Lysosomal unesterified cholesterol content correlates with liver cell death in murine Niemann-Pick type C disease

Beltroy, Eduardo P.; Liu, Benny; Dietschy, John M.; Turley, Stephen D.

doi:10.1194/jlr.m600488-jlr200

Cited by 59 publications

(77 citation statements)

References 49 publications

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“…One possible explanation for reduced expression of Rab9 TG in livers of the experimental animals compared to the founder strains is that there is an effect of the NP-C disease state on expression of the transgene (eg, there is known to be considerable hepatocyte damage in the NP-C liver 21 ). Thus, we investigated Rab9 TG expression in livers from Rab9…”

Section: Resultsmentioning

confidence: 99%

Development of a Rab9 Transgenic Mouse and Its Ability to Increase the Lifespan of a Murine Model of Niemann-Pick Type C Disease

Kaptzan

West

Holicky

et al. 2009

The American Journal of Pathology

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Niemann-Pick, type C (NP-C) disease is an autosomal recessive neurovisceral storage disorder in which cholesterol and sphingolipids accumulate. There is no specific treatment for this disease, which is characterized by progressive neurological deterioration, sometimes accompanied by hepatosplenomegaly. We and others have shown that overexpression of certain Rab GTPases corrects defective membrane trafficking and reduces lipid storage in cultured NP-C fibroblasts. Here, we tested the possibility that Rab protein overexpression might also have beneficial effects in vivo using a murine model of NP-C. We first generated several lines of transgenic mice that ubiquitously overexpress Rab9 up to ϳ30-fold more than endogenous levels and found that the transgene expression had no obvious effects on fertility, behavior, or lifespan in normal mice. These transgenic strains were then crossed with NP-C mutant mice to produce NP-C homozygous recessive mice with and without the Rab9 transgene. Life expectancy of the NPC1 homozygous recessive animals was extended up to 22% depending on gender and the transgenic strain that was used. Histological studies and lipid analysis of brain sections indicated that the NP-C mice carrying the Rab9 transgene had dramatically reduced storage of GM 2 and GM 3 gangliosides relative to NP-C animals lacking the transgene. These results demonstrate that Rab9 overexpression has the potential to reduce stored lipids and prolong lifespan in vivo. (Am J

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Section: Resultsmentioning

confidence: 99%

Development of a Rab9 Transgenic Mouse and Its Ability to Increase the Lifespan of a Murine Model of Niemann-Pick Type C Disease

Kaptzan

West

Holicky

et al. 2009

The American Journal of Pathology

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“…In both the human and the mouse, these histological changes, in turn, result in the clinical syndromes of pulmonary failure, liver dysfunction, and progressive neurological disease (3,8). Importantly, in a particular organ, the severity of disease is proportional to the amount of C sequestered in that tissue (3,9,10).…”

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confidence: 99%

“…Thus, blocking the intestinal absorption of sterol with a drug like ezetimibe, which lowers the amount of C reaching the liver carried in chylomicron remnants, markedly reduces hepatocyte damage and improves hepatic function (9). Increasing sterol excretion out of the brain across the blood-brain barrier, which presumably leaves less apoE-associated C available for uptake by neurons, slows neurodegeneration and prolongs the life of the npc1 Ϫ/Ϫ mouse (10).…”

