Integrated proteomic and phosphoproteomic profiling unravels an O-GlcNAc-dependent mechanism in DGAT1 inhibition-mediated protection of β-cells from lipotoxicity
文献类型：期刊论文
| 作者 | Guo, Jia-Ming3; Chen, Guang-Yun3; Huang, Jun-Shang3; Zhu, Zhen-Yun3; Dong, Lin-Yue2; Xie, Wen-Fan1; Li, Yi-Ming2; Hu, You-Hong3; Wang, He-Yao3; Zhou, Hu3,4 |
| 刊名 | DIABETES OBESITY & METABOLISM
 |
| 出版日期 | 2026-02-17 |
| 页码 | 16 |
| 关键词 | DGAT1 lipotoxicity O-GlcNAc phosphoproteomic proteomic |
| ISSN号 | 1462-8902 |
| DOI | 10.1111/dom.70554 |
| 英文摘要 | Aims Obesity-induced lipotoxicity is a key driver of pancreatic beta-cell dysfunction in Type 2 diabetes. Although Diacylglycerol O-acyltransferase 1 (DGAT1) inhibition has been reported to ameliorate lipotoxic injury, the underlying mechanisms remain incompletely understood. This study leverages integrated proteomic and phosphoproteomic analyses to systematically explore the novel protective mechanisms of DGAT1 inhibition.Methods We employed Min6 beta-cells subjected to palmitic acid (PA)-induced lipotoxicity, comparing control, PA-treated, and PA co-treated with two distinct DGAT1 inhibitor groups. We assessed lipid accumulation, ER stress, and inflammation. Integrated proteomic and phosphoproteomic analyses, combined with bioinformatic interrogation and experimental validation, were employed to delineate novel molecular mechanisms.Results DGAT1 inhibition effectively alleviated PA-induced lipid deposition, ER stress, and inflammatory responses. Our multi-omics data revealed that PA triggered ferroptosis, which was suppressed by DGAT1 inhibitors. Mechanistically, DGAT1 inhibition attenuated global O-GlcNAcylation, leading to the destabilization of the pro-ferroptotic protein ACSL4. This cascade resulted in reduced lipid peroxidation and restored glutathione levels, ultimately enhancing beta-cell survival.Conclusion Our study delineates the dynamic proteomic and phosphoproteomic landscape in Min6 cells under PA-induced lipotoxicity and its remediation by a DGAT1 inhibitor. We delineate the remodelling of key signalling pathways, changes in critical gene expression, and dysregulation of transcription factor activity that collectively contribute to PA-induced beta-cell injury. Furthermore, we reveal that DGAT1 inhibition attenuates ferroptosis through a novel mechanism involving DGAT1-driven regulation of O-GlcNAcylation. This study provides new insights into DGAT1 inhibition-mediated protection against lipotoxicity and offers valuable multi-omics data resources for the research community. |
| WOS关键词 | INSULIN-SECRETION ; MANAGEMENT ; ADULTS ; GENE |
| 资助项目 | Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830000] ; National Natural Science Foundation of China[22425703] ; National Key Research and Development Program of China[2022YFA1302902] ; Shanghai Leading Talent Program of Eastern Talent Plan[LJ2023123] ; National Science & Technology (Key New Drug Creation and Manufacturing Program)[2018ZX09711002-002-007] |
| WOS研究方向 | Endocrinology & Metabolism |
| 语种 | 英语 |
| WOS记录号 | WOS:001692762800001 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/323044]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Wang, He-Yao; Zhou, Hu |
| 作者单位 | 1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Jiangsu, Peoples R China 2.Shanghai Univ Tradit Chinese Med, Shanghai, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Analyt Res Ctr Organ & Biol Mol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Guo, Jia-Ming,Chen, Guang-Yun,Huang, Jun-Shang,et al. Integrated proteomic and phosphoproteomic profiling unravels an O-GlcNAc-dependent mechanism in DGAT1 inhibition-mediated protection of β-cells from lipotoxicity[J]. DIABETES OBESITY & METABOLISM,2026:16. |
| APA | Guo, Jia-Ming.,Chen, Guang-Yun.,Huang, Jun-Shang.,Zhu, Zhen-Yun.,Dong, Lin-Yue.,...&Zhou, Hu.(2026).Integrated proteomic and phosphoproteomic profiling unravels an O-GlcNAc-dependent mechanism in DGAT1 inhibition-mediated protection of β-cells from lipotoxicity.DIABETES OBESITY & METABOLISM,16. |
| MLA | Guo, Jia-Ming,et al."Integrated proteomic and phosphoproteomic profiling unravels an O-GlcNAc-dependent mechanism in DGAT1 inhibition-mediated protection of β-cells from lipotoxicity".DIABETES OBESITY & METABOLISM (2026):16. |
入库方式： OAI收割
来源：上海药物研究所
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