The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking

Zhang, Jessie; Dudley-Rucker, Nicole; Crowley, Jan R.; Lopez-Perez, Elvira; Issandou, Marc; Schaffer, Jean E.; Ory, Daniel S.

doi:10.1194/jlr.m300409-jlr200

Cited by 25 publications

(20 citation statements)

References 30 publications

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“…The lysosomal sequestration of LDL- derived cholesterol affects efflux activity by limiting cholesterol substrate for ABCA1-dependent efflux and by failing to appropriately generate LDL-cholesterol-derived side-chain oxysterols (15,17,18). In Npc1 -/-cells, decreased production of side-chain oxysterols, which serve as endogenous LXR ligands, results in reduced ABCA1 protein expression and lower cholesterol efflux activity (16,24).…”

Section: Discussionmentioning

confidence: 99%

“…Previously we showed that the sterol homeostatic defects in NPC1 mutant cells were associated with a profound decrease in synthesis of LDL-cholesterol-derived oxysterols (17,18). To assess whether decreased production of 27-HC, an endogenous LXR ligand, causes reduced LXR-mediated cholesterol efflux, we measured oxysterol production in peritoneal macrophages in response to acetylated LDL (AcLDL) cholesterol loading.…”

Section: Generation Of Mice With Deletion Of Npc1 In Bm-derived Cellsmentioning

confidence: 99%

“…In NPC1-deficient cells, expression of the ABCA1 sterol transporter is reduced, resulting in decreased cholesterol efflux (15,16). Recent studies have shown that the sterol homeostatic defects in NPC disease are caused by failure of lipoprotein cholesterol both to suppress SREBP-dependent gene expression and to promote LXR-mediated responses and are associated with impaired LDL-cholesterol-stimulated production of 25-HC and 27-HC (17,18). Based on these findings, we previously proposed that NPC proteins normally regulate cholesterol homeostasis by channeling excess LDL-cholesterol to intracellular sites of oxysterol synthesis, such as the mitochondrial sterol 27-hydroxylase (CYP27A1), resulting in the generation of LDLcholesterol-derived oxysterols (2).…”

Section: Introductionmentioning

confidence: 99%

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Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking

Zhang¹,

Coleman²,

Langmade³

et al. 2008

J. Clin. Invest.

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Niemann-Pick C1 (NPC1) is a key participant in cellular cholesterol trafficking. Loss of NPC1 function leads to defective suppression of SREBP-dependent gene expression and failure to appropriately activate liver X receptor-mediated (LXR-mediated) pathways, ultimately resulting in intracellular cholesterol accumulation. To determine whether NPC1 contributes to regulation of macrophage sterol homeostasis in vivo, we examined the effect of NPC1 deletion in BM-derived cells on atherosclerotic lesion development in the Ldlr -/-mouse model of atherosclerosis. High-fat diet-fed chimeric Npc1 -/-mice reconstituted with Ldlr -/-Npc1 -/-macrophages exhibited accelerated atherosclerosis despite lower serum cholesterol compared with mice reconstituted with wild-type macrophages. The discordance between the low serum lipoprotein levels and the presence of aortic atherosclerosis suggested that intrinsic alterations in macrophage sterol metabolism in the chimeric Npc1 -/-mice played a greater role in atherosclerotic lesion formation than did serum lipoprotein levels. Macrophages from chimeric Npc1 -/-mice showed decreased synthesis of 27-hydroxycholesterol (27-HC), an endogenous LXR ligand; decreased expression of LXR-regulated cholesterol transporters; and impaired cholesterol efflux. Lower 27-HC levels were associated with elevated cholesterol oxidation products in macrophages and plasma of chimeric Npc1 -/-mice and with increased oxidative stress. Our results demonstrate that NPC1 serves an atheroprotective role in mice through regulation of LXR-dependent cholesterol efflux and mitigation of cholesterol-induced oxidative stress in macrophages. IntroductionMacrophages regulate tissue lipid homeostasis through the uptake and catabolism of atherogenic plasma lipoproteins (1). Macrophages express scavenger receptor A and CD36, which bind and internalize modified lipoproteins, such as oxidized LDL. Upon internalization, lipoprotein-derived cholesterol is delivered to a late endosomal organelle, where cholesterol esters are hydrolyzed to free cholesterol. Delivery of free cholesterol from the endocytic pathway to the plasma membrane and ER requires the coordinated actions of the late endosomal Niemann-Pick C1 (NPC1) and lysosomal NPC2 proteins (2). Delivery of cholesterol to the ER rapidly stimulates esterification and accumulation of cholesterol ester in cytoplasmic droplets. Because the scavenger receptors, in contrast to the LDL receptor (LDLR), are not controlled by a sterol-regulated negative feedback loop, macrophages accumulate massive quantities of lipoprotein-derived lipids.

