Roles of glutamic pyruvate transaminase 2 in reprogramming of airway epithelial lipidomic and metabolomic profiles after smoking

Abstract

Metabolic abnormalities represent one of the pathological features of chronic obstructive pulmonary disease (COPD). Glutamic pyruvate transaminase 2 (GPT2) is involved in glutamate metabolism and lipid synthesis pathways, whilst the exact roles of GPT2 in the occurrence and development of COPD remains uncertain. This study aims at investigating how GPT2 and the associated genes modulate smoking-induced airway epithelial metabolism and damage by reprogramming lipid synthesis. The circulating or human airway epithelial metabolomic and lipidomic profiles of COPD patients or cell-lines explored with smoking were assessed to elucidate the pivotal roles of GPT2 in reprogramming processes. We found that GPT2 regulate the reprogramming of lipid metabolisms caused by smoking, especially phosphatidylcholine (PC) and triacylglycerol (TAG), along with changes in the expression of lipid metabolism-associated genes. GPT2 modulated cell sensitivities and survival in response to smoking by enhancing mitochondrial functions and maintaining lipid and energy homeostasis. Our findings provide evidence for the involvement of GPT2 in the reprogramming of airway epithelial lipids following smoking, as well as the molecular mechanisms underlying GPT2-mediated regulation, which may offer an alternative of therapeutic strategies for chronic lung diseases.

Keywords

chronic obstructive pulmonary disease / cigarette smoking / glutamic pyruvate transaminase 2 / lipidomics

References

[1] Lu Z, Van Eeckhoutte HP, Liu G, et al. Necroptosis signaling promotes inflammation, airway remodeling, and emphysema in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2021;204(6):667-681.

[2] Fu H, Liu X, Shi L, et al. Regulatory roles of Osteopontin in lung epithelial inflammation and epithelial-telocyte interaction. Clin Transl Med. 2023;13(8):e1381.

[3] Zheng N, Liu X, Yang Y, et al. Regulatory roles of NAT10 in airway epithelial cell function and metabolism in pathological conditions. Cell Biol Toxicol. 2023;39(4):1237-1256.

[4] Wang X, Adler KB, Erjefalt J, et al. Airway epithelial dysfunction in the development of acute lung injury and acute respiratory distress syndrome. Expert Rev Respir Med. 2007;1(1):149-155.

[5] Li L, Wang X. The relationship between cholesterol metabolism and mitochondrial function in chronic obstructive pulmonary diseases. Clin Transl Discov. 2022;2(3):e121.

[6] Agarwal AR, Yin F, Cadenas E. Short-term cigarette smoke exposure leads to metabolic alterations in lung alveolar cells. Am J Respir Cell Mol Biol. 2014;51(2):284-293.

[7] Li L, Wang X. Ferroptosis-associated cholesterol metabolism regulated by p85α in human bronchial epithelial cells with smoking. Clin Transl Discov. 2022;2(1):e30.

[8] Daye D, Wellen KE. Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol. 2012;23(4):362-369.

[9] Reverte L, Yeregui E, Olona M, et al. Fetuin-A, inter-alpha-trypsin inhibitor, glutamic acid and ChoE (18:0) are key biomarkers in a panel distinguishing mild from critical coronavirus disease 2019 outcomes. Clin Transl Med. 2022;12(1):e704.

[10] Guo Z, Yan F. Targeting glutamate metabolism in chronic lung diseases. Clin Transl Discov. 2024;4(2):e294.

[11] Zhang X, Yu K, Ma L, et al. Endogenous glutamate determines ferroptosis sensitivity via ADCY10-dependent YAP suppression in lung adenocarcinoma. Theranostics. 2021;11(12):5650-5674.

[12] Guo W, Li K, Sun B, et al. Dysregulated glutamate transporter SLC1A1 propels cystine uptake via Xc(-) for glutathione synthesis in lung cancer. Cancer Res. 2021;81(3):552-566.

[13] Bai W, Zhu WL, Ning YL, et al. Dramatic increases in blood glutamate concentrations are closely related to traumatic brain injury-induced acute lung injury. Sci Rep. 2017;7(1):5380.

[14] Qian K, Zhong S, Xie K, et al. Hepatic ALT isoenzymes are elevated in gluconeogenic conditions including diabetes and suppressed by insulin at the protein level. Diabetes Metab Res Rev. 2015;31(6):562-571.

[15] Yang RZ, Blaileanu G, Hansen BC, et al. cDNA cloning, genomic structure, chromosomal mapping, and functional expression of a novel human alanine aminotransferase. Genomics. 2002;79(3):445-450.

