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Mol Cell Endocrinol. 2014 Mar 5;383(1-2):48-59. doi: 10.1016/j.mce.2013.12.002. Epub 2013 Dec 11.

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.

Author information

1
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.
2
Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
3
Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
4
Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea. Electronic address: kangy@ajou.ac.kr.

Abstract

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.

KEYWORDS:

Anaplerosis; Carnitine palmitoyl transferase-1 (CPT-1); Endoplasmic reticulum (ER) stress; Glucolipotoxicity; INS-1 beta cell; Pyruvate carboxylase (PC)

PMID:
24333689
DOI:
10.1016/j.mce.2013.12.002
[Indexed for MEDLINE]
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