PMID- 30452878
OWN - NLM
STAT- MEDLINE
DCOM- 20191112
LR  - 20200309
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Print)
IS  - 0892-6638 (Linking)
VI  - 33
IP  - 3
DP  - 2019 Mar
TI  - Sphingosine kinase 2 promotes lipotoxicity in pancreatic beta-cells and the 
      progression of diabetes.
PG  - 3636-3646
LID - 10.1096/fj.201801496R [doi]
AB  - Loss of functional beta-cell mass caused by lipotoxicity is a key pathogenic factor 
      in the development of type 2 diabetes mellitus (T2DM). We have previously 
      reported that sphingosine kinase (SK)1 is an endogenous protector of beta-cells 
      against lipotoxicity. The current study reports that SK2, another isoform of SK, 
      is a crucial mediator of lipotoxicity in beta-cells. Exposure of beta-cells to 
      palmitatic acid (PA), a saturated free fatty acid, resulted in a nearly 2-fold 
      increase in SK2 expression, which paralleled the induction of cell death in a 
      similar dose- and time-dependent fashion. Silencing SK2 expression by its 
      specific small interfering RNAs significantly inhibited PA-induced cell death and 
      caspase-3 activation, whereas overexpression of SK2 promoted lipotoxicity in 
      beta-cells. Mechanistically, upon exposure to PA, endogenous SK2 was shuttled from 
      the nucleus to the cytoplasm, where it interacted with B-cell 
      lymphoma-extra-large (Bcl-xL), leading to mitochondrial apoptotic pathway 
      activation and cell death. By blocking SK2 translocation and its interaction with 
      Bcl-xL, either the nuclear export signal mutant (L423A/L425A) or the BH3 domain 
      mutant (L219A) of SK2 significantly attenuated beta-cell lipotoxicity. Furthermore, 
      SK2 deficiency in mice significantly prevented the loss of beta-cell mass, preserved 
      insulin production, and ameliorated the diabetic phenotype in an established T2DM 
      model induced by feeding a high-fat diet accompanied by administration of 
      streptozotocin. These findings provide the first evidence, in vitro and in vivo, 
      of a critical role for SK2 in mediating beta-cell lipotoxicity and the progression 
      of diabetes.-Song, Z., Wang, W., Li, N., Yan, S., Rong, K., Lan, T., Xia, P. 
      Sphingosine kinase 2 promotes lipotoxicity in pancreatic beta-cells and the 
      progression of diabetes.
FAU - Song, Ziyu
AU  - Song Z
AD  - Department of Endocrinology and Metabolism, Fudan Institute for Metabolic 
      Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Wang, Wei
AU  - Wang W
AD  - Department of Endocrinology and Metabolism, Fudan Institute for Metabolic 
      Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Li, Ning
AU  - Li N
AD  - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China; and.
FAU - Yan, Sishan
AU  - Yan S
AD  - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China; and.
FAU - Rong, Kuan
AU  - Rong K
AD  - Department of Endocrinology and Metabolism, Fudan Institute for Metabolic 
      Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Lan, Tian
AU  - Lan T
AD  - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China; and.
FAU - Xia, Pu
AU  - Xia P
AD  - Department of Endocrinology and Metabolism, Fudan Institute for Metabolic 
      Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
AD  - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China; and.
AD  - National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan 
      University, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181119
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (Insulin)
RN  - 0 (bcl-X Protein)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.91 (sphingosine kinase 2, human)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Animals
MH  - Apoptosis/physiology
MH  - Caspase 3/metabolism
MH  - Cell Death/physiology
MH  - Cells, Cultured
MH  - Cytoplasm/metabolism
MH  - Diabetes Mellitus, Type 2/*metabolism
MH  - Diet, High-Fat
MH  - Disease Progression
MH  - Humans
MH  - Insulin/metabolism
MH  - Insulin-Secreting Cells/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria/metabolism
MH  - Phosphotransferases (Alcohol Group Acceptor)/*metabolism
MH  - Signal Transduction/physiology
MH  - bcl-X Protein/metabolism
PMC - PMC6404568
OTO - NOTNLM
OT  - apoptosis
OT  - sphingolipids
OT  - type 2 diabetes
OT  - beta-cell biology
COIS- The authors thank Dr. Richard Proia (NIH, Bethesda, MD, USA) for providing 
      SK2(-/-) and SK2(+/+) mouse colonies and Dr. Carol Wadham (South Australia 
      Pathology, Adelaide, Australia) for reviewing and editing the manuscript. This 
      work was supported by National Natural Science Foundation of China Grants 
      81370937 and 81561128014 (to P.X.) and by a Fudan Distinguished Professorship (to 
      P.X.). The authors declare no conflicts of interest.
EDAT- 2018/11/20 06:00
MHDA- 2019/11/13 06:00
PMCR- 2020/03/01
CRDT- 2018/11/20 06:00
PHST- 2018/11/20 06:00 [pubmed]
PHST- 2019/11/13 06:00 [medline]
PHST- 2018/11/20 06:00 [entrez]
PHST- 2020/03/01 00:00 [pmc-release]
AID - FJ_201801496R [pii]
AID - 10.1096/fj.201801496R [doi]
PST - ppublish
SO  - FASEB J. 2019 Mar;33(3):3636-3646. doi: 10.1096/fj.201801496R. Epub 2018 Nov 19.