Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 383, Issue 1-2, Pages 48-59Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2013.12.002
Keywords
Anaplerosis; Carnitine palmitoyl transferase-1 (CPT-1); Endoplasmic reticulum (ER) stress; Glucolipotoxicity; INS-1 beta cell; Pyruvate carboxylase (PC)
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Funding
- National Research Foundation (NRF)
- Korea government [KRF 2011-0022041, MRC 2012R1A5A204813]
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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 [Ca2+](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. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
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