ArticleCellular and molecular life sciences : CMLS2023
TRIM21 ameliorates hepatic glucose and lipid metabolic disorders in type 2 diabetes mellitus by ubiquitination of PEPCK1 and FASN.
Article in Cellular and molecular life sciences : CMLS, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 19 citations in OpenAlex.
- ALDH2 inhibits FASN stabilization via the E3 ligase CBL to suppress lipid accumulation and liver cancer development.Biology direct · 2026Article
- Identification of the E3 ligase TRIM21 as a crucial regulator of STAT1 in metabolic dysfunction-associated steatohepatitis.Cell communication and signaling : CCS · 2026Article
- Ubiquitination modifications as central regulators of metabolic dysfunction in type 2 diabetes mellitus.Frontiers in endocrinology · 2026Review
- Inhibiting TRIM21 Neddylation Rejuvenates Oocyte Quality in PCOS by Regulating Ubiquitination of CPT1A.Research (Washington, D.C.) · 2026Article
- Ubiquitination in cancer: mechanisms and therapeutic opportunities.Cancer communications (London, England) · 2025Review
- NSUN2 knockdown ameliorates hepatic glucose and lipid metabolism disorders in type 2 diabetes mellitus through the Inhibition of ACSL6 m5C methylation.Lipids in health and disease · 2025Article
- Membrane-associated ring-CH-type finger 2 protects against metabolic dysfunction-associated fatty liver disease by targeting fatty acid synthase.Molecular metabolism · 2025Article
- Dangua Fang induces anti-glucolipid metabolism disorder effects similar to those of direct NFIL3 inhibition.Frontiers in microbiology · 2025Article
- PCK1 as a target for cancer therapy: from metabolic reprogramming to immune microenvironment remodeling.Cell death discovery · 2024Review
- Roles of posttranslational modifications in lipid metabolism and cancer progression.Biomarker research · 2024Review
- Antibodies targeting the Crimean-Congo Hemorrhagic Fever Virus nucleoprotein protect via TRIM21.Nature communications · 2024Article
- Ubiquitination and De-Ubiquitination in the Synthesis of Cow Milk Fat: Reality and Prospects.Molecules (Basel, Switzerland) · 2024Review
- The Role of Tripartite Motif Family Proteins in Chronic Liver Diseases: Molecular Mechanisms and Therapeutic Potential.Biomolecules · 2024Review
- Emerging roles of tripartite motif family proteins (TRIMs) in breast cancer.Cancer medicine · 2024Review
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Authors and funding
14 authors at 5 institutions in 1 country.
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Abstract
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.
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