Rewiring Neuronal Glycerolipid Metabolism Determines the Extent of Axon Regeneration

How adult neurons coordinate lipid metabolism to regenerate axons remains elusive. We found that depleting neuronal lipin1, a key enzyme controlling the balanced synthesis of glycerolipids through the glycerol phosphate pathway, enhanced axon regeneration after optic nerve injury. Axotomy elevated lipin1 in retinal ganglion cells, which contributed to regeneration failure in the CNS by favorably producing triglyceride (TG) storage lipids rather than phospholipid (PL) membrane lipids in neurons. Regrowth induced by lipin1 depletion required TG hydrolysis and PL synthesis. Decreasing TG synthesis by deleting neuronal diglyceride acyltransferases (DGATs) and enhancing PL synthesis through the Kennedy pathway promoted axon regeneration. In addition, peripheral neurons adopted this mechanism for their spontaneous axon regeneration. Our study reveals a critical role of lipin1 and DGATs as intrinsic regulators of glycerolipid metabolism in neurons and indicates that directing neuronal lipid synthesis away from TG synthesis and toward PL synthesis may promote axon regeneration.This study was supported by grants from the Hong Kong Research Grant Council (AoE/M-09/12, AoE/M-604/16, C6004-17G, 16103315, 16149316, and 16102519 to K.L. and C5031-14E to Z.Y.); Innovation and Technology Commission (ITCPD/17-9) of Hong Kong SAR; National Natural Science Foundation of China (81671214); Shenzhen Knowledge Innovation Program (JCYJ20160428145818099 and JCYJ20160427185601855); Guangdong Provincial Key S&T Program (2018B030336001); Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions; Nan Fung Group; and Wellcome Trust Seed award (108042 to S.S.). K.L. is Cheng Associate Professor of Science