PMID- 37013405 OWN - NLM STAT- MEDLINE DCOM- 20230927 LR - 20240116 IS - 1527-3350 (Electronic) IS - 0270-9139 (Linking) VI - 78 IP - 4 DP - 2023 Oct 1 TI - Antagonizing apolipoprotein J chaperone promotes proteasomal degradation of mTOR and relieves hepatic lipid deposition. PG - 1182-1199 LID - 10.1097/HEP.0000000000000185 [doi] AB - 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 microM 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. CI - Copyright (c) 2023 American Association for the Study of Liver Diseases. FAU - Duan, Shuangdi AU - Duan S AUID- ORCID: 0000-0003-1333-4715 AD - Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China. AD - Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China. FAU - Qin, Nong AU - Qin N AUID- ORCID: 0000-0001-5608-1354 AD - Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China. AD - Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China. FAU - Pi, Jiayi AU - Pi J AUID- ORCID: 0000-0001-8397-8239 AD - Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China. AD - Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China. FAU - Sun, Pei AU - Sun P AUID- ORCID: 0000-0001-6236-457 AD - Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China. AD - Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China. FAU - Gao, Yating AU - Gao Y AUID- ORCID: 0000-0002-1851-9252 AD - Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China. AD - Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China. FAU - Liu, Lamei AU - Liu L AUID- ORCID: 0000-0002-0614-1926 AD - Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China. FAU - Li, Zenghui AU - Li Z AUID- ORCID: 0000-0003-3746-7088 AD - School of Biomedical Sciences, Hunan University, Changsha, China. FAU - Li, Ya AU - Li Y AUID- ORCID: 0000-0002-4677-1236 AD - Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China. FAU - Shi, Liyang AU - Shi L AD - Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China. FAU - Gao, Qiang AU - Gao Q AD - School of Biomedical Sciences, Hunan University, Changsha, China. FAU - Qiu, Ye AU - Qiu Y AD - Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China. AD - Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China. FAU - Tang, Songqing AU - Tang S AD - Department of Biomedical Engineering, College of Biology, Hunan University, Changsha, China. AD - Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology of College of Biology, Hunan University, Changsha, China. FAU - Wang, Chun-Hsiang AU - Wang CH AD - Division of Gastroenterology, Tainan Municipal Hospital, Tainan, Taiwan. FAU - Chen, Tzu-Ying AU - Chen TY AD - Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Wang, Sin-Tian AU - Wang ST AD - Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Young, Kung-Chia AU - Young KC AUID- ORCID: 0000-0002-0622-211 AD - Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Sun, Hung-Yu AU - Sun HY AUID- ORCID: 0000-0001-5411-8424 AD - Institute of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230103 PL - United States TA - Hepatology JT - Hepatology (Baltimore, Md.) JID - 8302946 RN - 0 (Clusterin) RN - W36ZG6FT64 (Sirolimus) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - 0 (Ubiquitins) RN - 0 (Lipids) SB - IM MH - Humans MH - Mice MH - Animals MH - Clusterin/metabolism MH - *Non-alcoholic Fatty Liver Disease/pathology MH - Sirolimus MH - *Diabetes Mellitus, Type 2 MH - Liver/pathology MH - TOR Serine-Threonine Kinases/metabolism MH - Lipid Metabolism/physiology MH - Ubiquitins/metabolism MH - Lipids MH - Mice, Inbred C57BL MH - Mammals/metabolism EDAT- 2023/04/05 06:00 MHDA- 2023/09/27 06:42 CRDT- 2023/04/04 03:03 PHST- 2022/05/30 00:00 [received] PHST- 2022/11/26 00:00 [accepted] PHST- 2023/09/27 06:42 [medline] PHST- 2023/04/05 06:00 [pubmed] PHST- 2023/04/04 03:03 [entrez] AID - 01515467-202310000-00022 [pii] AID - 10.1097/HEP.0000000000000185 [doi] PST - ppublish SO - Hepatology. 2023 Oct 1;78(4):1182-1199. doi: 10.1097/HEP.0000000000000185. Epub 2023 Jan 3.