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

Abstract

Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes, and its exact pathogenesis remains unclear. Autophagy plays an important role in neurodegenerative diseases, ischemiareperfusion injury of nerve tissues, and nerve tissue injury repair. 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. Here, we show that induction of DPN rat model via STZ injection could reduce Lipin1 expression, prevent DAG synthesis, and results in autophagic hyperactivity. Interestingly, these effects 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, lipin1 downregulation exacerbates neuronal abnormalities and facilitates the genesis of DPN phenotypes in rats. In addition, overexpression of lipin1 in RSC96 cells also signi cantly 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.

A High-Fat Diet Disrupts Nerve Lipids and Mitochondrial Function in Murine Models of Neuropathy

“…In support of this idea, inhibiting DGAT and lipin1, a DG synthesizing enzyme, promotes axon regeneration in peripheral neurons by reducing TG/DG synthesis and stimulating phospholipid synthesis ( Yang et al, 2020 ). Furthermore, modulating DG levels in the sciatic nerve of STZ-treated rats confers neuroprotection and improves PN measures ( Wang et al, 2021 ). Future preclinical studies focused on nerve-specific TG/DG biology in the setting of dyslipidemia and metabolic dysfunction could facilitate the development of targeted interventions for the treatment of PN.…”

Network Pharmacology Study on the Mechanism of Qiang Huo-Yinchen Treating Diabetic Peripheral Neuropathy

“…DPN is mainly caused by microvascular lesions caused by metabolic abnormalities caused by hyperglycemia. Studies have shown that [16] the up-regulation of lipid in DPN rats improves the pathological changes of autophagy disorder and sciatic nerve, and the overexpression of lipin1 in RSC96 cells also significantly reduces the excessive autophagy activity and apoptosis caused by hyperglycemia. Therefore, it is speculated that Qianghuo-Yinchen pair may affect the metabolism and apoptosis of the body by regulating the lipid and atherosclerosis signaling pathways, and the signaling pathways of neurodegenerative diseases, so as to play a role in the treatment of DPN.…”

Interplay between exosomes and autophagy machinery in pain management: State of the art

“…Besides, these conditions predispose sciatic nerve damage that is mainly characterized by disordered myelin, axonal shrinkage, fibrosis, and inflammation. Recent work on damaged sciatic nerve induced by DPN showed a neuroprotective effect of lipin1, as a well-established enzyme to maintain normal conduction in peripheral nerve by modulating dysregulated autophagy and neutralizing the Schwann cell apoptosis ( Wang et al, 2021 ). This factor is diminished under diabetic conditions.…”