Differential Proteomics Reveals miR-155 as a Novel Indicator of Liver and Spleen Pathology in the Symptomatic Niemann-Pick Disease, Type C1 Mouse Model

Pergande, Melissa R; Cougnoux, Antony; Rathnayake, Rathnayake A C; Porter, Forbes D.; Cologna, Stephanie M.

doi:10.3390/molecules24050994

Cited by 11 publications

(15 citation statements)

References 51 publications

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“…The pathway analysis indicates that many differentially expressed proteins belong to canonical pathways such as those involved in autophagy, phagosome maturation, and iron homeostasis. Our results are in agreement with previous reports showing that these processes (autophagy [21,33], phagosome maturation [34] and iron homeostasis) are altered in different NPC models [21,[33][34][35].…”

Section: Differentially Expressed Proteins In Npc1 Deficient Hepatocytes Are Predominantly Related To Alterations In Metabolism and Liversupporting

confidence: 94%

“…Using MS-based approaches, the authors showed that high mannose and sialylated N-glycans were altered, with a potential role in the lysosomal impairments observed in NPCD [19]. Interestingly, previous reports have already shown differential liver proteome in the NPC1 mouse model using whole liver tissue [20,21]. The hepatocytes are the main cells involved in liver metabolism, and account for approximately 78% of liver tissue volume [22,23].…”

Section: Of 15mentioning

confidence: 99%

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Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Balboa

Marín

Oyarzún

et al. 2021

Cells

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Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

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Section: Differentially Expressed Proteins In Npc1 Deficient Hepatocytes Are Predominantly Related To Alterations In Metabolism and Liversupporting

confidence: 94%

Section: Of 15mentioning

confidence: 99%

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Balboa

Marín

Oyarzún

et al. 2021

Cells

View full text Add to dashboard Cite

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“…We have recently reported altered expression in late endosomal/lysosomal proteins, Limp2 and Rab7a, using differential proteomics in the liver of symptomatic Npc1 −/− mice . Additionally, we show microRNA‐155 is elevated in the liver of symptomatic Npc1 −/− mice …”

Section: Introductionmentioning

confidence: 58%

“…All animal experiments were performed according to UIC Institutional Animal Care Committee‐approved protocols. Npc1 +/+ and Npc1 −/‐ mice (BALB/cNctr‐Npc1 m1N/m1N , Jackson Laboratories) were euthanized at 11 weeks of age ( N = 5 for each genotype and age) via CO 2 asphyxiation, decapitated, and liver tissue collected, flash frozen on dry ice, and stored at –80 °C, as previously described …”

Section: Methodsmentioning

confidence: 99%

Lipidomic Analysis Reveals Altered Fatty Acid Metabolism in the Liver of the Symptomatic Niemann–Pick, Type C1 Mouse Model

et al. 2019

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Niemann–Pick disease, type C1 (NPC1) is a fatal, autosomal recessive, neurodegenerative disorder caused by mutations in the NPC1 gene. As a result of the genetic defect, there is accumulation of unesterified cholesterol and sphingolipids in the late endosomal/lysosomal system causing both visceral and neurological defects. These manifest clinically as hepatosplenomegaly, liver dysfunction, and neurodegeneration. While significant progress has been made to better understand NPC1, the downstream effects of cholesterol storage and the major mechanisms that drive these pathologies remains less understood. In this study, it is sought to investigate free fatty acid levels in Npc1−/− mice with focus on the polyunsaturated ω‐3 and ω‐6 fatty acids. Since fatty acids are the main constituents of numerous lipids species, a discovery based lipidomic study of liver tissue in Npc1−/− mice is also performed. To this end, alterations in fatty acid synthesis, including the ω‐3 and 6 fatty acids, are reported. Further, alterations in enzymes that regulate the synthesis of ω‐3 and 6 fatty acids are reported. Analysis of the liver lipidome reveals alterations in both storage and membrane lipids including ceramides, fatty acids, phosphatidylcholamines, phosphatidylglycerols, phosphatidylethanolamines, sphingomyelins, and triacylglycerols in Npc1−/− mice at a late stage of disease.

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“…Finally, our results also showed an increase of miR‐155 in NLSDM patients in comparison to the control group. MiR‐155 has important functions in inflammation and, recently, was described to contribute to liver pathology and arteriosclerosis …”

Section: Discussionmentioning

confidence: 99%

MiRNAs as biomarkers of phenotype in neutral lipid storage disease with myopathy

et al. 2019

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Background: Neutral lipid storage disease with myopathy (NLSDM) is a rare lipid metabolism disorder. In this study, we evaluated some circulating miRNAs levels in serum samples and the MRI of three affected siblings.Methods: Three members of one NLSDM family were identified: two brothers and one sister. Muscles of lower and right upper extremities were studied by MRI.Expression profile of miRNAs, obtained from serum samples, was detected using qRT-PCR.Results: Two brothers presented with progressive skeletal myopathy, while the sister had severe hepatosteatosis and diabetes. NLSDM patients showed a significant increase of muscle-specific miRNAs expression compared with healthy subjects. We found a correlation between hepatic damage and elevation of miRNAs expression profile of liver origin. Conclusions:The dysregulation of miRNAs might represent an indicator of skeletal and hepatic damage and it might be useful to monitor the progression of NLSDM. K E Y W O R D Slipid metabolism, miRNAs, myomiRs, neutral lipid storage disease with myopathy, PNPLA2

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Differential Proteomics Reveals miR-155 as a Novel Indicator of Liver and Spleen Pathology in the Symptomatic Niemann-Pick Disease, Type C1 Mouse Model

Cited by 11 publications

References 51 publications

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Lipidomic Analysis Reveals Altered Fatty Acid Metabolism in the Liver of the Symptomatic Niemann–Pick, Type C1 Mouse Model

MiRNAs as biomarkers of phenotype in neutral lipid storage disease with myopathy

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