[16] Li L, Liu Y, Liu X, et al. Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling. Clin Transl Med. 2022;12(6):e902.

[17] Chen C, Fang X, Wang Y, et al. Preventive and therapeutic effects of phosphoinositide 3-kinase inhibitors on acute lung injury. Chest. 2011;140(2):391-400.

[18] Fang X, Li K, Tao X, et al. Effects of phosphoinositide 3-kinase on protease-induced acute and chronic lung inflammation, remodeling, and emphysema in rats. Chest. 2013;143(4):1025-1035.

[19] Liu X, Zhang L, Zhu B, et al. Role of GSDM family members in airway epithelial cells of lung diseases: a systematic and comprehensive transcriptomic analysis. Cell Biol Toxicol. 2023;39(6):2743-2760.

[20] Zhu Z, Zhang L, Lv J, et al. Trans-omic profiling between clinical phenoms and lipidomes among patients with different subtypes of lung cancer. Clin Transl Med. 2020;10(4):e151.

[21] Wang XY, Zhang LL, Jiang C, et al. Altered lipidomic profiles in patients with and without osteonecrosis of the femoral head after 1-month glucocorticoid treatment. Clin Transl Med. 2021;11(2):e298.

[22] Liang X, He X, Li Y, et al. Lyn regulates epithelial-mesenchymal transition in CS-exposed model through Smad2/3 signaling. Respir Res. 2019;20(1):201.

[23] Zhang L, Zhu B, Zeng Y, et al. Clinical lipidomics in understanding of lung cancer: opportunity and challenge. Cancer Lett. 2020;470:75-83.

[24] Gao D, Zhang L, Song D, et al. Values of integration between lipidomics and clinical phenomes in patients with acute lung infection, pulmonary embolism, or acute exacerbation of chronic pulmonary diseases: a preliminary study. J Transl Med. 2019;17(1):162.

[25] Lv J, Gao D, Zhang Y, et al. Heterogeneity of lipidomic profiles among lung cancer subtypes of patients. J Cell Mol Med. 2018;22(10):5155-5159.

[26] Meng H, Sengupta A, Ricciotti E, et al. Deep phenotyping of the lipidomic response in COVID-19 and non-COVID-19 sepsis. Clin Transl Med. 2023;13(11):e1440.

[27] Thornburg JM, Nelson KK, Clem BF, et al. Targeting aspartate aminotransferase in breast cancer. Breast Cancer Res. 2008;10(5):R84.

[28] Hao Y, Samuels Y, Li Q, et al. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat Commun. 2016;7:11971.

[29] Hoda U, Pavlidis S, Bansal AT, et al. Clinical and transcriptomic features of persistent exacerbation-prone severe asthma in U-BIOPRED cohort. Clin Transl Med. 2022;12(4):e816.

[30] Thomson NC. Frequent exacerbators in severe asthma: focus on clinical and transcriptional factors. Clin Transl Med. 2022;12(5):e860.

[31] Ubhi BK, Cheng KK, Dong J, et al. Targeted metabolomics identifies perturbations in amino acid metabolism that sub-classify patients with COPD. Mol Biosyst. 2012;8(12):3125-3133.

[32] Ubhi BK, Riley JH, Shaw PA, et al. Metabolic profiling detects biomarkers of protein degradation in COPD patients. Eur Respir J. 2012;40(2):345-355.

[33] Liu X, Cui B, Wang Q, et al. Biomarkers for respiratory diseases: present applications and future discoveries. Clin Transl Discov. 2021;1(1):e11.

[34] Mao K, Luo P, Geng W, et al. An integrative transcriptomic and metabolomic study revealed that melatonin plays a protective role in chronic lung inflammation by reducing necroptosis. Front Immunol. 2021;12:668002.

[35] Kim J, Suresh B, Lim MN, et al. Metabolomics reveals dysregulated sphingolipid and amino acid metabolism associated with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2022;17:2343-2353.

[36] Cheng Q, Fang L, Feng D, et al. Memantine ameliorates pulmonary inflammation in a mice model of COPD induced by cigarette smoke combined with LPS. Biomed Pharmacother. 2019;109:2005-2013.

[37] Zhang L, Liu X, Liu Y, et al. Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long-chain acyl-coenzyme A synthase 5. Clin Transl Med. 2023;13(1):e1180.

[38] Liu X, Zhang H, Si Y, et al. High-coverage lipidomics analysis reveals biomarkers for diagnosis of acute exacerbation of chronic obstructive pulmonary disease. J Chromatogr B Analyt Technol Biomed Life Sci. 2022;1201-1202:123278.

