PMID- 37249651 OWN - NLM STAT- MEDLINE DCOM- 20230603 LR - 20230619 IS - 1420-9071 (Electronic) IS - 1420-682X (Print) IS - 1420-682X (Linking) VI - 80 IP - 6 DP - 2023 May 30 TI - TRIM21 ameliorates hepatic glucose and lipid metabolic disorders in type 2 diabetes mellitus by ubiquitination of PEPCK1 and FASN. PG - 168 LID - 10.1007/s00018-023-04820-w [doi] LID - 168 AB - Hepatic glucose and lipid metabolism disorders promote the development and progression of type 2 diabetes mellitus (T2DM), yet the underlying mechanisms are not fully understood. Here, we identify tripartite motif-containing protein 21 (TRIM21), a class IV TRIM family member, as a pivotal regulator of hepatic metabolism in T2DM for the first time. Bioinformatic analysis suggests that TRIM21 expression is significantly reduced in T2DM patients. Intriguingly, in a mouse model of obese diabetes, TRIM21 expression is predominantly reduced in the liver rather than in other metabolic organs. It is further demonstrated that hepatic overexpression of TRIM21 significantly ameliorates glucose intolerance, insulin resistance, hepatic steatosis, and dyslipidemia in obese diabetic mice. In contrast, the knockdown of TRIM21 promotes glucose intolerance, insulin resistance, and triglyceride accumulation. Mechanistically, both phosphoenolpyruvate carboxykinase 1 (PEPCK1) and fatty acid synthase (FASN) are the hepatic targets of TRIM21. We revealed that TRIM21 promotes the degradation of PEPCK1 and FASN through a direct protein-protein interaction mediated K48-linked ubiquitination. Notably, overexpression of PEPCK1 and FASN essentially abolished the beneficial effects achieved by TRIM21 overexpression in obese diabetic mice. Overall, our data demonstrate that TRIM21 is a novel regulator of hepatic metabolic disorder, and suggest TRIM21 as a promising therapeutic target for T2DM. CI - (c) 2023. The Author(s). FAU - Zhang, Kaini AU - Zhang K AD - Department of Pathophysiology, Nanjing Medical University, Nanjing, 211166, China. FAU - Yang, Chen AU - Yang C AD - Department of Pathology, Nanjing Medical University, Nanjing, 211166, China. FAU - Zhou, Xin AU - Zhou X AD - Department of Pathophysiology, Nanjing Medical University, Nanjing, 211166, China. FAU - Liang, Jin AU - Liang J AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China. FAU - Guo, Jianjin AU - Guo J AD - Department of General Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China. AD - Department of General Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Li, Min AU - Li M AD - Department of Pathology, Nanjing Medical University, Nanjing, 211166, China. FAU - Zhang, Yi AU - Zhang Y AD - Department of Pathology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, 211800, China. FAU - Shao, Shulin AU - Shao S AD - Department of Laboratory, Nanjing Pukou Hospital of Traditional Chinese Medicine, Nanjing, 211800, China. FAU - Sun, Peng AU - Sun P AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China. FAU - Li, Kai AU - Li K AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China. FAU - Huang, Jingjing AU - Huang J AD - Department of Geriatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 211166, China. FAU - Chen, Fang AU - Chen F AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, China. chenfang@njmu.edu.cn. FAU - Liang, Xiubin AU - Liang X AUID- ORCID: 0000-0001-9169-0390 AD - Department of Pathophysiology, Nanjing Medical University, Nanjing, 211166, China. liangxiubin@njmu.edu.cn. FAU - Su, Dongming AU - Su D AUID- ORCID: 0000-0003-0398-9013 AD - Department of Pathology, Nanjing Medical University, Nanjing, 211166, China. sudongming@njmu.edu.cn. LA - eng GR - 81570779/National Natural Science Foundation of China/ GR - 81170252/National Natural Science Foundation of China/ GR - 81070656/National Natural Science Foundation of China/ GR - 81870467/National Natural Science Foundation of China/ PT - Journal Article DEP - 20230530 PL - Switzerland TA - Cell Mol Life Sci JT - Cellular and molecular life sciences : CMLS JID - 9705402 RN - EC 2.3.1.85 (Fatty Acid Synthases) RN - IY9XDZ35W2 (Glucose) RN - 0 (Lipids) RN - 0 (SS-A antigen) RN - EC 4.1.1.32 (Pck1 protein, mouse) RN - EC 2.3.1.85 (Fasn protein, mouse) SB - IM MH - Animals MH - Mice MH - *Diabetes Mellitus, Experimental/metabolism MH - *Diabetes Mellitus, Type 2/metabolism MH - Fatty Acid Synthases/metabolism/therapeutic use MH - Glucose/metabolism MH - *Glucose Intolerance/metabolism MH - *Insulin Resistance MH - *Lipid Metabolism Disorders/metabolism MH - Lipids MH - Liver/metabolism MH - Obesity/metabolism MH - Ubiquitination MH - Humans PMC - PMC10229743 OTO - NOTNLM OT - FASN stability OT - Hepatic steatosis OT - Insulin resistance OT - PEPCK1 stability OT - TRIM21 OT - Ubiquitination COIS- No potential conflicts of interest relevant to this article were reported. EDAT- 2023/05/30 13:07 MHDA- 2023/06/01 06:42 PMCR- 2023/05/30 CRDT- 2023/05/30 11:07 PHST- 2023/01/17 00:00 [received] PHST- 2023/05/20 00:00 [accepted] PHST- 2023/05/18 00:00 [revised] PHST- 2023/06/01 06:42 [medline] PHST- 2023/05/30 13:07 [pubmed] PHST- 2023/05/30 11:07 [entrez] PHST- 2023/05/30 00:00 [pmc-release] AID - 10.1007/s00018-023-04820-w [pii] AID - 4820 [pii] AID - 10.1007/s00018-023-04820-w [doi] PST - epublish SO - Cell Mol Life Sci. 2023 May 30;80(6):168. doi: 10.1007/s00018-023-04820-w.