PMID- 26900161
OWN - NLM
STAT- MEDLINE
DCOM- 20161216
LR  - 20240325
IS  - 1539-7262 (Electronic)
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 57
IP  - 4
DP  - 2016 Apr
TI  - Lactosylceramide contributes to mitochondrial dysfunction in diabetes.
PG  - 546-62
LID - 10.1194/jlr.M060061 [doi]
AB  - Sphingolipids have been implicated as key mediators of cell-stress responses and 
      effectors of mitochondrial function. To investigate potential mechanisms 
      underlying mitochondrial dysfunction, an important contributor to diabetic 
      cardiomyopathy, we examined alterations of cardiac sphingolipid metabolism in a 
      mouse with streptozotocin-induced type 1 diabetes. Diabetes increased expression 
      of desaturase 1, (dihydro)ceramide synthase (CerS)2, serine palmitoyl transferase 
      1, and the rate of ceramide formation by mitochondria-resident CerSs, indicating 
      an activation of ceramide biosynthesis. However, the lack of an increase in 
      mitochondrial ceramide suggests concomitant upregulation of ceramide-metabolizing 
      pathways. Elevated levels of lactosylceramide, one of the initial products in the 
      formation of glycosphingolipids were accompanied with decreased respiration and 
      calcium retention capacity (CRC) in mitochondria from diabetic heart tissue. In 
      baseline mitochondria, lactosylceramide potently suppressed state 3 respiration 
      and decreased CRC, suggesting lactosylceramide as the primary sphingolipid 
      responsible for mitochondrial defects in diabetic hearts. Moreover, knocking down 
      the neutral ceramidase (NCDase) resulted in an increase in lactosylceramide 
      level, suggesting a crosstalk between glucosylceramide synthase- and 
      NCDase-mediated ceramide utilization pathways. These data suggest the 
      glycosphingolipid pathway of ceramide metabolism as a promising target to correct 
      mitochondrial abnormalities associated with type 1 diabetes.
CI  - Copyright (c) 2016 by the American Society for Biochemistry and Molecular Biology, 
      Inc.
FAU - Novgorodov, Sergei A
AU  - Novgorodov SA
AD  - Departments of Neuroscience Medical University of South Carolina, Charleston, SC 
      29425 novgoros@musc.edu.
FAU - Riley, Christopher L
AU  - Riley CL
AD  - Ralph H. Johnson Veteran Affairs Medical Center, Charleston, SC 29401.
FAU - Yu, Jin
AU  - Yu J
AD  - Departments of Neuroscience Medical University of South Carolina, Charleston, SC 
      29425.
FAU - Keffler, Jarryd A
AU  - Keffler JA
AD  - Departments of Neuroscience Medical University of South Carolina, Charleston, SC 
      29425.
FAU - Clarke, Christopher J
AU  - Clarke CJ
AD  - Department of Medicine, Stony Brook University, Stony Brook, NY 11794.
FAU - Van Laer, An O
AU  - Van Laer AO
AD  - Ralph H. Johnson Veteran Affairs Medical Center, Charleston, SC 29401 Medicine, 
      Medical University of South Carolina, Charleston, SC 29425.
FAU - Baicu, Catalin F
AU  - Baicu CF
AD  - Ralph H. Johnson Veteran Affairs Medical Center, Charleston, SC 29401 Medicine, 
      Medical University of South Carolina, Charleston, SC 29425.
FAU - Zile, Michael R
AU  - Zile MR
AD  - Ralph H. Johnson Veteran Affairs Medical Center, Charleston, SC 29401 Medicine, 
      Medical University of South Carolina, Charleston, SC 29425.
FAU - Gudz, Tatyana I
AU  - Gudz TI
AD  - Departments of Neuroscience Medical University of South Carolina, Charleston, SC 
      29425 Ralph H. Johnson Veteran Affairs Medical Center, Charleston, SC 29401.
LA  - eng
GR  - R56HL123478/HL/NHLBI NIH HHS/United States
GR  - R56 HL123478/HL/NHLBI NIH HHS/United States
GR  - R01 NS083544/NS/NINDS NIH HHS/United States
GR  - R01 HL123478/HL/NHLBI NIH HHS/United States
GR  - 1R01HL123478-01A1/HL/NHLBI NIH HHS/United States
GR  - I01 BX002991/BX/BLRD VA/United States
GR  - I01 CX000415/CX/CSRD VA/United States
GR  - R01NS083544/NS/NINDS NIH HHS/United States
GR  - P30 GM10333/GM/NIGMS NIH HHS/United States
GR  - I01 BX000487/BX/BLRD VA/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20160221
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - 0 (Lactosylceramides)
RN  - EC 3.5.1.23 (Neutral Ceramidase)
SB  - IM
MH  - Animals
MH  - Cell Respiration
MH  - Diabetes Mellitus, Type 1/enzymology/*metabolism/*pathology/physiopathology
MH  - Gene Expression Regulation, Enzymologic
MH  - Gene Knockdown Techniques
MH  - Heart/physiopathology
MH  - Hydrolysis
MH  - Lactosylceramides/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria, Heart/*metabolism/*pathology
MH  - Neutral Ceramidase/deficiency/genetics/metabolism
PMC - PMC4808764
OTO - NOTNLM
OT  - calcium
OT  - glycolipids
OT  - heart
OT  - mitochondria
OT  - respiration
OT  - sphingolipids
EDAT- 2016/02/24 06:00
MHDA- 2016/12/17 06:00
PMCR- 2017/04/01
CRDT- 2016/02/23 06:00
PHST- 2015/04/15 00:00 [received]
PHST- 2016/02/23 06:00 [entrez]
PHST- 2016/02/24 06:00 [pubmed]
PHST- 2016/12/17 06:00 [medline]
PHST- 2017/04/01 00:00 [pmc-release]
AID - S0022-2275(20)35411-0 [pii]
AID - m060061 [pii]
AID - 10.1194/jlr.M060061 [doi]
PST - ppublish
SO  - J Lipid Res. 2016 Apr;57(4):546-62. doi: 10.1194/jlr.M060061. Epub 2016 Feb 21.