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

Autor:	Duan S; Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China.; Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China., Qin N; Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China.; Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China., Pi J; Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China.; Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China., Sun P; Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China.; Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China., Gao Y; Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China.; Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China., Liu L; Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China., Li Z; School of Biomedical Sciences, Hunan University, Changsha, China., Li Y; Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China., Shi L; Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China., Gao Q; School of Biomedical Sciences, Hunan University, Changsha, China., Qiu Y; Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China.; Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China., Tang S; Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China.; Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China., Wang CH; Division of Gastroenterology, Tainan Municipal Hospital, Tainan, Taiwan., Chen TY; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Wang ST; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Young KC; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.; Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.; Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Sun HY; Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.; Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Jazyk:	angličtina
Zdroj:	Hepatology (Baltimore, Md.) [Hepatology] 2023 Oct 01; Vol. 78 (4), pp. 1182-1199. Date of Electronic Publication: 2023 Jan 03.
DOI:	10.1097/HEP.0000000000000185
Abstrakt:	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. (Copyright © 2023 American Association for the Study of Liver Diseases.)
Databáze:	MEDLINE
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