[39] Lv J, Zhang L, Yan F, et al. Clinical lipidomics: a new way to diagnose human diseases. Clin Transl Med. 2018;7(1):12.

[40] Wang X, Wu D, Shen H. Lipidomics in health & disease: Methods & application. Translational Bioinformatics. 2018:14.

[41] Liu C, Yan F, Song D, et al. Trans-omic analyses identified novel prognostic biomarkers for colorectal cancer survival. Clin Transl Med. 2023;13(6):e1304.

[42] Rodriguez-Roisin R, Rabe KF, Vestbo J, et al. Global initiative for chronic obstructive lung disease (GOLD) 20th anniversary: a brief history of time. Eur Respir J. 2017;50(1):1700671.

[43] Taylor OJ, Thatcher MO, Carr ST, et al. High-mobility group box 1 disrupts metabolic function with cigarette smoke exposure in a ceramide-dependent manner. Int J Mol Sci. 2017;18(5):1099.

[44] Bowman CE, Zhao L, Hartung T, et al. Requirement for the mitochondrial pyruvate carrier in mammalian development revealed by a hypomorphic allelic series. Mol Cell Biol. 2016;36(15):2089-2104.

[45] Yoo HC, Yu YC, Sung Y, et al. Glutamine reliance in cell metabolism. Exp Mol Med. 2020;52(9):1496-1516.

[46] Burr SP, Klimm F, Glynos A, et al. Cell lineage-specific mitochondrial resilience during mammalian organogenesis. Cell. 2023;186(6):1212-1229. e21

[47] Shaykhiev R, Crystal RG. Early events in the pathogenesis of chronic obstructive pulmonary disease. Smoking-induced reprogramming of airway epithelial basal progenitor cells. Ann Am Thorac Soc. 2014;11(5):S252-S258. Suppl

[48] Gohy ST, Hupin C, Fregimilicka C, et al. Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition. Eur Respir J. 2015;45(5):1258-1272.

[49] Michaeloudes C, Kuo CH, Haji G, et al. Metabolic re-patterning in COPD airway smooth muscle cells. Eur Respir J. 2017;50(5):1700202.

[50] Li L, Yang DC, Chen CH. Metabolic reprogramming: a driver of cigarette smoke-induced inflammatory lung diseases. Free Radic Biol Med. 2021;163:392-401.

[51] Olzmann JA, Carvalho P. Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol. 2019;20(3):137-155.

[52] Mejhert N, Kuruvilla L, Gabriel KR, et al. Partitioning of MLX-family transcription factors to lipid droplets regulates metabolic gene expression. Mol Cell. 2020;77(6):1251-1264. e9

[53] Parellada E, Gasso P. Glutamate and microglia activation as a driver of dendritic apoptosis: a core pathophysiological mechanism to understand schizophrenia. Transl Psychiatry. 2021;11(1):271.

[54] Hao Y, Bai S, Peng J, et al. TRIM27-mediated ubiquitination of PPARgamma promotes glutamate-induced cell apoptosis and inflammation. Exp Cell Res. 2021;400(1):112437.

[55] Fukui M, Song JH, Choi J, et al. Mechanism of glutamate-induced neurotoxicity in HT22 mouse hippocampal cells. Eur J Pharmacol. 2009;617(1-3):1-11.

[56] Tan S, Wood M, Maher P. Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells. J Neurochem. 1998;71(1):95-105.

[57] Ji AL, Rubin AJ, Thrane K, et al. Multimodal analysis of composition and spatial architecture in human squamous cell carcinoma. Cell. 2020;182(2):497-514. e22

[58] Ben Anes A, Ben Nasr H, Tabka Z, et al. Plasma lipid profiling identifies phosphatidylcholine 34:3 and triglyceride 52:3 as potential markers associated with disease severity and oxidative status in chronic obstructive pulmonary disease. Lung. 2022;200(4):495-503.

[59] Dorighello G, McPhee M, Halliday K, et al. Differential contributions of phosphotransferases CEPT1 and CHPT1 to phosphatidylcholine homeostasis and lipid droplet biogenesis. J Biol Chem. 2023;299(4):104578.

[60] Chen W, Dai G, Qian Y, et al. PIK3CA mutation affects the proliferation of colorectal cancer cells through the PI3K-MEK/PDK1-GPT2 pathway. Oncol Rep. 2022;47(1):11.

[61] Fritsch R, de Krijger I, Fritsch K, et al. RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms. Cell. 2013;153(5):1050-1063.

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