Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine
Pancreatic acinar cells require high rates of amino acid uptake for digestive enzyme synthesis, but excessive concentrations can trigger acute pancreatitis (AP) by mechanisms that are not well understood. We have used three basic natural amino acids L-arginine, L-ornithine, and L-histidine to determ...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2018.01922/full |
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| author | Xiaoying Zhang Xiaoying Zhang Tao Jin Tao Jin Na Shi Linbo Yao Xinmin Yang Chenxia Han Li Wen Dan Du Peter Szatmary Rajarshi Mukherjee Tingting Liu Qing Xia David N. Criddle Wei Huang Michael Chvanov Robert Sutton |
| author_facet | Xiaoying Zhang Xiaoying Zhang Tao Jin Tao Jin Na Shi Linbo Yao Xinmin Yang Chenxia Han Li Wen Dan Du Peter Szatmary Rajarshi Mukherjee Tingting Liu Qing Xia David N. Criddle Wei Huang Michael Chvanov Robert Sutton |
| author_sort | Xiaoying Zhang |
| collection | DOAJ |
| description | Pancreatic acinar cells require high rates of amino acid uptake for digestive enzyme synthesis, but excessive concentrations can trigger acute pancreatitis (AP) by mechanisms that are not well understood. We have used three basic natural amino acids L-arginine, L-ornithine, and L-histidine to determine mechanisms of amino acid-induced pancreatic injury and whether these are common to all three amino acids. Caffeine markedly inhibited necrotic cell death pathway activation in isolated pancreatic acinar cells induced by L-arginine, but not L-ornithine, whereas caffeine accelerated L-histidine-induced cell death. Both necroptosis inhibitors of RIPK1 and RIPK3 and a necroptosis activator/apoptosis inhibitor z-VAD increased cell death caused by L-histidine, but not L-arginine or L-ornithine. Cyclophilin D knock-out (Ppif-/-) significantly attenuated cell death induced by L-histidine, but not L-arginine, or L-ornithine. Allosteric modulators of calcium-sensing receptor (CaSR) and G-protein coupled receptor class C group 6 member A (GPRC6A) had inhibitory effects on cell death induced by L-arginine but not L-ornithine or L-histidine. We developed a novel amino acid-induced AP murine model with high doses of L-histidine and confirmed AP severity was significantly reduced in Ppif-/- vs. wild type mice. In L-arginine-induced AP neither Ppif-/-, caffeine, or allosteric modulators of CaSR or GPRC6A reduced pancreatic damage, even though CaSR inhibition with NPS-2143 significantly reduced pancreatic and systemic injury in caerulein-induced AP. These findings demonstrate marked differences in the mechanisms of pancreatic injury induced by different basic amino acids and suggest the lack of effect of treatments on L-arginine-induced AP may be due to conversion to L-ornithine in the urea cycle. |
| first_indexed | 2024-12-20T09:01:22Z |
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| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-20T09:01:22Z |
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| spelling | doaj.art-40656b3802294c548a2855ce675c20e92022-12-21T19:45:51ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2019-01-01910.3389/fphys.2018.01922422768Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-HistidineXiaoying Zhang0Xiaoying Zhang1Tao Jin2Tao Jin3Na Shi4Linbo Yao5Xinmin Yang6Chenxia Han7Li Wen8Dan Du9Peter Szatmary10Rajarshi Mukherjee11Tingting Liu12Qing Xia13David N. Criddle14Wei Huang15Michael Chvanov16Robert Sutton17Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, ChinaLiverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomDepartment of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, ChinaLiverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomDepartment of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, ChinaLiverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomWest China-Washington Mitochondria and Metabolism Centre, West China Hospital of Sichuan University, Chengdu, ChinaLiverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomLiverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomDepartment of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United KingdomDepartment of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United KingdomLiverpool Pancreatitis Study Group, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomPancreatic acinar cells require high rates of amino acid uptake for digestive enzyme synthesis, but excessive concentrations can trigger acute pancreatitis (AP) by mechanisms that are not well understood. We have used three basic natural amino acids L-arginine, L-ornithine, and L-histidine to determine mechanisms of amino acid-induced pancreatic injury and whether these are common to all three amino acids. Caffeine markedly inhibited necrotic cell death pathway activation in isolated pancreatic acinar cells induced by L-arginine, but not L-ornithine, whereas caffeine accelerated L-histidine-induced cell death. Both necroptosis inhibitors of RIPK1 and RIPK3 and a necroptosis activator/apoptosis inhibitor z-VAD increased cell death caused by L-histidine, but not L-arginine or L-ornithine. Cyclophilin D knock-out (Ppif-/-) significantly attenuated cell death induced by L-histidine, but not L-arginine, or L-ornithine. Allosteric modulators of calcium-sensing receptor (CaSR) and G-protein coupled receptor class C group 6 member A (GPRC6A) had inhibitory effects on cell death induced by L-arginine but not L-ornithine or L-histidine. We developed a novel amino acid-induced AP murine model with high doses of L-histidine and confirmed AP severity was significantly reduced in Ppif-/- vs. wild type mice. In L-arginine-induced AP neither Ppif-/-, caffeine, or allosteric modulators of CaSR or GPRC6A reduced pancreatic damage, even though CaSR inhibition with NPS-2143 significantly reduced pancreatic and systemic injury in caerulein-induced AP. These findings demonstrate marked differences in the mechanisms of pancreatic injury induced by different basic amino acids and suggest the lack of effect of treatments on L-arginine-induced AP may be due to conversion to L-ornithine in the urea cycle.https://www.frontiersin.org/article/10.3389/fphys.2018.01922/fullacute pancreatitisamino acidsmitochondriacaffeinecyclophilin Dnecroptosis |
| spellingShingle | Xiaoying Zhang Xiaoying Zhang Tao Jin Tao Jin Na Shi Linbo Yao Xinmin Yang Chenxia Han Li Wen Dan Du Peter Szatmary Rajarshi Mukherjee Tingting Liu Qing Xia David N. Criddle Wei Huang Michael Chvanov Robert Sutton Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine Frontiers in Physiology acute pancreatitis amino acids mitochondria caffeine cyclophilin D necroptosis |
| title | Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine |
| title_full | Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine |
| title_fullStr | Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine |
| title_full_unstemmed | Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine |
| title_short | Mechanisms of Pancreatic Injury Induced by Basic Amino Acids Differ Between L-Arginine, L-Ornithine, and L-Histidine |
| title_sort | mechanisms of pancreatic injury induced by basic amino acids differ between l arginine l ornithine and l histidine |
| topic | acute pancreatitis amino acids mitochondria caffeine cyclophilin D necroptosis |
| url | https://www.frontiersin.org/article/10.3389/fphys.2018.01922/full |
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