TRIB3 suppresses milk fatty acids metabolism by inhibiting p-AKT/PPARG signaling in goat mammary epithelial cells

Xinglong Gong , Tan Pan , Tiantian Xiong , Yifan Zhu , Juan J. Loor , Chengming Han , Yifan Li , Huan Lei , Jun Luo , Cong Li

Animal Research and One Health ›› 2025, Vol. 3 ›› Issue (3) : 268 -277.

PDF
Animal Research and One Health ›› 2025, Vol. 3 ›› Issue (3) : 268 -277. DOI: 10.1002/aro2.98
ARTICLE

TRIB3 suppresses milk fatty acids metabolism by inhibiting p-AKT/PPARG signaling in goat mammary epithelial cells

Author information +
History +
PDF

Abstract

Tribbles pseudokinase 3 (TRIB3) interacts with a variety of proteins and plays a key role in the regulation of glucose metabolism and glycolysis in nonruminants, but whether it has a specific role in goat mammary lipid metabolism has still been kept unknown. In this study, we observed that TRIB3 is highly expressed in the mammary tissues of lactating dairy goats. Overexpressing TRIB3 in goat mammary epithelial cells (GMECs) suppressed the mRNA expression of GPAM, DGAT1, and PLIN1, which are associated with the formation of triacylglycerol and lipid droplets (p < 0.05). The fatty acid-sensitive transcription regulator PPARG was also downregulated. Interfering TRIB3 had the opposite effect and decreased Akt phosphorylation. The TRIB3 gene influenced fatty acid composition in GMECs, and its overexpression reduced the total concentration of intracellular triacylglycerol (p < 0.01), this response was verified using BODIPY staining. Overall, these data indicated that TRIB3 suppresses milk fatty acids metabolism through inhibiting p-AKT/PPARG signaling in GMECs.

Keywords

AKT/PPARG / GMECs / lipid metabolism / TRIB3

Cite this article

Download citation ▾
Xinglong Gong, Tan Pan, Tiantian Xiong, Yifan Zhu, Juan J. Loor, Chengming Han, Yifan Li, Huan Lei, Jun Luo, Cong Li. TRIB3 suppresses milk fatty acids metabolism by inhibiting p-AKT/PPARG signaling in goat mammary epithelial cells. Animal Research and One Health, 2025, 3(3): 268-277 DOI:10.1002/aro2.98

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

Dhasmana, S., Das, S., & Shrivastava, S. (2022). Potential nutraceuticals from the casein fraction of goat's milk. Journal of Food Biochemistry, 46(6), e13982. https://doi.org/10.1111/jfbc.13982

[2]

Prosser, C.G. (2021). Compositional and functional characteristics of goat milk and relevance as a base for infant formula. Journal of Food Science, 86(2), 257-265. https://doi.org/10.1111/1750-3841.15574

[3]

Strucken, E.M., Laurenson, Y.C., & Brockmann, G.A. (2015). Go with the flow-biology and genetics of the lactation cycle. Frontiers in Genetics, 6, 118. https://doi.org/10.3389/fgene.2015.00118

[4]

Lucena, R., Gallego, M., Cárdenas, S., & Valcárcel, M. (2003). Autoanalyzer for milk quality control based on the lactose, fat, and total protein contents. Analytical Chemistry, 75(6), 1425-1429. https://doi.org/10.1021/ac020553n

[5]

Liu, W., Ding, H., Erdene, K., Chen, R., Mu, Q., & Ao, C. (2019). Effects of flavonoids from Allium mongolicum Regel as a dietary additive on meat quality and composition of fatty acids related to flavor in lambs. Canadian Journal of Animal Science, 99(1), 15-23. https://doi.org/10.1139/cjas-2018-0008

[6]

Teng, F., Reis, M.G., Ma, Y., & Day, L. (2018). Effects of season and industrial processes on volatile 4-alkyl-branched chain fatty acids in sheep milk. Food Chemistry, 260, 327-335. https://doi.org/10.1016/j.foodchem.2018.04.011

[7]

Bionaz, M., & Loor, J.J. (2008). Gene networks driving bovine milk fat synthesis during the lactation cycle. BMC Genomics, 9(1), 366. https://doi.org/10.1186/1471-2164-9-366

[8]

Dobens, L.L., Nauman, C., Fischer, Z., & Yao, X. (2021). Control of cell growth and proliferation by the tribbles pseudokinase: Lessons from Drosophila. Cancers, 13(4), 883. https://doi.org/10.3390/cancers13040883

[9]

Yu, J.M., Sun, W., Wang, Z.H., Liang, X., Hua, F., Li, K., Lv, X.X., Zhang, X.W., Liu, Y.Y., Yu, J.J., Liu, S.S., Shang, S., Wang, F., Yang, Z.N., Zhao, C.X., Hou, X.Y., Li, P.P., Huang, B., Cui, B., & Hu, Z.W. (2019). TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription. Nature Communications, 10(1), 5720. https://doi.org/10.1038/s41467-019-13700-6

