PMID- 37524243
OWN - NLM
STAT- MEDLINE
DCOM- 20230911
LR  - 20230918
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 76
DP  - 2023 Oct
TI  - Chaperone-mediated autophagy dysregulation during aging impairs hepatic fatty 
      acid oxidation via accumulation of NCoR1.
PG  - 101784
LID - S2212-8778(23)00118-7 [pii]
LID - 10.1016/j.molmet.2023.101784 [doi]
LID - 101784
AB  - OBJECTIVE: Alterations in lipid metabolism are associated with aging and 
      age-related diseases. Chaperone-mediated autophagy (CMA) is a lysosome-dependent 
      process involved in specific protein degradation. Heat shock cognate 71 kDa 
      protein (Hsc70) recognizes cytosolic proteins with KFERQ motif and allows them to 
      enter the lysosome via lysosome-associated membrane glycoprotein 2 isoform A 
      (LAMP2A). CMA deficiency is associated with dysregulated lipid metabolism in the 
      liver. In this study, we examined the effect of CMA on lipid metabolism in the 
      aged liver. METHODS: 12-week-old and 88-week-old mice were employed to assess the 
      effect of aging on hepatic CMA activity. We generated CMA-deficient mouse primary 
      hepatocytes using siRNA for Lamp2a and liver-specific LAMP2A knockdown mice via 
      adeno-associated viruses expressing short hairpin RNAs to investigate the 
      influence of CMA on lipid metabolism. RESULTS: We noted aging-induced progression 
      toward fatty liver and a decrease in LAMP2A levels in total protein and 
      lysosomes. The expression of genes associated with fatty acid oxidation was 
      markedly downregulated in the aged liver, as verified in CMA-deficient mouse 
      primary hepatocytes. In addition, the aged liver accumulated nuclear receptor 
      corepressor 1 (NCoR1), a negative regulator of peroxisome proliferator-activated 
      receptor alpha (PPARalpha). We found that Hsc70 binds to NCoR1 via the KFERQ motif. 
      Lamp2a siRNA treatment accumulated NCoR1 and decreased the fatty acid oxidation 
      rate. Pharmacological activation of CMA by AR7 treatment increased LAMP2A 
      expression, leading to NCoR1 degradation. A liver-specific LAMP2A knockdown via 
      adeno-associated viruses expressing short hairpin RNAs caused NCoR1 accumulation, 
      inactivated PPARalpha, downregulated the expression of fatty acid oxidation-related 
      genes and significantly increased liver triglyceride levels. CONCLUSIONS: Our 
      results elucidated a novel PPARalpha regulatory mechanism involving CMA-mediated 
      NCoR1 degradation during aging. These findings demonstrate that CMA dysregulation 
      is crucial for the progression of aging-related fatty liver diseases.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.
FAU - Choi, You-Jin
AU  - Choi YJ
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul 08826, Republic of Korea.
FAU - Yun, Sung Ho
AU  - Yun SH
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul 08826, Republic of Korea.
FAU - Yu, Jihyeon
AU  - Yu J
AD  - Division of Life Science, Korea Polar Research Institute, Incheon 21990, Republic 
      of Korea.
FAU - Mun, Yewon
AU  - Mun Y
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul 08826, Republic of Korea.
FAU - Lee, Wonseok
AU  - Lee W
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul 08826, Republic of Korea.
FAU - Park, Cheon Jun
AU  - Park CJ
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul 08826, Republic of Korea.
FAU - Han, Byung Woo
AU  - Han BW
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul 08826, Republic of Korea.
FAU - Lee, Byung-Hoon
AU  - Lee BH
AD  - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul 
      National University, Seoul 08826, Republic of Korea. Electronic address: 
      lee@snu.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230729
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
RN  - 0 (PPAR alpha)
RN  - 0 (Fatty Acids)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Chaperone-Mediated Autophagy
MH  - Autophagy
MH  - PPAR alpha/genetics
MH  - Aging
MH  - Liver
MH  - Lipid Metabolism
MH  - Fatty Acids/pharmacology
PMC - PMC10448198
OTO - NOTNLM
OT  - Aging
OT  - Chaperone-mediated autophagy
OT  - Fatty acid oxidation
OT  - NCoR1
OT  - PPARalpha
COIS- Declaration of competing interest The authors have no conflicts of interest to 
      disclose.
EDAT- 2023/08/01 01:07
MHDA- 2023/09/11 06:42
PMCR- 2023/07/29
CRDT- 2023/07/31 19:13
PHST- 2023/03/13 00:00 [received]
PHST- 2023/07/21 00:00 [revised]
PHST- 2023/07/27 00:00 [accepted]
PHST- 2023/09/11 06:42 [medline]
PHST- 2023/08/01 01:07 [pubmed]
PHST- 2023/07/31 19:13 [entrez]
PHST- 2023/07/29 00:00 [pmc-release]
AID - S2212-8778(23)00118-7 [pii]
AID - 101784 [pii]
AID - 10.1016/j.molmet.2023.101784 [doi]
PST - ppublish
SO  - Mol Metab. 2023 Oct;76:101784. doi: 10.1016/j.molmet.2023.101784. Epub 2023 Jul 
      29.