PMID- 24333689
OWN - NLM
STAT- MEDLINE
DCOM- 20140919
LR  - 20151124
IS  - 1872-8057 (Electronic)
IS  - 0303-7207 (Linking)
VI  - 383
IP  - 1-2
DP  - 2014 Mar 5
TI  - Toxicity generated through inhibition of pyruvate carboxylase and carnitine 
      palmitoyl transferase-1 is similar to high glucose/palmitate-induced 
      glucolipotoxicity in INS-1 beta cells.
PG  - 48-59
LID - S0303-7207(13)00517-0 [pii]
LID - 10.1016/j.mce.2013.12.002 [doi]
AB  - This work was initiated to determine whether toxicity generated through 
      inhibition of mitochondrial fuel metabolism is similar to high glucose/palmitate 
      (HG/PA)-induced glucolipotoxicity. Influx of glucose and free fatty acids into 
      the tricarboxylic acid (TCA) cycle was inhibited by treatment with the pyruvate 
      carboxylase (PC) inhibitor phenylacetic acid (PAA) and carnitine palmitoyl 
      transferase-1 (CPT-1) inhibitor etomoxir (Eto), or knockdown of PC and CPT-1. 
      Treatment of PAA/Eto or knockdown of PC/CPT-1 induced apoptotic death in INS-1 
      beta cells. Similar to HG/PA treatment, PAA/Eto increased endoplasmic reticulum 
      stress responses but decreased the Akt signal. JNK inhibitor or chemical 
      chaperone was protective against both PAA/Eto- and HG/PA-induced cell death. All 
      attempts to reduce [Ca(2)(+)](i), stimulate lipid metabolism, and increase the TCA 
      cycle intermediate pool protected PAA/Eto-induced death as well as HG/PA-induced 
      death. These data suggest that signals induced from impaired mitochondrial fuel 
      metabolism play a critical role in HG/PA-induced glucolipotoxicity.
CI  - Copyright (c) 2013 Elsevier Ireland Ltd. All rights reserved.
FAU - Lee, Ji-Hyun
AU  - Lee JH
AD  - Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 
      442-749, Republic of Korea; Department of Life Science, Korea University Seoul 
      136-701, Republic of Korea.
FAU - Jung, Ik-Rak
AU  - Jung IR
AD  - Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 
      442-749, Republic of Korea.
FAU - Choi, Sung-E
AU  - Choi SE
AD  - Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 
      442-749, Republic of Korea.
FAU - Lee, Sung-Mi
AU  - Lee SM
AD  - Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 
      442-749, Republic of Korea.
FAU - Lee, Soo-Jin
AU  - Lee SJ
AD  - Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 
      442-749, Republic of Korea.
FAU - Han, Seung Jin
AU  - Han SJ
AD  - Department of Endocrinology and Metabolism, Ajou University School of Medicine, 
      Suwon, Kyunggi-do 442-749, Republic of Korea.
FAU - Kim, Hae Jin
AU  - Kim HJ
AD  - Department of Endocrinology and Metabolism, Ajou University School of Medicine, 
      Suwon, Kyunggi-do 442-749, Republic of Korea.
FAU - Kim, Dae Jung
AU  - Kim DJ
AD  - Department of Endocrinology and Metabolism, Ajou University School of Medicine, 
      Suwon, Kyunggi-do 442-749, Republic of Korea.
FAU - Lee, Kwan-Woo
AU  - Lee KW
AD  - Department of Endocrinology and Metabolism, Ajou University School of Medicine, 
      Suwon, Kyunggi-do 442-749, Republic of Korea.
FAU - Kang, Yup
AU  - Kang Y
AD  - Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 
      442-749, Republic of Korea. Electronic address: kangy@ajou.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131211
PL  - Ireland
TA  - Mol Cell Endocrinol
JT  - Molecular and cellular endocrinology
JID - 7500844
RN  - 0 (Epoxy Compounds)
RN  - 0 (Phenylacetates)
RN  - 0 (RNA, Small Interfering)
RN  - 2V16EO95H1 (Palmitic Acid)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - EC 6.4.1.1 (Pyruvate Carboxylase)
RN  - ER5I1W795A (phenylacetic acid)
RN  - IY9XDZ35W2 (Glucose)
RN  - MSB3DD2XP6 (etomoxir)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Calcium/metabolism
MH  - Carnitine O-Palmitoyltransferase/*antagonists & inhibitors/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Citric Acid Cycle/drug effects/genetics
MH  - Endoplasmic Reticulum Stress/genetics
MH  - Epoxy Compounds/pharmacology
MH  - Gene Expression Regulation
MH  - Glucose/*toxicity
MH  - Insulin-Secreting Cells/cytology/*drug effects/metabolism
MH  - MAP Kinase Kinase 4/genetics/metabolism
MH  - Male
MH  - Mitochondria/drug effects/metabolism
MH  - Palmitic Acid/*toxicity
MH  - Phenylacetates/pharmacology
MH  - Primary Cell Culture
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Pyruvate Carboxylase/*antagonists & inhibitors/genetics/metabolism
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Rats
MH  - Signal Transduction
OTO - NOTNLM
OT  - Anaplerosis
OT  - Carnitine palmitoyl transferase-1 (CPT-1)
OT  - Endoplasmic reticulum (ER) stress
OT  - Glucolipotoxicity
OT  - INS-1 beta cell
OT  - Pyruvate carboxylase (PC)
EDAT- 2013/12/18 06:00
MHDA- 2014/09/23 06:00
CRDT- 2013/12/17 06:00
PHST- 2013/07/20 00:00 [received]
PHST- 2013/11/14 00:00 [revised]
PHST- 2013/12/01 00:00 [accepted]
PHST- 2013/12/17 06:00 [entrez]
PHST- 2013/12/18 06:00 [pubmed]
PHST- 2014/09/23 06:00 [medline]
AID - S0303-7207(13)00517-0 [pii]
AID - 10.1016/j.mce.2013.12.002 [doi]
PST - ppublish
SO  - Mol Cell Endocrinol. 2014 Mar 5;383(1-2):48-59. doi: 10.1016/j.mce.2013.12.002. 
      Epub 2013 Dec 11.