Long-chain acyl-CoA synthetase regulates systemic lipid homeostasis via glycosylation-dependent lipoprotein production  

作　　者：Jie Li Yue Dong Tianxing Zhou He Tian Xiahe Huang Yong Q.Zhang Yingchun Wang Sin Man Lam Guanghou Shui 

机构地区：[1]State Key Laboratory of Molecular Developmental Biology,Institute of Genetics and Developmental Biology,Chinese Academy of Sciences,Beijing 100101,China [2]University of Chinese Academy of Sciences,Beijing 100101,China [3]Lipidall Technologies Company Limited,Changzhou,Jiangsu 213000,China

出　　处：《Life Metabolism》2024年第2期38-54,共17页生命代谢（英文）

基　　金：supported by grants from the National Natural Science Foundation of China(92057202 and 31871194);the National Key R&D Program of China(2018YFA0506900 and 2018YFA0800901).

摘　　要：Interorgan lipid transport is crucial for organism development and the maintenance of physiological function.Here,we demonstrate that Drosophila long-chain acyl-CoA synthetase(dAcsl),which catalyzes the conversion of fatty acids into acyl-coenzyme As(acyl-CoAs),plays a critical role in regulating systemic lipid homeostasis.dAcsl deficiency in the fat body led to the ectopic accumulation of neutral lipids in the gut,along with significantly reduced lipoprotein contents in both the fat body and hemolymph.The aberrant phenotypes were rescued by fat body-specific overexpression of apolipophorin.A multi-omics investigation comprising lipidomics,metabolomics,and proteomics in conjunction with genetic screening revealed that glycosylation processes were suppressed in dAcsl knockdown flies.Overexpression of CG9035,human ortholog of which is implicated in the congenital disorder of glycosylation,ame-liorated gut lipid accumulation in Drosophila.Aberrant lipoprotein glycosylation led to accelerated proteasome-related degradation and induced ER stress in dAcsl knockdown flies,impairing lipoprotein release into the circulation which compromised interorgan lipid transport between the fat body and the gut.Inhibition of ubiquitin-proteasome-dependent degradation alleviated the phenotype of gut ectopic fat accumulation in dAcsl knockdown flies.Finally,we verified that ACSL4,the human homolog of dAcsl,also regulated lipoprotein levels in HepG2 cells,indicating that the role of dAcsl in modulating lipoprotein secretion and systemic lipid homeostasis is possibly conserved in humans.

关 键 词：lipid homeostasis APOLIPOPROTEIN GLYCOSYLATION LIPIDOMICS metabolomics proteomics 

分 类 号：Q251[生物学—细胞生物学]