The role of glutathione S-transferase mu 2 in mitigating fatty acid–induced hepatic inflammation in dairy cows
ABSTRACT: Fatty liver is a major metabolic disorder in perinatal dairy cows, characterized by elevated plasma concentrations of nonesterified fatty acids (NEFA) and hepatic inflammation. Glutathione S-transferase mu 2 (GSTM2), a phase II detoxification enzyme, regulates cellular antioxidant and deto...
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Elsevier
2025-04-01
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| Series: | Journal of Dairy Science |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022030225000736 |
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| author | Jinxia Li Chenchen Zhao Dandan Qi Fanrong Kong Menglin Liu Jie Gao Enzhu Li Wenwen Gao Xiliang Du Yuxiang Song Xinwei Li Haihua Feng Lin Lei |
| author_facet | Jinxia Li Chenchen Zhao Dandan Qi Fanrong Kong Menglin Liu Jie Gao Enzhu Li Wenwen Gao Xiliang Du Yuxiang Song Xinwei Li Haihua Feng Lin Lei |
| author_sort | Jinxia Li |
| collection | DOAJ |
| description | ABSTRACT: Fatty liver is a major metabolic disorder in perinatal dairy cows, characterized by elevated plasma concentrations of nonesterified fatty acids (NEFA) and hepatic inflammation. Glutathione S-transferase mu 2 (GSTM2), a phase II detoxification enzyme, regulates cellular antioxidant and detoxification processes in nonruminants. However, its involvement in NEFA-induced hepatic inflammation in dairy cows with fatty liver remains unclear. This study aimed to elucidate the role of GSTM2 in mediating hepatic inflammation caused by elevated NEFA levels in dairy cows with severe fatty liver. An in vivo study was conducted using 10 healthy cows (hepatic triacylglycerol [TG] content <1%) and 10 cows with severe fatty liver (hepatic TG content >10%), matched for the number of lactations (median = 3, range = 2–4) and DIM (median = 9 d, range = 3–15 d). Liver tissue and blood samples were collected before feeding. Compared with healthy cows, cows with severe fatty liver had higher plasma concentrations of NEFA, BHB, haptoglobin (HP), plasma amyloid A (SAA), and lower plasma concentration of glucose. These cows also showed significantly lower abundance of hepatic GSTM2 and overactivated hepatic inflammatory pathways, as indicated by increased abundance of phosphorylated inhibitor of κB (IκB)α and nuclear factor κB (NF-κB) p65, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 (CASP1), as well as mRNA levels of tumor necrosis factor α (TNFA), IL6, and IL1B. In vitro, hepatocytes isolated from 5 healthy calves (1 d old, fasted female, 30–40 kg of BW) were used to determine the effects of GSTM2 on hepatic inflammation. First, hepatocytes were treated with NEFA (1.2 mM) for varying durations (0.5, 1, 3, 6, 9, 12, 15, or 18 h). The NEFA treatment significantly increased the phosphorylation of IκBα and NF-κB p65, protein abundance of NLRP3, ASC and CASP1, and mRNA levels of TNFA, IL6 and IL1B, peaking at 9 and 12 h. Second, hepatocytes were treated with different concentrations of NEFA (0, 0.6, 1.2, or 2.4 mM) for 9 h, which decreased GSTM2 protein and mRNA abundance. Meanwhile, GSTM2 was silenced using small interfering RNA or overexpressed using adenovirus for 48 h in hepatocytes, followed by NEFA treatment. Silencing GSTM2 augmented the NEFA-induced increase in phosphorylation of IκBα and NF-κB p65, as well as protein abundance of NLRP3, ASC and CASP1, and mRNA levels of TNFA, IL6 and IL1B. Conversely, overexpression of GSTM2 mitigated these inflammatory signals upon NEFA treatment. In summary, these findings indicate that GSTM2 plays a crucial role in modulating NEFA-induced hepatic inflammation. Targeting GSTM2 may offer new strategies to treat or prevent fatty liver disease in dairy cows. |
| format | Article |
| id | doaj-art-7d7512f73e314de28ce1f8845d80290c |
| institution | OA Journals |
| issn | 0022-0302 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
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| series | Journal of Dairy Science |
