A neutral lipid-enriched diet improves myelination and alleviates peripheral nerve pathology in neuropathic mice

Ye Zhou, Hannah Bazick, Joshua R. Miles, Alexander I. Fethiere, Mohammed Omar Al Salihi, Sergio Fazio, Hagai Tavori, L. Notterpek

    Research output: Contribution to journalArticle

    Abstract

    Charcot-Marie-Tooth (CMT) diseases comprise a genetically heterogeneous group of hereditary peripheral neuropathies. Trembler J (TrJ) mice carry a spontaneous mutation in peripheral myelin protein 22 (PMP22) and model early-onset, severe CMT type 1E disease. Recent studies indicate that phospholipid substitution, or cholesterol-enriched diet, benefit myelinated nerves, however such interventions have not been tested in early-onset dysmyelinating neuropathies. Here, we examined the lipid profile of peripheral nerves from 6-month-old TrJ mice with advanced neuropathy and tested the impact of a 6-week-long neutral lipid-enriched high-fat diet (HFD) on neuropathy progression in young, newly-weaned mice. Oil Red O staining showed pronounced neutral lipid accumulation in nerves from 6-month-old TrJ mice, along with elevated levels of key cholesterol and triglyceride transport proteins including apoE, LRP1 and ABCA1, compared with wild type (Wt). In young mice, the short-term HFD intervention increased serum cholesterol levels without impacting triglycerides, or body and liver weights. Tissue samples from neuropathic TrJ mice showed improvements in the maintenance of myelinated axons after the 6-week-long dietary intervention, and this effect was evident both in the sciatic and phrenic nerves. Concomitantly, aberrant Schwann cell proliferation was attenuated, as detected by reduction in mitotic markers and in c-Jun expression. Nerves from HFD-fed TrJ mice contained fewer macrophages, with a normalized count of CD11b + cells. In addition, we detected an increase in neutral lipids in the nerve endoneurium and a trend toward normalization of apoE, LRP1, and ABCA1 expression after the HFD feeding. Together, these results demonstrate the beneficial influence of a short-term neutral lipid-enriched diet on neuropathy progression in young TrJ mice and support further work in investigating the potential benefits of dietary lipids on hereditary neuropathies.

    Original languageEnglish (US)
    Article number113031
    JournalExperimental Neurology
    Volume321
    DOIs
    StatePublished - Nov 1 2019

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    Peripheral Nerves
    Pathology
    Diet
    Lipids
    High Fat Diet
    Cholesterol
    Apolipoproteins E
    Triglycerides
    Myelin Proteins
    Charcot-Marie-Tooth Disease
    Phrenic Nerve
    Schwann Cells
    Peripheral Nervous System Diseases
    Sciatic Nerve
    Axons
    Phospholipids
    Carrier Proteins
    Cell Count
    Macrophages
    Body Weight

    Keywords

    • Cholesterol
    • Lipid-enriched diet
    • Macrophage
    • Peripheral myelin protein 22
    • Peripheral neuropathy
    • Trembler J mice

    ASJC Scopus subject areas

    • Neurology
    • Developmental Neuroscience

    Cite this

    A neutral lipid-enriched diet improves myelination and alleviates peripheral nerve pathology in neuropathic mice. / Zhou, Ye; Bazick, Hannah; Miles, Joshua R.; Fethiere, Alexander I.; Salihi, Mohammed Omar Al; Fazio, Sergio; Tavori, Hagai; Notterpek, L.

    In: Experimental Neurology, Vol. 321, 113031, 01.11.2019.

    Research output: Contribution to journalArticle

    Zhou, Ye ; Bazick, Hannah ; Miles, Joshua R. ; Fethiere, Alexander I. ; Salihi, Mohammed Omar Al ; Fazio, Sergio ; Tavori, Hagai ; Notterpek, L. / A neutral lipid-enriched diet improves myelination and alleviates peripheral nerve pathology in neuropathic mice. In: Experimental Neurology. 2019 ; Vol. 321.
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    abstract = "Charcot-Marie-Tooth (CMT) diseases comprise a genetically heterogeneous group of hereditary peripheral neuropathies. Trembler J (TrJ) mice carry a spontaneous mutation in peripheral myelin protein 22 (PMP22) and model early-onset, severe CMT type 1E disease. Recent studies indicate that phospholipid substitution, or cholesterol-enriched diet, benefit myelinated nerves, however such interventions have not been tested in early-onset dysmyelinating neuropathies. Here, we examined the lipid profile of peripheral nerves from 6-month-old TrJ mice with advanced neuropathy and tested the impact of a 6-week-long neutral lipid-enriched high-fat diet (HFD) on neuropathy progression in young, newly-weaned mice. Oil Red O staining showed pronounced neutral lipid accumulation in nerves from 6-month-old TrJ mice, along with elevated levels of key cholesterol and triglyceride transport proteins including apoE, LRP1 and ABCA1, compared with wild type (Wt). In young mice, the short-term HFD intervention increased serum cholesterol levels without impacting triglycerides, or body and liver weights. Tissue samples from neuropathic TrJ mice showed improvements in the maintenance of myelinated axons after the 6-week-long dietary intervention, and this effect was evident both in the sciatic and phrenic nerves. Concomitantly, aberrant Schwann cell proliferation was attenuated, as detected by reduction in mitotic markers and in c-Jun expression. Nerves from HFD-fed TrJ mice contained fewer macrophages, with a normalized count of CD11b + cells. In addition, we detected an increase in neutral lipids in the nerve endoneurium and a trend toward normalization of apoE, LRP1, and ABCA1 expression after the HFD feeding. Together, these results demonstrate the beneficial influence of a short-term neutral lipid-enriched diet on neuropathy progression in young TrJ mice and support further work in investigating the potential benefits of dietary lipids on hereditary neuropathies.",
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    AU - Salihi, Mohammed Omar Al

    AU - Fazio, Sergio

    AU - Tavori, Hagai

    AU - Notterpek, L.

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