Neuron. Liu Kai's team found that regulating lipid metabolism processes in neurons contributed to axon regeneration.

The goal of regenerative medicine is to repair the function of various tissues or organs lost due to injury, aging or disease.although many tissues or organs can be recovered by drug therapy or surgical transplantation, it is still a huge medical problem to repair the damaged central nervous system.nervous system is a complex network structure formed by neurons and other cells through connection, which is divided into central nervous system and peripheral nervous system. It is an important structure for animals to perceive the outside world and control body activities.neurons are the basic units of the nervous system. They have special cellular structures, including cell bodies, dendrites and axons.neuronal axons often have super long structures, and the damage leads to the interruption of nerve signal at the damaged site, which affects the normal function of the nervous system.neurons in the peripheral nervous system can regenerate after injury, and the lost function can also be partially recovered.unfortunately, adult central nervous system neurons do not have axonal regeneration capacity, and severe injury usually leads to permanent loss of function.typical examples include paralysis caused by spinal cord injury, visual field disturbance caused by optic atrophy and even complete blindness in glaucoma patients.although there have been studies in animal models to explore the molecular mechanism of axonal regeneration of central neurons [1], it is still unable to achieve axonal regeneration in clinical practice, so it is particularly important to study the basic biological processes affecting axonal regeneration.the nervous system is rich in lipids, and a large number of lipids are required to participate in the formation of cell membrane during axonal regeneration. However, the effect of lipid metabolism on axonal regeneration is still unclear.on November 27, 2019, the research group of Liu Kai of Hong Kong University of science and technology published a long paper on neuron: Rewiring neural glycolipid metrics determine the extent of axon It was found that the synthesis of phospholipids involved in cell membrane structure increased by regulating the lipid metabolism of neurons, while the synthesis of storage lipids such as triglycerides decreased, which could promote axonal regeneration of injured central neurons.to explore the effect of lipid metabolism on axon growth, researchers first knocked down some key genes involved in fatty acid metabolism, cholesterol synthesis and glycerophosphate pathway in cultured dorsal root ganglion (DRG) neurons in vitro.it was found that knockdown of lipin1 can significantly promote neurite growth in DRG.in vivo experiments, knockdown or knockout of lipin1 of retinal ganglion cells by adeno-associated virus can significantly promote optic nerve regeneration.lipin1 is a key gene in the glycerophosphate pathway. Lipin1 can catalyze phospholipid and free fatty acids to synthesize diacylglycerol, which is the substrate for the synthesis of various phospholipids and triglycerides.triglyceride is the most important energy storage substance in mammals, and phospholipid containing phospholipid (PC) and phosphatidylethanolamine (PE) is the main component of cell membrane.with the increase of the level of lipin1 in retinal ganglion cells, axonal injury will further increase the expression of lipin1, which hinders axonal regeneration of central neurons.lipin1 not only participates in the synthesis of diacylglycerol, but also regulates gene expression in the nucleus [2].in order to find out which function is related to axonal regeneration, the researchers overexpressed lipin1 gene with phosphatase function mutation and nuclear localization sequence deletion in retinal ganglion cells with lipin1 knockdown. The results showed that its phosphatase function was the main factor affecting axonal regeneration.this indicates that lipid metabolism in neurons plays an important role in axonal regeneration.the next question the researchers are concerned about is what effect lipin1 elimination has on the lipid metabolism balance of neurons.after the elimination of lipin1, the contents of cholesterol and fatty acids in neurons did not change significantly, while the contents of triglyceride decreased significantly, while the levels of PC and PE increased significantly.this suggests that lipin1 may make neurons tend to synthesize triglycerides rather than phospholipids. What effects do triglycerides and phospholipids have on axonal regeneration? Triglycerides in neurons can be hydrolyzed by ATGL and ddhd2, and its synthesis is catalyzed by DGAT1 and dgat2 [5].elimination of ATGL or ddhd2 in neurons increased triglyceride content and inhibited axonal regeneration after lipin1 knockout.on the contrary, eliminating DGAT1 or dgat2 in neurons significantly promoted axonal regeneration.similar to lipin1, the triglyceride content in neurons was significantly decreased and the phospholipid level was significantly increased after DGAT1 or dgat2 elimination.this indicates that inhibition of triglyceride synthesis can promote axonal regeneration, and the mechanism may be that lipid metabolism in neurons leads to the direction of phospholipid synthesis.PC and PE in cells are mainly synthesized by Kennedy pathway [6].to explore the effect of phospholipids on axonal regeneration, the researchers selected genes encoding key enzymes for the synthesis of PC and PE, including chka, chkb, PCYT1A, PCYT1B and pcyt2.knocking down these genes can inhibit axonal regeneration induced by lipin1 or DGAT1 knockout.on the contrary, overexpression of PCYT1A or pcyt2 to promote PC and PE synthesis promoted axonal regeneration.this indicates that the synthesis of PC and PE plays a key role in axonal regeneration.in peripheral nervous system with regenerative ability, does lipid metabolism also play a key role in axonal regeneration? Different from central neurons, the expression of DGAT1 in peripheral neurons decreased after injury, suggesting that peripheral neurons can adapt to injury by regulating lipid metabolism, thus promoting axonal regeneration. inhibition of triglyceride hydrolysis by inhibitors of ATGL and ddhd2 can significantly reduce the regeneration ability of sciatic nerve. this suggests that lipid metabolism is also essential for peripheral nerve regeneration. in conclusion, regulating the lipid metabolism process in neurons so that lipid synthesis tends to participate in the formation of cell membrane phospholipids rather than storage triglycerides is conducive to neuronal axonal regeneration. this study provides a new explanation for the difference of regeneration ability between central and peripheral nervous system, and provides a new drug target for related central nervous system injury. this article was completed by Yang Chao, a postdoctoral student of HKUST, Wang Xu, and other collaborators. original link: plate maker: Ke reference 1. 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