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Section: Discussionmentioning

confidence: 99%

Section: Generation Of Mice With Deletion Of Npc1 In Bm-derived Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking

Zhang¹,

Coleman²,

Langmade³

et al. 2008

J. Clin. Invest.

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“…Hence, targeting several of these pathways would likely be more beneficial than targeting a single pathway. For example, NP-C mice fail to use lipoprotein-derived cholesterol for synthesis of 25-and 27-hydroxycholesterol (Frolov, et al, 2003,Zhang, et al, 2004. These compounds are ligands for the liver X receptor (LXR) that promote cellular cholesterol efflux and catabolism.…”

Section: Mechanism Of Allopregnanolone Action: Gaba a Receptormentioning

confidence: 99%

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Mellon

Gong

Schonemann

2008

Brain Research Reviews

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The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3ß HSD, as well as those that expressed 3α HSD and 5α reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of lifespan, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABA A receptors may play a role. We treated NP-C mice with a synthetic GABA A neurosteroid, ganaxolone (3α-hydroxy-3β-methyl-5α -pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABA A receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.

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“…2 was not signifi cantly different from that observed for the wild-type (circles) in both the magnitude of the 27-HC biosynthetic response and in the position of the infl ection point. It has been shown that ingested cholesterol accumulates to high levels in the endolysosomal compartments of these mutant cells both in vivo and in vitro but that the movement of PM cholesterol to the ER is intact under experimental conditions (19)(20)(21)(22). This is presumably because, while the effl ux of ingested 3-fold increase in 27-HC; there was no corresponding change in cellular cholesterol (not shown).…”

Section: Dependence Of 27-hc Production On the Level Of Pm Cholesterolmentioning

confidence: 99%

Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol

Lange

Steck

et al. 2009

Journal of Lipid Research

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This study addresses the regulation of the biosynthesis of oxysterol signal molecules. Side chain oxysterols such as 24-, 25-, and 27-hydroxycholesterol (HC) are derived from cholesterol in the endoplasmic reticulum (ER) and mitochondria and trigger downregulation of the abundance of cell cholesterol through diverse pathways ( 1-4 ). In particular, the association of oxysterols with nuclear liver X receptors (LXR) promotes the expression of ATP-binding cassette (ABC) transport proteins that transfer excess cholesterol out of cells such as macrophages ( 5 ). Furthermore, because the oxysterol derivatives are more water-soluble than cholesterol, they readily exit cells and are transported via circulating lipoproteins to the liver for conversion to bile acids and excretion ( 6, 7 ). In addition, side-chain oxysterols promote the interaction of Insig proteins with sterol regulatory element-binding protein (SREBP) cleavage-activating protein-SREBP complexes; this action sequesters SREBP in the ER and, as a result, reduces the expression of genes for cholesterol accretion ( 8 ). By activating Insig, side-chain oxysterols also stimulate the proteolysis of hydroxy-3-methylglutaryl CoA reductase (HMGR) through a ubiquitination-proteasomal pathway ( 9, 10 ).The mechanism by which oxysterol biosynthesis is set according to the level of cell cholesterol so as to execute these homeostatic functions is obscure. Indeed, despite the cogency of the oxysterol hypothesis, the physiological relevance of the underlying in vitro fi ndings has long been debated ( 1, 11 ). To carry out its postulated role in vivo, oxysterol production should represent the level of cellular Abstract Side chain oxysterols are cholesterol derivatives thought to signal the abundance of cell cholesterol to homeostatic effector proteins. Here, we investigated how plasma membrane (PM) cholesterol might regulate 27-hydroxycholesterol (HC) biosynthesis in cultured fi broblasts. We showed that PM cholesterol was a major substrate for 27-HC production. Biosynthesis commenced within minutes of loading depleted cells with cholesterol, concurrent with the rapid inactivation of hydroxy-3-methylglutaryl CoA reductase (HMGR). 27-HC production rose ~ 30-fold in normal and Niemann-Pick C1 fi broblasts when PM cholesterol was increased by ~ 60%. 27-HC production was also stimulated by 1-octanol, which displaces PM cholesterol from its phospholipid complexes and thereby increases its activity (escape tendency) and elevates its intracellular abundance. Conversely, lysophosphatidylserine and U18666A inhibited 27-HC biosynthesis and the inactivation of HMGR, presumably by reducing the activity of PM cholesterol and, therefore, its circulation to mitochondria. We conclude that, in this in vitro system, excess ( Press, April 28, 2009 DOI 10.1194 Regulation of fi broblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol Abbreviations: ER, endoplasmic reticulum; HC, hydroxycholesterol; HMGR, hydroxy-3-methylglutaryl CoA reductase; HPCD, 2-␤ -...

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The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking

Cited by 25 publications

References 30 publications

Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking

Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Regulation of fibroblast mitochondrial 27-hydroxycholesterol production by active plasma membrane cholesterol

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