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Home/Equine Research Bank/Front Endocrinol (Lausanne)/The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensi...
Frontiers in endocrinology2023; 14; 1149610; doi: 10.3389/fendo.2023.1149610

The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses.

Abstract: Equine metabolic syndrome (EMS) is a multifactorial pathology gathering insulin resistance, low-grade inflammation and past or chronic laminitis. Among the several molecular mechanisms underlying EMS pathogenesis, increased negative insulin signalling regulation mediated by protein tyrosine phosphatase 1 B (PTP1B) has emerged as a critical axis in the development of liver insulin resistance and general metabolic distress associated to increased ER stress, inflammation and disrupted autophagy. Thus, the use of PTP1B selective inhibitors such as MSI-1436 might be considered as a golden therapeutic tool for the proper management of EMS and associated conditions. Therefore, the present investigation aimed at verifying the clinical efficacy of MSI-1436 systemic administration on liver metabolic balance, insulin sensitivity and inflammatory status in EMS affected horses. Moreover, the impact of MSI-1436 treatment on liver autophagy machinery and associated ER stress in liver tissue has been analysed. Liver explants isolated from healthy and EMS horses have been treated with MSI-1436 prior to gene and protein expression analysis of main markers mediating ER stress, mitophagy and autophagy. Furthermore, EMS horses have been intravenously treated with a single dose of MSI-1436, and evaluated for their metabolic and inflammatory status. Clinical application of MSI-1436 to EMS horses restored proper adiponectin levels and attenuated the typical hyperinsulinemia and hyperglycemia. Moreover, administration of MSI-1436 further reduced the circulating levels of key pro-inflammatory mediators including IL-1β, TNF-α and TGF-β and triggered the Tregs cells activation. At the molecular level, PTP1B inhibition resulted in a noticeable mitigation of liver ER stress, improvement of mitochondrial dynamics and consequently, a regulation of autophagic response. Similarly, short-term ex vivo treatment of EMS liver explants with trodusquemine (MSI-1436) substantially enhanced autophagy by upregulating the levels of HSC70 and Beclin-1 at both mRNA and protein level. Moreover, the PTP1B inhibitor potentiated mitophagy and associated expression of MFN2 and PINK1. Interestingly, inhibition of PTP1B resulted in potent attenuation of ER stress key mediators' expression namely, CHOP, ATF6, HSPA5 and XBP1. Presented findings shed for the first time promising new insights in the development of an MSI-1436-based therapy for proper equine metabolic syndrome intervention and may additionally find potential translational application to human metabolic syndrome treatment.
Copyright © 2023 Bourebaba, Serwotka-Suszczak, Pielok, Sikora, Mularczyk and Marycz.
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Publication Date: 2023-03-20 PubMed ID: 37020593PubMed Central: PMC10067883DOI: 10.3389/fendo.2023.1149610Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study investigates the impact of PTP1B inhibitor MSI-1436 on equine metabolic syndrome (EMS), which is characterized by insulin resistance, inflammation, and laminitis in horses. The researchers found that the systemic administration of MSI-1436 improves insulin sensitivity, reduces inflammation, and modulates liver autophagy and ER stress in horses with EMS.

Objective and Significance of the Research

  • This study aims to discern the therapeutic impact of a protein tyrosine phosphatase 1B (PTP1B) inhibitor, known as MSI-1436, on Equine Metabolic Syndrome (EMS) – a disorder in horses that combines insulin resistance, minor inflammation, and a history of laminitis.
  • One of the key contributors to EMS is a boosted regulation of negative insulin signalling via PTP1B which often leads to insulin resistance in the liver and wider metabolic issues closely tied to increased inflammation and broken down autophagy.
  • The findings of this research could potentially provide valuable insights into the development of MSI-1436-based therapies for EMS, and its potential applicability to human metabolic syndrome treatments.

Methodology

  • Healthy and EMS-affected horse liver explants were treated with MSI-1436 and analyzed for gene and protein expression related to ER stress, mitophagy, and autophagy.
  • Horses with EMS were treated with a single intravenous dose of MSI-1436 and assessed for metabolic and inflammatory status.

Findings

  • The use of MSI-1436 in horses with EMS restored healthy levels of adiponectin and mitigated hyperinsulinemia and hyperglycemia.
  • MSI-1436 also reduced key pro-inflammatory mediators (IL-1β, TNF-α, and TGF-β) and activated Tregs cells.
  • At a molecular level, MSI-1436 moderated liver ER stress, improved mitochondrial functions, and regulated the autophagic response.
  • PTP1B inhibition notably mitigated the expression of key ER stress mediators such as CHOP, ATF6, HSPA5, and XBP1.

Conclusion and Implications

  • The learnings provide a foundation for the development of an MSI-1436-based therapeutic approach to treating EMS, potentially offering benefits for the management of human metabolic syndrome as well.
  • The experiment demonstrated the potential of MSI-1436 not only in improving insulin sensitivity and reducing inflammation, but also in modulating vital biological processes such as autophagy and ER stress, many of these being shared across equine and human metabolic syndromes.

Cite This Article

APA
Bourebaba L, Serwotka-Suszczak A, Pielok A, Sikora M, Mularczyk M, Marycz K. (2023). The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses. Front Endocrinol (Lausanne), 14, 1149610. https://doi.org/10.3389/fendo.2023.1149610

Publication

Frontiers in endocrinology
ISSN: 1664-2392
NlmUniqueID: 101555782
Country: Switzerland
Language: English
Volume: 14
Pages: 1149610
PII: 1149610

Researcher Affiliations

Bourebaba, Lynda
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocu0142aw University of Environmental and Life Sciences, Wrocu0142aw, Poland.
  • International Institute of Translational Medicine, Wisznia Mau0142a, Poland.
Serwotka-Suszczak, Anna
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocu0142aw University of Environmental and Life Sciences, Wrocu0142aw, Poland.
Pielok, Ariadna
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocu0142aw University of Environmental and Life Sciences, Wrocu0142aw, Poland.
Sikora, Mateusz
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocu0142aw University of Environmental and Life Sciences, Wrocu0142aw, Poland.
Mularczyk, Malwina
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocu0142aw University of Environmental and Life Sciences, Wrocu0142aw, Poland.
  • International Institute of Translational Medicine, Wisznia Mau0142a, Poland.
Marycz, Krzysztof
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocu0142aw University of Environmental and Life Sciences, Wrocu0142aw, Poland.
  • Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.

MeSH Terms

  • Animals
  • Humans
  • Autophagy
  • Enzyme Inhibitors
  • Horses
  • Inflammation
  • Insulin Resistance
  • Liver / metabolism
  • Metabolic Syndrome / metabolism
  • Endoplasmic Reticulum Stress

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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