ORP8 acts as a lipophagy receptor to mediate lipid droplet turnover.

Maomao PU; Wenhui Zheng; Hongtao Zhang; Wei Wan; Chao Peng; Xuebo Chen; Xinchang Liu; Zizhen XU; Tianhua Zhou; Qiming Sun; Dante Neculai; Wei Liu

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ORP8 acts as a lipophagy receptor to mediate lipid droplet turnover.

Author: Maomao PU ¹ ; Wenhui ZHENG ¹ ; Hongtao ZHANG ¹ ; Wei WAN ¹ ; Chao PENG ² ; Xuebo CHEN ¹ ; Xinchang LIU ¹ ; Zizhen XU ¹ ; Tianhua ZHOU ¹ ; Qiming SUN ¹ ; Dante NECULAI ¹ ; Wei LIU ¹
Author Information

1. Metabolic Medicine Center, International Institutes of Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China.
2. National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Publication Type:Research Support, Non-U.S. Gov't
Keywords: ORP8; autophagy; lipid; lipophagy
MeSH: Animals; Mice; Lipid Droplets; Autophagy; Autophagosomes; Homeostasis; Triglycerides
From: Protein & Cell 2023;14(9):653-667
CountryChina
Language:English
Abstract: 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.