ϫ/Ϫ mice as compared with WT mice (14).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann–Pick C disease

Langmade

Gale

Frolov

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

152

145

View full text Add to dashboard Cite

Niemann-Pick type C1 (NPC1) disease is a fatal neurodegenerative disease characterized by neuronal lipid storage and progressive Purkinje cell loss in the cerebellum. We investigated whether therapeutic approaches to bypass the cholesterol trafficking defect in NPC1 disease might delay disease progression in the npc1 ؊/؊ mouse model. We show that the neurosteroid allopregnanolone (ALLO) and T0901317, a synthetic oxysterol ligand, act in concert to delay onset of neurological symptoms and prolong the lifespan of npc1 ؊/؊ mice. ALLO and T0901317 therapy preserved Purkinje cells, suppressed cerebellar expression of microglial-associated genes and inflammatory mediators, and reduced infiltration of activated microglia in the cerebellar tissue. To establish whether the mechanism of neuroprotection in npc1 ؊/؊ mice involves GABAA receptor activation, we compared treatment of natural ALLO and ent-ALLO, a stereoisomer that has identical physical properties of natural ALLO but is not a GABA A receptor agonist. ent-ALLO provided identical functional and survival benefits as natural ALLO in npc1 ؊/؊ mice, strongly supporting a GABAA receptor-independent mechanism for ALLO action. On the other hand, the efficacy of ALLO, ent-ALLO, and T0901317 therapy correlated with the ability of these compounds to activate pregnane X receptor-dependent pathways in vivo. These findings suggest that treatment with pregnane X receptor ligands may be useful clinically in delaying the progressive neurodegeneration in human NPC disease.cholesterol ͉ neurosteroid ͉ allopregnanolone ͉ neurodegeneration N iemann-Pick type C (NPC) disease is an autosomal recessive neurodegenerative disorder characterized by accumulation of cholesterol and other lipids in the viscera and central nervous system and patterned Purkinje cell death in the cerebellum (1). Mutations in the NPC1 gene are responsible for Ϸ95% of human NPC disease. NPC1 loss-of-function mutants exhibit marked impairment of low-density lipoprotein (LDL) cholesterol esterification and mobilization of newly hydrolyzed LDL cholesterol to the plasma membrane (2-4), resulting in lysosomal sequestration of LDL cholesterol, delayed down-regulation of the LDL receptor and de novo cholesterol biosynthesis, and impaired ABCA1-mediated cholesterol efflux (5-7). Despite recent progress in characterizing the biochemical and genetic defects in NPC disease, the mechanisms underlying the neurodegenerative phenotype are not well understood. Moreover, at present there are no effective therapies that delay progression of human NPC disease.Many of the prominent neuropathological features of human NPC disease [e.g., neuronal lipid storage and progressive loss of Purkinje neurons (1)] are recapitulated in the BALB͞c NPC nih (npc1 Ϫ/Ϫ ) mouse, a naturally occurring murine model that harbors a retroposon insertion in the Npc1 gene (8, 9). In NPC1 mice, accumulation of unesterified cholesterol and gangliosides occurs in morphologically normal neurons as early as postnatal day 9 (P9) and precedes neuronal injury and c...

show abstract

Section: T0901317 and Allo Therapy Improves Function And Survival Inmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann–Pick C disease

Langmade

Gale

Frolov

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

152

145

View full text Add to dashboard Cite

show abstract

NPC2 is expressed in human and murine liver and secreted into bile

et al. 2006

View full text Add to dashboard Cite

The liver plays a critical role in the metabolism of lipoprotein cholesterol and in controlling its elimination through the bile. Niemann-Pick type C 2 (NPC2), a cholesterol-binding protein, is key for normal intracellular trafficking of lipoprotein cholesterol, allowing its exit from the endolysosomal pathway into the metabolically active pool of the cell. In addition, NPC2 is a secretory protein from astrocytes and epididymal cells. Although NPC2 mRNA is detected in the liver, plasma and biliary NPC2 protein levels and function have not been reported. This study demonstrates that NPC2 is present in murine and human plasma and bile. In addition, hepatic NPC2 protein expression was dramatically increased in NPC1-deficient mice but not regulated by cholesterol feeding or pharmacological modulation of various nuclear receptors involved in cholesterol and bile acid metabolism. Interestingly, biliary NPC2 levels were 3-fold increased in gallstone-susceptible C57BL6/J versus gallstone-resistant BALB/c mice. Furthermore, NPC2 was exclusively found in the cholesterol pro-nucleating ConA-binding fraction of human bile. In conclusion, NPC2 is secreted from the liver into bile and plasma, where it may have a functional role in cholesterol transport in normal and disease conditions. (HEPATOLOGY 2006;43:126-133.)

show abstract

Novel function of Niemann-Pick C1-like 1 as a negative regulator of Niemann-Pick C2 protein

et al. 2012

View full text Add to dashboard Cite

The hepatic expression of Niemann-Pick C1-like 1 (NPC1L1), which is a key molecule in intestinal cholesterol absorption, is high in humans. In addition to NPC1L1, NiemannPick C2 (NPC2), a secretory cholesterol-binding protein involved in intracellular cholesterol trafficking and the stimulation of biliary cholesterol secretion, is also expressed in the liver. In this study, we examined the molecular interaction and functional association between NPC1L1 and NPC2. In vitro studies with adenovirus-based or plasmid-mediated gene transfer systems revealed that NPC1L1 negatively regulated the protein expression and secretion of NPC2 without affecting the level of NPC2 messenger RNA. Experiments with small interfering RNA against NPC1L1 confirmed the endogenous association of these proteins. In addition, endocytosed NPC2 could compensate for the reduction of NPC2 in NPC1L1-overexpressing cells, and this demonstrated that the posttranscriptional regulation of NPC2 was dependent on a novel ability of NPC1L1 to inhibit the maturation of NPC2 and accelerate the degradation of NPC2 during its maturation. Furthermore, to confirm the physiological relevance of NPC1L1-mediated regulation, we analyzed human liver specimens and found a negative correlation between the protein levels of hepatic NPC1L1 and hepatic NPC2. Conclusion: NPC1L1 down-regulates the expression and secretion of NPC2 by inhibiting its maturation and accelerating its degradation. NPC2 functions as a regulator of intracellular cholesterol trafficking and biliary cholesterol secretion; therefore, in addition to its role in cholesterol re-uptake from the bile by hepatocytes, hepatic NPC1L1 may control cholesterol homeostasis via the downregulation of NPC2. (HEPATOLOGY 2012;55:953-964)

show abstract

NPC1 and NPC2 Regulate Cellular Cholesterol Homeostasis through Generation of Low Density Lipoprotein Cholesterol-derived Oxysterols

Cited by 192 publications

References 49 publications

Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann–Pick C disease

Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann–Pick C disease

NPC2 is expressed in human and murine liver and secreted into bile

Novel function of Niemann-Pick C1-like 1 as a negative regulator of Niemann-Pick C2 protein

Contact Info

Product

Resources

About