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Lipin1 Alleviates Autophagy Disorder in Sciatic Nerve and Improves Diabetic Peripheral Neuropathy

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Abstract

Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes, and its neural mechanisms underlying the pathogenesis remain unclear. Autophagy plays an important role in neurodegenerative diseases and nerve tissue injury. Lipin1 is a phosphatidic acid phosphatase enzyme that converts phosphatidic acid (PA) into diacylglycerol (DAG), a precursor of triacylglycerol and phospholipids which plays an important role in maintaining normal peripheral nerve conduction function. However, whether Lipin1 involved in the pathogenesis of DPN via regulation of autophagy is not elucidated. Here, we show that the Lipin1 expression was downregulated in streptozotocin (STZ)-induced DPN rat model. Interestingly, STZ prevented DAG synthesis, and resulted in autophagic hyperactivity, effects which may increase the apoptosis of Schwann cells and lead to demyelination in sciatic nerve in DPN rats. More importantly, upregulation of lipin1 in the DPN rats ameliorated autophagy disorders and pathological changes of the sciatic nerve, which associated with the increase of the motor nerve conductive velocity (MNCV) in DPN rats. In contrast, knockdown of lipin1 exacerbates neuronal abnormalities and facilitates the genesis of DPN phenotypes in rats. In addition, overexpression of lipin1 in RSC96 cells also significantly decreased the autophagic hyperactivity and apoptosis induced by hyperglycemia. These results suggest that lipin1 may exert neuroprotection within the sciatic nerve anomalies and may serve as a potential therapeutic target for the treatment of DPN.

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Data Availability

All data generated or analyzed during this study are included in this published article and are available from the corresponding author upon reasonable request.

Abbreviations

7-AAD:

7-Aminoactinomycin D

ADV:

Adenovirus

ADVs:

Adenoviral vectors

BCA:

Bicinchoninic acid

CCK-8:

Cell counting kit-8

DAG:

Diacylglycerol

DAPI:

4′,6-Diamidine-2-phenylidole dihydrochloride

DM:

Diabetes mellitus

DMEM:

Dulbecco’s modified Eagle’s medium

DPN:

Diabetic peripheral neuropathy

ELISA:

Enzyme-linked immunosorbent assay

EM:

Electron microscopy

FBS:

Fetal bovine serum

FBG:

Fasting-blood-glucose

FITC:

Fluorescein isothiocyanate

LV:

Lentivirus

LVs:

Lentiviral vectors

MNCV:

Motor nerve conduction velocity

MOI:

Multiplicity of infection

NC:

Negative control

PA:

Phosphatidic acid

PAP:

Phosphatidic acid phosphatase

PBS:

Phosphate-buffered saline

PKD:

Protein kinase D

PMWT:

Paw mechanical withdrawal threshold

PVDF:

Polyvinylidene fluoride

qPCR:

Quantitative real-time polymerase chain reaction

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

STZ:

Streptozotocin

TBS-T:

Tris-buffered saline Tween

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Acknowledgements

Thanks for the guidance of the teachers from the Institute of basic medicine of Shandong University and the provision of the rat sciatic nerve conduction velocity meter. We also thank the teachers of the basic laboratory of the Second Hospital of Shandong University for their guidance in the research of apoptosis.

Funding

This study was supported by the National Natural Science Foundation of China (NNSFC) (NO.81670753 and NO. 82070847) to S.C., and NNSFC (NO.81800722) to X.Z., the grants from the Key R & D programs of Shandong Province (No.2018GSF118108) to S.C., and the Hospital Youth Foundation of Qilu Hospital of Shandong University, Qingdao (QDKY2017QN12) to M.W.

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Authors and Affiliations

  1. Department of Endocrinology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Street, Ji’nan, Shandong, 250033, People’s Republic of China

    Meijian Wang, Min Xie, Pan Shang, Xiaolin Han, Xianghua Zhuang & Shihong Chen

  2. Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Qingdao, 758 Hefei Road, Qingdao, Shandong, 266035, People’s Republic of China

    Meijian Wang & Li Chen

  3. Department of Endocrinology, Binzhou Medical University Hospital, 661 Huanghe Second Road, Binzhou, Shandong, 256603, People’s Republic of China

    Min Xie

  4. Department of Physiology, School of Basic Medical Sciences, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong, 250012, People’s Republic of China

    Shuyan Yu & Cuiqin Fan

  5. Department of School of Biological & Chemical Engineering, Qingdao Technical College, 369 Qiantangjiang Road, Qingdao, Shandong, 266555, People’s Republic of China

    Cong Zhang

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  1. Meijian Wang
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Contributions

S.C. conceived the study. X.Z., S.Y., L.C., and S.C. designed the study. M.W., M.X., P.S, C.Z., X.H., and C.F. performed the experiments and interpreted data analyses. M.W. wrote the first version of the paper. All authors critically reviewed, revised, and approved the final version of the manuscript.

Corresponding authors

Correspondence to Xianghua Zhuang or Shihong Chen.

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Wang, M., Xie, M., Yu, S. et al. Lipin1 Alleviates Autophagy Disorder in Sciatic Nerve and Improves Diabetic Peripheral Neuropathy. Mol Neurobiol 58, 6049–6061 (2021). https://doi.org/10.1007/s12035-021-02540-5

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