title: Excessive L-cysteine induces vacuole-like cell death by activating endoplasmic reticulum stress and mitogen-activated protein kinase signaling in intestinal porcine epithelial cells.
abstract: High intake of dietary cysteine is extremely toxic to animals and the underlying mechanism remains largely unknown. This study was conducted to test the hypothesis that excessive L-cysteine induces cell death by activating endoplasmic reticulum (ER) stress and mitogen-activated protein kinase (MAPK) signaling in intestinal porcine epithelial cells. Jejunal enterocytes were cultured in the presence of 0-10 mmol/L L-cysteine. Cell viability, morphologic alterations, mRNA levels for genes involved in ER stress, protein abundances for glucose-regulated protein 78, C/EBP homologous protein (CHOP), alpha subunit of eukaryotic initiation factor-2 (eIF2α), extracellular signal-regulated kinase (ERK1/2), p38 MAPK, and c-Jun N-terminal protein kinase (JNK1/2) were determined. The results showed that L-cysteine (5-10 mmol/L) reduced cell viability (P < 0.05) and led to vacuole-like cell death in intestinal porcine epithelial cells. These adverse effects of L-cysteine were not affected by the autophagy inhibitor 3-methyladenine. The protein abundances for CHOP, phosphorylated (p)-eIF2α, p-JNK1/2, p-p38 MAPK, and the spliced form of XBP-1 mRNA were enhanced (P < 0.05), whereas those for p-ERK1/2 were reduced (P < 0.05). Collectively, excessive L-cysteine induces vacuole-like cell death via the activation of ER stress and MAPK signaling in small intestinal epithelial cells. These signaling pathways may be potential targets for developing effective strategies to prevent the toxicity of dietary cysteine.
authors: State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, 100193, Beijing, China.
authors: Yun
authors: Y
authors: Ji
authors: State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, 100193, Beijing, China. bio2046@hotmail.com.
authors: Zhenlong
authors: Z
authors: Wu
authors: State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, 100193, Beijing, China.
authors: Zhaolai
authors: Z
authors: Dai
authors: State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, 100193, Beijing, China.
authors: Kaiji
authors: K
authors: Sun
authors: State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, 100193, Beijing, China.
authors: Qing
authors: Q
authors: Zhang
authors: State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, 100193, Beijing, China.|Department of Animal Science, Texas A&M University, College Station, TX, 77843, USA.
authors: Guoyao
authors: G
authors: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D003545:Cysteine / Q000378:metabolism / Q000633:toxicity*; D059865:Endoplasmic Reticulum Stress; D020895:Enterocytes / Q000166:cytology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism*
chemical_list: D051742:Transcription Factor CHOP; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D003545:Cysteine
keywords: Cell death; Endoplasmic reticulum stress; Intestinal epithelial cells; L-Cysteine; Mitogen-activated protein kinase