PMID- 35239504
OWN - NLM
STAT- MEDLINE
DCOM- 20220405
LR  - 20220531
IS  - 1741-7899 (Electronic)
IS  - 1470-1626 (Linking)
VI  - 163
IP  - 5
DP  - 2022 Mar 24
TI  - T2DM-elicited oxidative stress represses MTA3 expression in mouse Leydig cells.
PG  - 267-280
LID - 10.1530/REP-21-0413 [doi]
AB  - Metastasis-associated protein 3 (MTA3) functions as a versatile coregulator in 
      cancers and in physiological contexts. A predominant expression of MTA3 in 
      interstitial Leydig cells (LCs) and its role as a local modulator of testicular 
      steroidogenesis have recently emerged. Incubation with insulin decreased MTA3 
      expression in a concentration- and exposure time-dependent manner in LCs. This 
      raises the possibility of additional endocrine actions of insulin in the direct 
      control of MTA3 expression, which remains so far unexplored. Herein, we reported 
      that type 2 diabetes mellitus (T2DM)-mediated inhibition of MTA3 was associated 
      with an increase in testicular oxidative stress. In contrast, a gavage of the 
      strong antioxidant melatonin effectively ameliorated oxidative stress and 
      restored the expression of MTA3, but failed to change serum insulin levels in the 
      diabetic mice with testosterone deficiency (TD). Using multiple biochemical 
      approaches, we demonstrated that oxidative stress suppressed MTA3 expression via 
      repression of nuclear receptor subfamily 4 group A member 1 (NR4A1)-mediated 
      transactivation of MTA3 in mouse LCs. By contrast, ectopic expression of NR4A1 
      ameliorated oxidative stress-impaired MTA3 expression in LCs. By employing an 
      effective in vivo gene transfer method with microinjection of lentiviral 
      plasmids, we showed that replenishment of MTA3 expression in vivo partially 
      restored testicular steroidogenesis and improved male fertility in diabetic mice 
      with TD. Thus, we have unveiled a central regulatory hub, involving oxidative 
      stress-impaired NR4A1-driven transactivation of MTA3 in stimulated LCs, as a 
      potential mechanism regulating crosstalk between hyperinsulinemia and male 
      infertility associated with TD.
FAU - Liu, Fei
AU  - Liu F
AD  - Department of Urology, Xijing Hospital, Air Force Medical University, Xi'an, 
      Shaanxi Province, People's Republic of China.
FAU - Chen, Zhen-Zhen
AU  - Chen ZZ
AD  - Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 
      Shaanxi Province, People's Republic of China.
FAU - Zhao, Jie
AU  - Zhao J
AD  - Department of Human Anatomy, Histology and Embryology, Air Force Medical 
      University, Xi'an, Shaanxi Province, People's Republic of China.
FAU - Zhang, Yuan-Qiang
AU  - Zhang YQ
AD  - Department of Human Anatomy, Histology and Embryology, Air Force Medical 
      University, Xi'an, Shaanxi Province, People's Republic of China.
FAU - Ma, Jing
AU  - Ma J
AD  - Department of Traditional Chinese Medicine, Xijing Hospital, Air Force Medical 
      University, Xi'an, Shaanxi Province, People's Republic of China.
FAU - Li, Wei
AU  - Li W
AUID- ORCID: 0000-0003-2487-3773
AD  - Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 
      Shaanxi Province, People's Republic of China.
AD  - Department of Human Anatomy, Histology and Embryology, Air Force Medical 
      University, Xi'an, Shaanxi Province, People's Republic of China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220324
PL  - England
TA  - Reproduction
JT  - Reproduction (Cambridge, England)
JID - 100966036
RN  - 3XMK78S47O (Testosterone)
SB  - IM
MH  - Animals
MH  - *Diabetes Mellitus, Experimental/metabolism
MH  - *Diabetes Mellitus, Type 2
MH  - Leydig Cells/metabolism
MH  - Male
MH  - Mice
MH  - *Neoplasms/metabolism
MH  - Oxidative Stress
MH  - Testosterone
EDAT- 2022/03/04 06:00
MHDA- 2022/04/06 06:00
CRDT- 2022/03/03 17:13
PHST- 2021/10/15 00:00 [received]
PHST- 2022/03/03 00:00 [accepted]
PHST- 2022/03/04 06:00 [pubmed]
PHST- 2022/04/06 06:00 [medline]
PHST- 2022/03/03 17:13 [entrez]
AID - 10.1530/REP-21-0413 [doi]
PST - epublish
SO  - Reproduction. 2022 Mar 24;163(5):267-280. doi: 10.1530/REP-21-0413.