| spelling | doaj-art-7d7512f73e314de28ce1f8845d80290c2025-08-20T02:27:34ZengElsevierJournal of Dairy Science0022-03022025-04-0110844149416210.3168/jds.2024-25740The role of glutathione S-transferase mu 2 in mitigating fatty acid–induced hepatic inflammation in dairy cowsJinxia Li0Chenchen Zhao1Dandan Qi2Fanrong Kong3Menglin Liu4Jie Gao5Enzhu Li6Wenwen Gao7Xiliang Du8Yuxiang Song9Xinwei Li10Haihua Feng11Lin Lei12State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaState Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaCorresponding author; State Key Laboratory for Zoonotic Diseases, Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, ChinaABSTRACT: Fatty liver is a major metabolic disorder in perinatal dairy cows, characterized by elevated plasma concentrations of nonesterified fatty acids (NEFA) and hepatic inflammation. Glutathione S-transferase mu 2 (GSTM2), a phase II detoxification enzyme, regulates cellular antioxidant and detoxification processes in nonruminants. However, its involvement in NEFA-induced hepatic inflammation in dairy cows with fatty liver remains unclear. This study aimed to elucidate the role of GSTM2 in mediating hepatic inflammation caused by elevated NEFA levels in dairy cows with severe fatty liver. An in vivo study was conducted using 10 healthy cows (hepatic triacylglycerol [TG] content <1%) and 10 cows with severe fatty liver (hepatic TG content >10%), matched for the number of lactations (median = 3, range = 2–4) and DIM (median = 9 d, range = 3–15 d). Liver tissue and blood samples were collected before feeding. Compared with healthy cows, cows with severe fatty liver had higher plasma concentrations of NEFA, BHB, haptoglobin (HP), plasma amyloid A (SAA), and lower plasma concentration of glucose. These cows also showed significantly lower abundance of hepatic GSTM2 and overactivated hepatic inflammatory pathways, as indicated by increased abundance of phosphorylated inhibitor of κB (IκB)α and nuclear factor κB (NF-κB) p65, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 (CASP1), as well as mRNA levels of tumor necrosis factor α (TNFA), IL6, and IL1B. In vitro, hepatocytes isolated from 5 healthy calves (1 d old, fasted female, 30–40 kg of BW) were used to determine the effects of GSTM2 on hepatic inflammation. First, hepatocytes were treated with NEFA (1.2 mM) for varying durations (0.5, 1, 3, 6, 9, 12, 15, or 18 h). The NEFA treatment significantly increased the phosphorylation of IκBα and NF-κB p65, protein abundance of NLRP3, ASC and CASP1, and mRNA levels of TNFA, IL6 and IL1B, peaking at 9 and 12 h. Second, hepatocytes were treated with different concentrations of NEFA (0, 0.6, 1.2, or 2.4 mM) for 9 h, which decreased GSTM2 protein and mRNA abundance. Meanwhile, GSTM2 was silenced using small interfering RNA or overexpressed using adenovirus for 48 h in hepatocytes, followed by NEFA treatment. Silencing GSTM2 augmented the NEFA-induced increase in phosphorylation of IκBα and NF-κB p65, as well as protein abundance of NLRP3, ASC and CASP1, and mRNA levels of TNFA, IL6 and IL1B. Conversely, overexpression of GSTM2 mitigated these inflammatory signals upon NEFA treatment. In summary, these findings indicate that GSTM2 plays a crucial role in modulating NEFA-induced hepatic inflammation. Targeting GSTM2 may offer new strategies to treat or prevent fatty liver disease in dairy cows.http://www.sciencedirect.com/science/article/pii/S0022030225000736dairy cowssevere fatty liverGSTM2inflammation |
| spellingShingle | Jinxia Li Chenchen Zhao Dandan Qi Fanrong Kong Menglin Liu Jie Gao Enzhu Li Wenwen Gao Xiliang Du Yuxiang Song Xinwei Li Haihua Feng Lin Lei The role of glutathione S-transferase mu 2 in mitigating fatty acid–induced hepatic inflammation in dairy cows Journal of Dairy Science dairy cows severe fatty liver GSTM2 inflammation |
| title | The role of glutathione S-transferase mu 2 in mitigating fatty acid–induced hepatic inflammation in dairy cows |
| title_full | The role of glutathione S-transferase mu 2 in mitigating fatty acid–induced hepatic inflammation in dairy cows |
| title_fullStr | The role of glutathione S-transferase mu 2 in mitigating fatty acid–induced hepatic inflammation in dairy cows |
| title_full_unstemmed | The role of glutathione S-transferase mu 2 in mitigating fatty acid–induced hepatic inflammation in dairy cows |
| title_short | The role of glutathione S-transferase mu 2 in mitigating fatty acid–induced hepatic inflammation in dairy cows |
| title_sort | role of glutathione s transferase mu 2 in mitigating fatty acid induced hepatic inflammation in dairy cows |
| topic | dairy cows severe fatty liver GSTM2 inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S0022030225000736 |
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