Phlorizin regulates lipid metabolism and protects against Aβ toxicity in Caenorhabditis elegans via NHR-49 dependent pathway

Background and Purpose: Phlorizin is the active ingredient in the Cynomorium songaricum ethyl acetate extract, and it has been shown that Phlorizin can regulate lipid metabolism disorders as well as anti-ageing.But there are no studies on the relevance of PHZ in attenuating Aβ-induced toxicity in Alzheimer’s disease(AD) by regulating lipid metabolism.Our purpose is to investigate the effects of phlorizin on the regulation of lipid metabolism disorders and resistance to Aβ-associated toxicity in the AD Caenorhabditis elegans and their mechanisms of action. Experimental Approach: Wild-type N2 and AD model CL4176 C.elegans was used, the lifespan, heat stress, chronic paraquat stress, behavioral testing and lipofuscin assay was exaimed to detected anti-ageing efficacy,non-esterified fatty acid,triglyceride and lipidomic contents were quantified after PHZ treatment. The detection of genes related to lipid metabolism pathways was performed using qpcr. nhr-49 knockout mutant RB1716,GFP-binding mutants PMD150 WBM170 were uesd to observed the effect of PHZ on NHR-49 pathways and molecular docking studies were performed combining phlorizin and NHR-49 proteins. Key Results: PHZ improved worms survival and delayed senescence in lifespan, heat stress and chronic paraquat assays, PHZ also reduced lipid accumulation in worms, affected the unsaturated fatty acid pathway and significantly increased the expression of fatty acid metabolism-related genes nhr-49, acs-2 and cpt-5, and can be tightly coupled to NHR-49 targets. Conclusion: PHZ may play an anti-Aβ toxicity role by regulating lipid metabolism disorders through nhr-49 related pathway and anti-ageing in AD worms. Keywords：Phlorizin；C.elegans；AD；lipid metabilosm