Lipophagy,the selective engulfment of lipid droplets(LDs)by autophagosomes for lysosomal degradation,is critical to lipid and energy homeostasis.Here we show that the lipid transfer protein ORP8 is located on LDs and ...Lipophagy,the selective engulfment of lipid droplets(LDs)by autophagosomes for lysosomal degradation,is critical to lipid and energy homeostasis.Here we show that the lipid transfer protein ORP8 is located on LDs and mediates the encapsulation of LDs by autophagosomal membranes.This function of oRP8 is independent of its lipid transporter activity and is achieved through direct interaction with phagophore-anchored LC3/GABARAPs.Upon lipophagy induction,ORP8 has increased localization on LDs and is phosphorylated by AMPK,thereby enhancing its affinity for LC3/GABARAPs.Deletion of ORP8 or interruption of ORP8-LC3/GABARAP interaction results in accumulation of LDs and increased intracellular triglyceride.Overexpression of ORP8 alleviates LD and triglyceride deposition in the liver of ob/ob mice,and Osbpl8 mice exhibit liver lipid clearance defects.Our results suggest that ORP8 is a lipophagy receptor that plays a key role in cellular lipid metabolism.展开更多
基金supported by the National Natural Science Foundation of China(Nos.92057203,31790402 and 32230023)the National Key Research and Development Program of China(Nos.2021YFA1300303 and 2017YFA0503402)+1 种基金the Fundamental Research Funds for the Central Universities(2020xzzX002-16)Innovative Institute of Basic Medical Sciences of Zhejiang University.
文摘Lipophagy,the selective engulfment of lipid droplets(LDs)by autophagosomes for lysosomal degradation,is critical to lipid and energy homeostasis.Here we show that the lipid transfer protein ORP8 is located on LDs and mediates the encapsulation of LDs by autophagosomal membranes.This function of oRP8 is independent of its lipid transporter activity and is achieved through direct interaction with phagophore-anchored LC3/GABARAPs.Upon lipophagy induction,ORP8 has increased localization on LDs and is phosphorylated by AMPK,thereby enhancing its affinity for LC3/GABARAPs.Deletion of ORP8 or interruption of ORP8-LC3/GABARAP interaction results in accumulation of LDs and increased intracellular triglyceride.Overexpression of ORP8 alleviates LD and triglyceride deposition in the liver of ob/ob mice,and Osbpl8 mice exhibit liver lipid clearance defects.Our results suggest that ORP8 is a lipophagy receptor that plays a key role in cellular lipid metabolism.
基金supported by the National Key Research and Development Program of China(2016YFC1300100)the National Natural Science Foundation of China(81974042)+1 种基金the CAMS Innovation Fund for Medical Sciences(2022-I2M-C&T-A-010,2022I2M-C&T-A-011,and 2022-I2M-C&T-B-041)the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019XK320057 and 2019XK320058)。
