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Stem cell reviews and reports2023; 19(7); 2251-2273; doi: 10.1007/s12015-023-10580-8

Sex Hormone-Binding Globulin (SHBG) Maintains Proper Equine Adipose-Derived Stromal Cells (ASCs)’ Metabolic Functions and Negatively Regulates their Basal Adipogenic Potential.

Abstract: Sex hormone binding globulin (SHBG) deteriorated expression has been recently strongly correlated to increased level of circulating pro-inflammatory cytokines and insulin resistance, which are typical manifestations of equine metabolic syndrome (EMS). Despite previous reports demonstrated the potential therapeutic application of SHBG for liver-related dysfunctions, whether SHBG might modulate equine adipose-derived stem/stromal cells (EqASCs) metabolic machinery remains unknown. Therefore, we evaluated for the first time the impact of SHBG protein on metabolic changes in ASCs isolated from healthy horses. Beforehand, SHBG protein expression has been experimentally lowered using a predesigned siRNA in EqASCs to verify its metabolic implications and potential therapeutic value. Then, apoptosis profile, oxidative stress, mitochondrial network dynamics and basal adipogenic potential have been evaluated using various molecular and analytical techniques. The SHBG knockdown altered the proliferative and metabolic activity of EqASCs, while dampening basal apoptosis via Bax transcript suppression. Furthermore, the cells treated with siRNA were characterized by senescent phenotype, accumulation of reactive oxygen species (ROS), nitric oxide, as well as decreased mitochondrial potential that was shown by mitochondrial membrane depolarization and lower expression of key mitophagy factors: PINK, PARKIN and MFN. The addition of SHBG protein reversed the impaired and senescent phenotype of EMS-like cells that was proven by enhanced proliferative activity, reduced apoptosis resistance, lower ROS accumulation and greater mitochondrial dynamics, which is proposed to be related to a normalization of Bax expression. Crucially, SHBG silencing enhanced the expression of key pro-adipogenic effectors, while decreased the abundance of anti-adipogenic factors namely HIF1-α and FABP4. The addition of exogenous SHBG further depleted the expression of PPARγ and C/EBPα and restored the levels of FABP4 and HIF1-α evoking a strong inhibitory potential toward ASCs adipogenesis. Herein, we provide for the first time the evidence that SHBG protein in importantly involved in various key metabolic pathways governing EqASCs functions, and more importantly we showed that SHBG negatively affect the basal adipogenic potential of tested ASCs through a FABP4-dependant pathway, and provide thus new insights for the development of potential anti-obesity therapeutic approach in both animals and humans.
© 2023. The Author(s).
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Publication Date: 2023-07-04 PubMed ID: 37402098PubMed Central: PMC10579166DOI: 10.1007/s12015-023-10580-8Google Scholar: Lookup
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  • Journal Article
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  • Non-U.S. Gov't

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 research explores the role of the Sex Hormone Binding Globulin (SHBG) in metabolic activities within equine adipose-derived stromal cells (ASCs), and its potential use in developing anti-obesity treatments in animals and humans.

Introduction

  • The study investigates an association between Sex Hormone Binding Globulin (SHBG) and the metabolic behavior of equine adipose-derived stem/stromal cells (EqASCs).
  • An imbalance in SHBG expression can lead to insulin resistance and increased pro-inflammatory cytokines, which are common features of equine metabolic syndrome (EMS).
  • Earlier research had suggested potential therapeutic effects of SHBG on liver dysfunction, but its impact on EqASC’s metabolic machinery was not known.

Methods

  • The researchers experimentally reduced the expression of SHBG protein in EqASCs using siRNA.
  • They studied various metabolic and cellular aspects such as apoptosis profile, oxidative stress, mitochondrial network dynamics and basal adipogenic potential, utilizing a variety of molecular and analytical techniques.

Results

  • The reduction of SHBG disrupted proliferative and metabolic activities in EqASCs and lowered basal apoptosis, indicated by Bax transcript suppression.
  • siRNA-treated cells displayed a senescent phenotype with increased levels of reactive oxygen species, nitric oxide, and a lower mitochondrial potential.
  • Adding SHBG protein reversed the senescent phenotype, leading to increased cellular activity, reduced resistance to apoptosis, decreased ROS levels and enhanced mitochondrial dynamics.
  • SHBG silencing led to increased expression of pro-adipogenic factors and reduced expression of anti-adipogenic factors like HIF1-α and FABP4.
  • Exogenous SHBG further reduced the expression of PPARγ and C/EBPα and restored the levels of FABP4 and HIF1-α, asserting its strong anti-adipogenic effect.

Conclusions

  • This unique study provides evidence that SHBG plays a significant role in several metabolic pathways governing EqASCs functions.
  • It showed that SHBG negatively impacts the basal adipogenic potential of ASCs through a FABP4-dependent pathway.
  • The results could provide vital insights for creating potential anti-obesity treatments in both animals and humans.

Cite This Article

APA
Bourebaba L, Zyzak M, Sikora M, Serwotka-Suszczak A, Mularczyk M, Al Naem M, Marycz K. (2023). Sex Hormone-Binding Globulin (SHBG) Maintains Proper Equine Adipose-Derived Stromal Cells (ASCs)’ Metabolic Functions and Negatively Regulates their Basal Adipogenic Potential. Stem Cell Rev Rep, 19(7), 2251-2273. https://doi.org/10.1007/s12015-023-10580-8

Publication

Stem cell reviews and reports
ISSN: 2629-3277
NlmUniqueID: 101752767
Country: United States
Language: English
Volume: 19
Issue: 7
Pages: 2251-2273

Researcher Affiliations

Bourebaba, Lynda
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland.
Zyzak, Magdalena
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland.
Sikora, Mateusz
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland.
Serwotka-Suszczak, Anna
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland.
Mularczyk, Malwina
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland.
Al Naem, Mohamad
  • Faculty of Veterinary Medicine, Equine Clinic - Equine Surgery, Justus-Liebig-University, 35392, Gießen, Germany.
Marycz, Krzysztof
  • Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland. krzysztof.marycz@upwr.edu.pl.
  • Department of Veterinary Medicine and Epidemiology, Veterinary Institute for Regenerative Cures, School of Veterinary Medicine, University of California, Davis, CA, USA. krzysztof.marycz@upwr.edu.pl.

MeSH Terms

  • Animals
  • Horses
  • Humans
  • Adipose Tissue / metabolism
  • Sex Hormone-Binding Globulin / genetics
  • Sex Hormone-Binding Globulin / metabolism
  • Reactive Oxygen Species / metabolism
  • Adipogenesis / genetics
  • bcl-2-Associated X Protein / metabolism
  • bcl-2-Associated X Protein / therapeutic use
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism
  • Mesenchymal Stem Cells / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism

Conflict of Interest Statement

Not Applicable.

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Citations

This article has been cited 4 times.
  1. Verhoog NJD, Africander D, Storbeck KH. Sex steroids, SHBG and type 2 diabetes in women: what do we really know?. Diabetologia 2026 Apr;69(4):837-854.
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