[10]

Li, K., Wang, F., Yang, Z.N., Zhang, T.T., Yuan, Y.F., Zhao, C.X., Yeerjiang, Z., Cui, B., Hua, F., Lv, X.X., Zhang, X.W., Yu, J.J., Liu, S.S., Yu, J.M., Shang, S., Xiao, Y., & Hu, Z.W. (2020). TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation. Nature Communications, 11(1), 6316. https://doi.org/10.1038/s41467-020-20107-1

[11]

Kiss-Toth, E., Velasco, G., & Pear, W.S. (2015). Tribbles at the cross-roads. Biochemical Society Transactions, 43(5), 1049-1050. https://doi.org/10.1042/BST20150122

[12]

Yu, J.J., Zhou, D.D., Yang, X.X., Cui, B., Tan, F.W., Wang, J., Li, K., Shang, S., Zhang, C., Lv, X.X., Zhang, X.W., Liu, S.S., Yu, J.M., Wang, F., Huang, B., Hua, F., & Hu, Z.W. (2020). TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target. Nature Communications, 11(1), 3660. https://doi.org/10.1038/s41467-020-17385-0

[13]

Hernández-Quiles, M., Baak, R., Orea-Soufi, A., Borgman, A., den Haan, S., Sobrevals Alcaraz, P., Jongejan, A., van Es, R., Velasco, G., Vos, H., & Kalkhoven, E. (2022). TRIB3 modulates PPARγ-mediated growth inhibition by interfering with the MLL complex in breast cancer cells. International Journal of Molecular Sciences, 23(18), 10535. https://doi.org/10.3390/ijms231810535

[14]

Li, K., Wang, F., Yang, Z.N., Cui, B., Li, P.P., Li, Z.Y., Hu, Z.W., & Zhu, H.H. (2020). PML-RARα interaction with TRIB3 impedes PPARγ/RXR function and triggers dyslipidemia in acute promyelocytic leukemia. Theranostics, 10(22), 10326-10340. https://doi.org/10.7150/thno.45924

[15]

Lee, S.K., Park, C.Y., Kim, J., Kim, D., Choe, H., Kim, J.H., Hong, J.P., Lee, Y.J., Heo, Y., Park, H.S., & Jang, Y.J. (2022). TRIB3 is highly expressed in the adipose tissue of obese patients and is associated with insulin resistance. Journal of Clinical Endocrinology & Metabolism, 107(3), e1057-e1073. https://doi.org/10.1210/clinem/dgab780

[16]

Wu, J., Luo, J., Xia, Y., An, X., Guo, P., He, Q., Tian, H., Hu, Q., Li, C., & Wang, H. (2023). Goat FADS2 controlling fatty acid metabolism is directly regulated by SREBP1 in mammary epithelial cells. Journal of Animal Science, 101, skad030. https://doi.org/10.1093/jas/skad030

[17]

Tian, H., Luo, J., Guo, P., Li, C., & Zhang, X. (2023). C/EBPα promotes triacylglycerol synthesis via regulating PPARG promoter activity in goat mammary epithelial cells. Journal of Animal Science, 101, skac412. https://doi.org/10.1093/jas/skac412

[18]

Shen, P., Zhang, T.Y., & Wang, S.Y. (2021). TRIB3 promotes oral squamous cell carcinoma cell proliferation by activating the AKT signaling pathway. Experimental and Therapeutic Medicine, 21(4), 313. https://doi.org/10.3892/etm.2021.9744

[19]

Shang, S., Yang, Y.W., Chen, F., Yu, L., Shen, S.H., Li, K., Cui, B., Lv, X.X., Zhang, C., Yang, C., Liu, J., Yu, J.J., Zhang, X.W., Li, P.P., Zhu, S.T., Zhang, H.Z., & Hua, F. (2022). TRIB3 reduces CD8+ T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer. Science Translational Medicine, 14(626), eabf0992. https://doi.org/10.1126/scitranslmed.abf0992

[20]

Hua, F., Shang, S., Yang, Y.W., Zhang, H.Z., Xu, T.L., Yu, J.J., Zhou, D.D., Cui, B., Li, K., Lv, X.X., Zhang, X.W., Liu, S.S., Yu, J.M., Wang, F., Zhang, C., Huang, B., & Hu, Z.W. (2019). TRIB3 interacts with β-catenin and TCF4 to increase stem cell features of colorectal cancer stem cells and tumorigenesis. Gastroenterology, 156(3), 708-721.e15. https://doi.org/10.1053/j.gastro.2018.10.031

[21]

Osorio, J.S., Lohakare, J., & Bionaz, M. (2016). Biosynthesis of milk fat, protein, and lactose: Roles of transcriptional and posttranscriptional regulation. Physiological Genomics, 48(4), 231-256. https://doi.org/10.1152/physiolgenomics.00016.2015

[22]

