Sex hormone-binding globulin (SHBG) mitigates ER stress and improves viability and insulin sensitivity in adipose-derived mesenchymal stem cells (ASC) of equine metabolic syndrome (EMS)-affected horses

Abstract

Background Equine metabolic syndrome (EMS), which encompasses insulin resistance, low-grade inflammation and predisposition to laminitis is a critical endocrine disorder among the most prevalent conditions affecting horses from different breeds. According to the most recent research, low human sex hormone-binding globulin (SHBG) serum levels correlate with an increased risk of obesity, insulin resistance and diabetes, and may contribute to overall metabolic dysregulations. This study aimed to test whether exogenous SHBG could protect EMS affected adipose-derived stromal stem cells (EqASCEMS) from apoptosis, oxidative stress, ER stress and thus improve insulin sensitivity. Methods EqASCEMS wells were treated with two different concentrations (50 and 100 nM) of exogenous SHBG, whose biocompatibility was tested after 24, 48 and 72 h of incubation. Several parameters including cell viability, apoptosis, cell cycle, reactive oxygen species levels, ER stress, Pi3K/MAPK activation and insulin transducers expression were analysed. Results Obtained data demonstrated that exogenous SHBG treatment significantly promoted ASCs cells proliferation, cell cycle and survival with reduced expression of p53 and p21 pro-apoptotic mediators. Furthermore, SHBG alleviated the oxidative stress caused by EMS and reduced the overaccumulation of intracellular ROS, by reducing ROS + cell percentage and regulating gene expression of endogenous antioxidant enzymes (Sod 1, Cat, GPx), SHBG treatment exhibited antioxidant activity by modulating total nitric oxide (NO) levels in EMS cells as well. SHBG treatment dampened the activation of ER stress sensors and effectors in EqASCEMS cells via the upregulation of MiR-7a-5p, the decrease in the expression levels of ATF-6, CHOP and eiF2A and the restoration of PDIA3 chaperone protein levels. As a consequence, SHBG application substantially improved insulin sensitivity through the modulation of Pi3K/Akt/Glut4 insulin signalling cascades. Conclusion Our results suggest that the SHBG is endowed with crucial beneficial effects on ASCs metabolic activities and could serve as a valuable therapeutic target for the development of efficient EMS treatment protocols.

Correlation of Sex Hormone Binding Globulin with Metabolic Syndrome in US Adults: Insights from National Health and Nutrition Examination Survey (NHANES) 2013–2016

“…Furthermore, a study proposed that SHBG might serve as a promising therapeutic option for liver metabolic disorders [18]. Other studies have indicated that SHBG can improve lipid metabolism [19], and enhance insulin sensitivity [20]. While some researches has explored the relationship between metabolic syndrome and SHBG levels [21][22][23][24][25], the association between SHBG and metabolic syndrome remains a topic of debate.…”

Association between sex hormone binding globulin and metabolic syndrome in US adults: insights from National Health and Nutrition Examination Survey (NHANES) 2013–2016

“…Furthermore, a study proposed that SHBG might serve as a promising therapeutic option for liver metabolic disorders [ 15 ]. Some studies have indicated that SHBG can improve lipid metabolism [ 16 ], and enhance insulin sensitivity [ 17 ]. While some researches has explored the relationship between MetS and SHBG levels [ 18 – 23 ], the association between SHBG and MetS remains a topic of debate.…”