PMID- 34048566
OWN - NLM
STAT- MEDLINE
DCOM- 20220223
LR  - 20220223
IS  - 1759-4685 (Electronic)
IS  - 1674-2788 (Print)
IS  - 1759-4685 (Linking)
VI  - 13
IP  - 7
DP  - 2021 Oct 21
TI  - PSA controls hepatic lipid metabolism by regulating the NRF2 signaling pathway.
PG  - 527-539
LID - 10.1093/jmcb/mjab033 [doi]
AB  - The activity of proteinase is reported to correlate with the development and 
      progression of nonalcoholic fatty liver disease (NAFLD). Puromycin-sensitive 
      aminopeptidase (PSA/NPEPPS) is an integral nontransmembrane enzyme that functions 
      to catalyze the cleavage of amino acids near the N-terminus of polypeptides. A 
      previous study suggested that this enzyme acts as a regulator of neuropeptide 
      activity; however, the metabolic function of this enzyme in the liver has not 
      been explored. Here, we identified the novel role of PSA in hepatic lipid 
      metabolism. Specifically, PSA expression was lower in fatty livers from NAFLD 
      patients and mice (HFD, ob/ob, and db/db). PSA knockdown in cultured hepatocytes 
      exacerbated diet-induced triglyceride accumulation through enhanced lipogenesis 
      and attenuated fatty acid beta-oxidation. Moreover, PSA mediated activation of the 
      master regulator of antioxidant response, nuclear factor erythroid 2-related 
      factor 2 (NRF2), by stabilizing NRF2 protein expression, which further induced 
      downstream antioxidant enzymes to protect the liver from oxidative stress and 
      lipid overload. Accordingly, liver-specific PSA overexpression attenuated hepatic 
      lipid accumulation and steatosis in ob/ob mice. Furthermore, in human liver 
      tissue samples, decreased PSA expression correlated with the progression of 
      NAFLD. Overall, our findings suggest that PSA is a pivotal regulator of hepatic 
      lipid metabolism and its antioxidant function occurs by suppressing NRF2 
      ubiquitination. Moreover, PSA may be a potential biomarker and therapeutic target 
      for treating NAFLD.
CI  - (c) The Author(s) (2021). Published by Oxford University Press on behalf of Journal 
      of Molecular Cell Biology, CEMCS, CAS.
FAU - Huang, Bangliang
AU  - Huang B
AD  - Department of Endocrinology, Translational Research of Diabetes Key Laboratory of 
      Chongqing Education Commission of China, The Second Affiliated Hospital of Army 
      Medical University, Chongqing, China.
FAU - Xiong, Xin
AU  - Xiong X
AD  - Department of Endocrinology, Translational Research of Diabetes Key Laboratory of 
      Chongqing Education Commission of China, The Second Affiliated Hospital of Army 
      Medical University, Chongqing, China.
FAU - Zhang, Linlin
AU  - Zhang L
AD  - Department of Endocrinology, Translational Research of Diabetes Key Laboratory of 
      Chongqing Education Commission of China, The Second Affiliated Hospital of Army 
      Medical University, Chongqing, China.
FAU - Liu, Xiufei
AU  - Liu X
AD  - Department of Endocrinology, Translational Research of Diabetes Key Laboratory of 
      Chongqing Education Commission of China, The Second Affiliated Hospital of Army 
      Medical University, Chongqing, China.
FAU - Wang, Yuren
AU  - Wang Y
AD  - Department of Endocrinology, Translational Research of Diabetes Key Laboratory of 
      Chongqing Education Commission of China, The Second Affiliated Hospital of Army 
      Medical University, Chongqing, China.
FAU - Gong, Xiaoli
AU  - Gong X
AD  - Department of Endocrinology, Translational Research of Diabetes Key Laboratory of 
      Chongqing Education Commission of China, The Second Affiliated Hospital of Army 
      Medical University, Chongqing, China.
FAU - Sang, Qian
AU  - Sang Q
AD  - Department of Endocrinology, Translational Research of Diabetes Key Laboratory of 
      Chongqing Education Commission of China, The Second Affiliated Hospital of Army 
      Medical University, Chongqing, China.
FAU - Lu, Yongling
AU  - Lu Y
AD  - Medical Research Center, Southwest Hospital of Army Medical University, 
      Chongqing, China.
FAU - Qu, Hua
AU  - Qu H
AD  - Department of Endocrinology, Translational Research of Diabetes Key Laboratory of 
      Chongqing Education Commission of China, The Second Affiliated Hospital of Army 
      Medical University, Chongqing, China.
FAU - Zheng, Hongting
AU  - Zheng H
AD  - Department of Endocrinology, Translational Research of Diabetes Key Laboratory of 
      Chongqing Education Commission of China, The Second Affiliated Hospital of Army 
      Medical University, Chongqing, China.
FAU - Zheng, Yi
AU  - Zheng Y
AUID- ORCID: 0000-0002-5945-4432
AD  - Department of Endocrinology, Translational Research of Diabetes Key Laboratory of 
      Chongqing Education Commission of China, The Second Affiliated Hospital of Army 
      Medical University, Chongqing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Mol Cell Biol
JT  - Journal of molecular cell biology
JID - 101503669
RN  - 0 (Antioxidants)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Triglycerides)
RN  - EC 3.4.11.- (Aminopeptidases)
RN  - EC 3.4.11.14 (enkephalin degrading enzyme)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.- (NPEPPS protein, human)
SB  - IM
MH  - Aminopeptidases/genetics/*metabolism
MH  - Animals
MH  - Antioxidants/*metabolism
MH  - Cell Line
MH  - Diet, High-Fat/adverse effects
MH  - Disease Models, Animal
MH  - Gene Knockdown Techniques
MH  - Hepatocytes/metabolism
MH  - Humans
MH  - Lipid Metabolism/*genetics
MH  - Liver/metabolism/pathology
MH  - Male
MH  - Metalloendopeptidases/genetics/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Non-alcoholic Fatty Liver Disease/etiology/*metabolism/pathology
MH  - Oxidative Stress/genetics
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/*genetics
MH  - Transfection
MH  - Triglycerides/metabolism
PMC - PMC8530519
OTO - NOTNLM
OT  - NAFLD
OT  - NRF2
OT  - PSA
OT  - fatty acid beta-oxidation
OT  - lipogenesis
EDAT- 2021/05/29 06:00
MHDA- 2022/02/24 06:00
PMCR- 2021/05/28
CRDT- 2021/05/28 17:28
PHST- 2020/12/23 00:00 [received]
PHST- 2021/02/26 00:00 [revised]
PHST- 2021/03/30 00:00 [accepted]
PHST- 2021/05/29 06:00 [pubmed]
PHST- 2022/02/24 06:00 [medline]
PHST- 2021/05/28 17:28 [entrez]
PHST- 2021/05/28 00:00 [pmc-release]
AID - 6287622 [pii]
AID - mjab033 [pii]
AID - 10.1093/jmcb/mjab033 [doi]
PST - ppublish
SO  - J Mol Cell Biol. 2021 Oct 21;13(7):527-539. doi: 10.1093/jmcb/mjab033.