Dörr, D., Obermayer, B., Weiner, J.M., Zimmermann, K., Anania, C., Wagner, L.K., Lyras, E.M., Sapozhnikova, V., Lara-Astiaso, D., Prósper, F., Lang, R., Lupiáñez, D.G., Beule, D., Höpken, U.E., Leutz, A., & Mildner, A. (2022). C/EBPβ regulates lipid metabolism and Pparg isoform 2 expression in alveolar macrophages. Science immunology, 7(75), eabj0140. https://doi.org/10.1126/sciimmunol.abj0140

[23]

Salles, C., Sommerer, N., Septier, C., Issanchou, S., Chabanet, C., Garem, A., & Le Quéré, J.L. (2002). Goat cheese flavor: Sensory evaluation of branched-chain fatty acids and small peptides. Journal of Food Science, 67(2), 835-841. https://doi.org/10.1111/j.1365-2621.2002.tb10686.x

[24]

Sañudo, C., Enser, M.E., Campo, M.M., Nute, G.R., María, G., Sierra, I., & Wood, J.D. (2000). Fatty acid composition and sensory characteristics of lamb carcasses from Britain and Spain. Meat Science, 54(4), 339-346. https://doi.org/10.1016/s0309-1740(99)00108-4

[25]

Mondal, D., Mathur, A., & Chandra, P.K. (2016). Tripping on TRIB3 at the junction of health, metabolic dysfunction and cancer. Biochimie, 124, 34-52. https://doi.org/10.1016/j.biochi.2016.02.005

[26]

Erazo, T., Lorente, M., López-Plana, A., Muñoz-Guardiola, P., Fernández-Nogueira, P., García-Martínez, J.A., Bragado, P., Fuster, G., Salazar, M., Espadaler, J., Hernández-Losa, J., Bayascas, J.R., Cortal, M., Vidal, L., Gascón, P., Gómez-Ferreria, M., Alfón, J., Velasco, G., Domènech, C., & Lizcano, J.M. (2016). The new antitumor drug ABTL0812 inhibits the akt/mTORC1 Axis by upregulating tribbles-3 pseudokinase. Clinical Cancer Research: an official journal of the American Association for Cancer Research, 22(10), 2508-2519. https://doi.org/10.1158/1078-0432.CCR-15-1808

[27]

Du, K., Herzig, S., Kulkarni, R.N., & Montminy, M. (2003). TRB3: A tribbles homolog that inhibits akt/PKB activation by insulin in liver. Science (New York, N.Y.), 300(5625), 1574-1577. https://doi.org/10.1126/science.1079817

[28]

Salazar, M., Lorente, M., García-Taboada, E., Pérez Gómez, E., Dávila, D., Zúñiga-García, P., María Flores, J., Rodríguez, A., Hegedus, Z., Mosén-Ansorena, D., Aransay, A.M., Hernández-Tiedra, S., López-Valero, I., Quintanilla, M., Sánchez, C., Iovanna, J.L., Dusetti, N., Guzmán, M., Francis, S.E., … Velasco, G. (2015). Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation. Cell Death & Differentiation, 22(1), 131-144. https://doi.org/10.1038/cdd.2014.133

[29]

Glaviano, A., Foo, A. S.C., Lam, H.Y., Yap, K. C.H., Jacot, W., Jones, R.H., Eng, H., Nair, M.G., Makvandi, P., Geoerger, B., Kulke, M.H., Baird, R.D., Prabhu, J.S., Carbone, D., Pecoraro, C., Teh, D. B.L., Sethi, G., Cavalieri, V., Lin, K.H., … Kumar, A.P. (2023). PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Molecular Cancer, 22(1), 138. https://doi.org/10.1186/s12943-023-01827-6

[30]

Ohoka, N., Yoshii, S., Hattori, T., Onozaki, K., & Hayashi, H. (2005). TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. The EMBO Journal, 24(6), 1243-1255. https://doi.org/10.1038/sj.emboj.7600596

[31]

Wang, L., Zhao, W., Xia, C., Li, Z., Zhao, W., Xu, K., Wang, N., Lian, H., Rosas, I.O., & Yu, G. (2022). TRIB3 mediates fibroblast activation and fibrosis though interaction with ATF4 in IPF. International Journal of Molecular Sciences, 23(24), 15705. https://doi.org/10.3390/ijms232415705

[32]

Tang, Y.Q., Li, Z.W., Feng, Y.F., Yang, H.Q., Hou, C.L., Geng, C., Yang, P.R., Zhao, H.M., & Wang, J. (2022). MK2206 attenuates atherosclerosis by inhibiting lipid accumulation, cell migration, proliferation, and inflammation. Acta Pharmacologica Sinica, 43(4), 897-907. https://doi.org/10.1038/s41401-021-00729-x

RIGHTS & PERMISSIONS

2024 The Author(s). Animal Research and One Health published by John Wiley & Sons Australia, Ltd on behalf of Institute of Animal Science, Chinese Academy of Agricultural Sciences.

AI Summary AI Mindmap
PDF

48

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/