title: 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.
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.
authors: 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.
authors: Ji-Hyun
authors: JH
authors: Lee
authors: Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors: Ik-Rak
authors: IR
authors: Jung
authors: Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors: Sung-E
authors: SE
authors: Choi
authors: Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors: Sung-Mi
authors: SM
authors: Lee
authors: Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors: Soo-Jin
authors: SJ
authors: Lee
authors: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors: Seung Jin
authors: SJ
authors: Han
authors: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors: Hae Jin
authors: HJ
authors: Kim
authors: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors: Dae Jung
authors: DJ
authors: Kim
authors: Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea.
authors: Kwan-Woo
authors: KW
authors: Lee
authors: Department of physiology, Ajou University School of Medicine, Suwon, Kyunggi-do 442-749, Republic of Korea. Electronic address: kangy@ajou.ac.kr.
authors: Yup
authors: Y
authors: Kang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000187:drug effects / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004852:Epoxy Compounds / Q000494:pharmacology; D005786:Gene Expression Regulation; D005947:Glucose / Q000633:toxicity*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019308:Palmitic Acid / Q000633:toxicity*; D010648:Phenylacetates / Q000494:pharmacology; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011766:Pyruvate Carboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D004852:Epoxy Compounds; D010648:Phenylacetates; D034741:RNA, Small Interfering; D019308:Palmitic Acid; D002334:Carnitine O-Palmitoyltransferase; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4; D011766:Pyruvate Carboxylase; C025136:phenylacetic acid; D005947:Glucose; C054207:etomoxir; D002118:Calcium
keywords: Anaplerosis; Carnitine palmitoyl transferase-1 (CPT-1); Endoplasmic reticulum (ER) stress; Glucolipotoxicity; INS-1 beta cell; Pyruvate carboxylase (PC)