Phosphatidate phosphatase Lipin1 involves in diabetic encephalopathy pathogenesis via regulating synaptic mitochondrial dynamics.

Diabetic encephalopathy (DE) is a common central nervous system complication of diabetes mellitus without effective therapy currently. Recent studies have highlighted synaptic mitochondrial damages as a possible pathological basis for DE, but the underlying mechanisms remain unclear. Our previous work has revealed that phosphatidate phosphatase Lipin1, a critical enzyme involved with phospholipid synthesis, is closely related to the pathogenesis of DE. Here, we demonstrate that Lipin1 is significantly down-regulated in rat hippocampus of DE. Knock-down of Lipin1 within hippocampus of normal rats induces dysregulation of homeostasis in synaptic mitochondrial dynamics with an increase of mitochondrial fission and a decrease of fusion, then causes synaptic mitochondrial dysfunction, synaptic plasticity deficits as well as cognitive impairments, similar to that observed in response to chronic hyperglycemia exposure. In contrast, an up-regulation of Lipin1 within hippocampus in the DE model ameliorates this cascade of dysfunction. We also find that the effect of Lipin1 that regulating mitochondrial dynamics results from maintaining appropriate phospholipid components in the mitochondrial membrane. In conclusion, alterations in hippocampal Lipin1 contribute to hippocampal synaptic mitochondrial dysfunction and cognitive deficits observed in DE. Targeting Lipin1 might be a potential therapeutic strategy for the clinical treatment of DE.

Lipin2 ameliorates diabetic encephalopathy via suppressing JNK/ERK-mediated NLRP3 inflammasome overactivation.

OBJECTIVES: Diabetic encephalopathy (DE) is a common complication of diabetes in the central nervous system, which can cause cognitive dysfunction in patients. However, its pathophysiological mechanism has not been elucidated, and thus effective prevention and treatment methods are still lacking.Previous studies reported that neuroinflammation involved in the central neuropathy, while lipin2 plays an important role in inflammatory response.Therefore, we aimed to investigate the effects of lipin2 on regulating inflammatory response in the pathogenesis of DE. METHODS: BV2 cells were treated with high glucose and infected with lipin2 overexpression or knockdown virus to observe the cell viability. Then, we constructed a mouse model of DE, and constructed a lipin2 knockdown or overexpression model by injecting lentivirus into the brain with stereotaxis. The expression of lipin2 in inflammatory bodies and related inflammatory factor signaling pathway-related proteins were examined by western blot and quantitative real-time PCR. Morris water maze was used to evaluate the spatial learning and memory of mice. RESULTS: High glucose decreased the expression of lipin2 in BV2 cells, while overexpression of lipin2 in BV2 cells significantly suppressed the inflammatory response and apoptosis induced by high glucose. Meanwhile, the expression of lipin2 was down-regulated in the hippocampus in a DE mice model. Up-regulation of lipin2 in the hippocampus of DE mice inhibited JNK/ERK signaling pathway, reduced NLRP3 inflammasome-mediated inflammatory response, down-regulated IL-1/TNF-α expression, and improved synaptic plasticity and cognitive dysfunction in mice. Conversely, knockdown of lipin2 increased NLRP3 inflammasome overactivation, caused neuronal abnormalities and cognitive impairment in mice. CONCLUSIONS: Lipin2 may play a neuroprotective role in DE by inhibiting JNK/ERK-mediated NLRP3 inflammasome overactivation and subsequent inflammatory responses. It may be a potential therapeutic target for DE therapy.