Antagonizing apolipoprotein J chaperone promotes proteasomal degradation of mTOR and relieves hepatic lipid deposition

Shuangdi Duan, Nong Qin, Jiayi Pi, Pei Sun, Yating Gao, Lamei Liu, Zenghui Li, Ya Li, Liyang Shi, Qiang Gao, Ye Qiu, Songqing Tang, Chun Hsiang Wang, Tzu Ying Chen, Sin Tian Wang, Kung Chia Young, Hung Yu Sun

研究成果: Article同行評審

摘要

Background and Aims: Overnutrition-induced activation of mammalian target of rapamycin (mTOR) dysregulates intracellular lipid metabolism and contributes to hepatic lipid deposition. Apolipoprotein J (ApoJ) is a molecular chaperone and participates in pathogen-induced and nutrient-induced lipid accumulation. This study investigates the mechanism of ApoJ-regulated ubiquitin-proteasomal degradation of mTOR, and a proof-of-concept ApoJ antagonist peptide is proposed to relieve hepatic steatosis. Approach and Results: By using omics approaches, upregulation of ApoJ was found in high-fat medium-fed hepatocytes and livers of patients with NAFLD. Hepatic ApoJ level associated with the levels of mTOR and protein markers of autophagy and correlated positively with lipid contents in the liver of mice. Functionally, nonsecreted intracellular ApoJ bound to mTOR kinase domain and prevented mTOR ubiquitination by interfering FBW7 ubiquitin ligase interaction through its R324 residue. In vitro and in vivo gain-of-function or loss-of-function analysis further demonstrated that targeting ApoJ promotes proteasomal degradation of mTOR, restores lipophagy and lysosomal activity, thus prevents hepatic lipid deposition. Moreover, an antagonist peptide with a dissociation constant (Kd) of 2.54 µM interacted with stress-induced ApoJ and improved hepatic pathology, serum lipid and glucose homeostasis, and insulin sensitivity in mice with NAFLD or type II diabetes mellitus. Conclusions: ApoJ antagonist peptide might be a potential therapeutic against lipid-associated metabolic disorders through restoring mTOR and FBW7 interaction and facilitating ubiquitin-proteasomal degradation of mTOR.

原文English
頁(從 - 到)1182-1199
頁數18
期刊Hepatology
78
發行號4
DOIs
出版狀態Published - 2023 10月

All Science Journal Classification (ASJC) codes

  • 肝病

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