Investigating the mechanism of insulin receptor degradation by the new E3 ubiquitin ligase TRIM32 in the context of Nonalcoholic Fatty Liver Disease and obesity.
Author interview: Shilpa Thakur joined the Ph.D. programme in 2020 in the School of Biosciences and Bioengineering at IIT Mandi. She is investigating the mechanisms of insulin action to identify sites and mediators of insulin resistance.
Lab: Dr. Prosenjit Mondal, Indian Institute of Technology Mandi
Research Summary: Our study reveals a novel E3 Ubiquitin ligase, TRIM32, which is increased in obesity, Type 2 Diabetes (T2DM), and Nonalcoholic Fatty Liver conditions and degrades the insulin receptor through the ubiquitin-mediated proteasomal degradation pathway, ultimately resulting in insulin resistance.
What was the core problem you aimed to solve with this research?
The objective was to ascertain the unidentified mechanism responsible for the onset of insulin resistance in obesity, T2DM, and non-alcoholic fatty liver disease. The insulin receptor is the principal molecule implicated in the onset of insulin resistance; therefore, we endeavored to elucidate the potential mechanism of INSR degradation. Our analysis reveals TRIM32 as a target for the proteasomal degradation of INSR. We also discovered that SREBP1-c, a crucial transcription factor, binds to the promoter of the TRIM32 gene and boosts its transcriptional activity. Blocking hepatic TRIM32 with lentiviral treatment in mice preserves INSR levels in the liver and enhances insulin sensitivity.
How did you go about solving this problem?
To address this issue, we targeted E3 ubiquitin ligases that play a crucial role in the degradation of their substrate proteins. RNA sequencing conducted on the livers of lean and obese mice revealed a considerably increased expression of the ubiquitin ligase TRIM32, whose role in the degradation of the insulin receptor remains unidentified. Insulin receptor levels diminished in the insulin-resistant condition within the livers of these obese patients, who are unable to adequately dispose of excess insulin, leading to hyperglycemia and hyperinsulinemia.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Diet rich in fat, carbohydrates lead to an increase insulin secretion and people suffering from bad eating habits have insulin spikes even without meals. Higher glucose as well as insulin levels are the key features of the patients suffering from Type 2 Diabetes often leads to fatty liver and vice versa. This gradually develops insulin resistant state in the cells. The glucose from diet cannot be further metabolized by the metabolically active organs. Having diet rich in fat, carbohydrates leads to increased SREBP1-c transactivation from cytosol to nucleus and further increases the transcription of TRIM32 gene. This increased TRIM32 degrades insulin receptors and makes the situation more severe. Our study provides a novel insight into the therapeutics targeting liver TRIM32. We saw that treating cells with an AMPK activator protects from TRIM32-induced fatty liver and insulin resistance.
Our results define a new pathway regulating insulin receptors’ biological activity and demonstrate the potential therapeutic benefits of modulating this pathway.
What are the potential implications of your findings for the field and society?
This study indicates that targeting hepatic TRIM32 may serve as a potential therapy for fatty liver and insulin resistance. Current pharmacological agents that inhibit SREBP1-c activity (statins, AMPK activators, GLP-1R agonists) may be utilized in the management of fatty liver, thereby reducing TRIM32 levels and enhancing insulin sensitivity through the elevation of hepatic insulin receptor levels.
What was the exciting moment during your research?
The most exciting moment during my research was the data, in which we overexpressed TRIM32 in liver cells isolated from the mouse liver and checked the insulin receptor levels. We found that TRIM32 overexpression significantly downregulated surface as well as total insulin receptor levels and blunts insulin signaling. That data was the most exciting part of my research.
Reference: Thakur S, Rawat P, Dehury B & Mondal P (2025) TRIM32 regulates insulin sensitivity by controlling insulin receptor degradation in the liver. EMBO Reports https://doi.org/10.1038/s44319-024-00348-7
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