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confidence: 99%

Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1 ^−/− mouse

Liu¹,

Turley²,

Burns³

et al. 2009

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

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Niemann-Pick type C disease is largely attributable to an inactivating mutation of NPC1 protein, which normally aids movement of unesterified cholesterol (C) from the endosomal/lysosomal (E/L) compartment to the cytosolic compartment of cells throughout the body. This defect results in activation of macrophages in many tissues, progressive liver disease, and neurodegeneration. In the npc1 ؊/؊ mouse, a model of this disease, the whole-animal C pool expands from 2,082 to 4,925 mg/kg body weight (bw) and the hepatic C pool increases from 132 to 1,485 mg/kg bw between birth and 49 days of age. A single dose of 2-hydroxypropyl-␤-cyclodextrin (CYCLO) administered at 7 days of age immediately caused this sequestered C to flow from the lysosomes to the cytosolic pool in many organs, resulting in a marked increase in cholesteryl esters, suppression of C but not fatty acid synthesis, down-regulation of genes controlled by sterol regulatory element 2, and up-regulation of many liver X receptor target genes. There was also decreased expression of proinflammatory proteins in the liver and brain. In the liver, where the rate of C sequestration equaled 79 mg⅐d ؊1 ⅐kg ؊1 , treatment with CYCLO within 24 h increased C movement out of the E/L compartment from near 0 to 233 mg⅐d ؊1 ⅐kg ؊1 . By 49 days of age, this single injection of CYCLO resulted in a reduction in whole-body C burden of >900 mg/kg, marked improvement in liver function tests, much less neurodegeneration, and, ultimately, significant prolongation of life. These findings suggest that CYCLO acutely reverses the lysosomal transport defect seen in NPC disease.cholesterol ͉ lysosome ͉ cyclodextrin ͉ liver X receptor

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“…It has been demonstrated that cholesterol loading in liver fat causes hepatocytes to be susceptible to inflammatory factors, which then promotes steatohepatitis (18). In NiemannPick type C (NPC) disease which is caused by NPC1 and NPC2 protein mutations, cholesterol loading is closely correlated with liver cell death (19). Yet, it is still unknown whether cholesterol loading can induce the UPR of hepatocytes, and the underlined mechanism of hepatic injury resulting from cholesterol loading remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Cholesterol overloading leads to hepatic L02 cell damage through activation of the unfolded protein response

Liu²,

Guo³

et al. 2009

Int J Mol Med

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Abstract.Reported data indicate that cholesterol loading in the liver can cause hepatic injury. To explore the possible mechanisms of cell damage resulting from cholesterol overloading in hepatocytes, cell apoptosis, the unfolded protein response (UPR) and the correlation between them were assessed in the cholesterol-overloaded normal human hepatic cell line L02. L02 cells were incubated with 200 μg/ ml of low density lipoprotein (LDL) for 24 h with or without 20 μg/ml 58035, an inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT). In the LDL+58035 group, the intracellular cholesterol level was dramatically increased, which was measured by an enzymatic combined high performance liquid chromatography assay. Expression of immunoglobulin-binding protein, X-box binding protein 1, activating transcription factor 6, activating transcription factor 4, CCAAT/enhancer-binding protein homologous protein-10, markers of endoplasmic reticulum stress (ERS)/ UPR, were up-regulated as determined using reverse transcription-polymerase chain reaction (RT-PCR) or Western blot analysis. The rate of cell apoptic death increased 21.3±2.4%. Meanwhile, the active caspase-3 protein expression was increased 8.4-fold compared to the active caspase-3 protein expression in the controls. Furthermore, 4-phenylbutyric acid, an inhibitor of UPR, partly reduced cell apoptosis and activation of caspase-3. This study suggests that cholesterol overloading in hepatic L02 cells induces ERS and activates the UPR which, in part, leads to the apoptotic damage of cells.

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Lysosomal unesterified cholesterol content correlates with liver cell death in murine Niemann-Pick type C disease

Cited by 59 publications

References 49 publications

Development of a Rab9 Transgenic Mouse and Its Ability to Increase the Lifespan of a Murine Model of Niemann-Pick Type C Disease

Development of a Rab9 Transgenic Mouse and Its Ability to Increase the Lifespan of a Murine Model of Niemann-Pick Type C Disease

Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1 ^−/− mouse

Cholesterol overloading leads to hepatic L02 cell damage through activation of the unfolded protein response

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Lysosomal unesterified cholesterol content correlates with liver cell death in murine Niemann-Pick type C disease

Cited by 59 publications

References 49 publications

Development of a Rab9 Transgenic Mouse and Its Ability to Increase the Lifespan of a Murine Model of Niemann-Pick Type C Disease

Development of a Rab9 Transgenic Mouse and Its Ability to Increase the Lifespan of a Murine Model of Niemann-Pick Type C Disease

Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1 −/− mouse

Cholesterol overloading leads to hepatic L02 cell damage through activation of the unfolded protein response

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Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1 ^−/− mouse