PMID- 37928506
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231107
IS  - 1792-1015 (Electronic)
IS  - 1792-0981 (Print)
IS  - 1792-0981 (Linking)
VI  - 26
IP  - 6
DP  - 2023 Dec
TI  - PP2Ac knockdown attenuates lipotoxicity‑induced pancreatic beta‑cell dysfunction and 
      apoptosis.
PG  - 549
LID - 10.3892/etm.2023.12247 [doi]
LID - 549
AB  - Protein phosphatase 2A (PP2A) is one of the most common serine/threonine 
      phosphatases in mammalian cells, and it primarily functions to regulate cell 
      signaling, glycolipid metabolism and apoptosis. The catalytic subunit of PP2A 
      (PP2Ac) plays an important role in the functions of the protein. However, there 
      are few reports on the regulatory role of PP2Ac in pancreatic beta-cells under 
      lipotoxic conditions. In the present study, mouse insulinoma 6 (MIN6) pancreatic 
      cells were transfected with short hairpin RNAs to generate PP2Ac knockdown cells 
      and incubated with palmitate (PA) to establish a lipotoxicity model. 
      Serine/threonine phosphatase assay system, Cell Counting Kit-8, flow cytometry, 
      enzyme-linked immunosorbent assay and western blotting were used to measure PP2A 
      activity, cell viability, apoptosis, oxidative stress and insulin secretion in 
      the cells. In addition, a mouse model of lipotoxicity was established with a 
      high-fat diet (HFD) and the knockdown of PP2Ac using adeno-associated viruses to 
      interfere with PP2Ac expression in the pancreatic tissues. The activity of PP2A 
      in the mouse pancreatic tissue and the serum insulin level were measured. 
      Furthermore, the proliferation of mouse pancreatic beta-cells was assessed using 
      pancreatic tissue immunofluorescence. PP2Ac knockdown inhibited 
      lipotoxicity-induced PP2A hyperactivation, increased the resistance of pancreatic 
      beta-cells to lipotoxicity and attenuated PA-induced apoptosis in MIN6 cells. It 
      also protected the endoplasmic reticulum and mitochondria, and ameliorated 
      insulin secretion. The results of mRNA sequencing and western blotting analysis 
      suggested that the protective effects of PP2Ac knockdown in MIN6 cells may be 
      mediated via the MAPK pathway. Moreover, the results of the animal experiments 
      suggested that specific knockdown of pancreatic PP2Ac effectively attenuated 
      HFD-induced insulin resistance and reduced the compensatory proliferation of 
      pancreatic beta-cells in mice. In summary, the present study revealed the effects of 
      interfering with PP2Ac gene expression on pancreatic beta-cells in vivo and in vitro 
      and the underlying mechanisms, which may provide insights for the treatment of 
      type 2 diabetes mellitus in the clinic.
CI  - Copyright: (c) Zhang et al.
FAU - Zhang, Zhengwei
AU  - Zhang Z
AD  - Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 
      430071, P.R. China.
FAU - Tong, Beier
AU  - Tong B
AD  - Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 
      430071, P.R. China.
FAU - Liu, Jie
AU  - Liu J
AD  - Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 
      430071, P.R. China.
FAU - Feng, Jieyuan
AU  - Feng J
AD  - Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 
      430071, P.R. China.
FAU - Song, Linyang
AU  - Song L
AD  - Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 
      430071, P.R. China.
FAU - Wang, Huawei
AU  - Wang H
AD  - Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 
      430071, P.R. China.
FAU - Ke, Mengting
AU  - Ke M
AD  - Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 
      430071, P.R. China.
FAU - Xu, Chengkai
AU  - Xu C
AD  - Department of Endocrinology, Suizhou Central Hospital, Suizhou, Hubei 441300, 
      P.R. China.
FAU - Xu, Yancheng
AU  - Xu Y
AD  - Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 
      430071, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20231010
PL  - Greece
TA  - Exp Ther Med
JT  - Experimental and therapeutic medicine
JID - 101531947
PMC - PMC10623214
OTO - NOTNLM
OT  - PP2Ac
OT  - apoptosis
OT  - dysfunction
OT  - lipotoxicity
OT  - beta-cell
COIS- The authors declare that they have no competing interests.
EDAT- 2023/11/06 06:42
MHDA- 2023/11/06 06:43
PMCR- 2023/10/10
CRDT- 2023/11/06 04:35
PHST- 2023/06/29 00:00 [received]
PHST- 2023/09/20 00:00 [accepted]
PHST- 2023/11/06 06:43 [medline]
PHST- 2023/11/06 06:42 [pubmed]
PHST- 2023/11/06 04:35 [entrez]
PHST- 2023/10/10 00:00 [pmc-release]
AID - ETM-26-6-12247 [pii]
AID - 10.3892/etm.2023.12247 [doi]
PST - epublish
SO  - Exp Ther Med. 2023 Oct 10;26(6):549. doi: 10.3892/etm.2023.12247. eCollection 
      2023 Dec.