Fetuin-A is a multifactorial glycoprotein predominantly produced by liver but also found in adipose tissue, and tightly regulated by the FBXW7 E3 ubiquitin ligase. Recently, the hepatokine has been implicated in the pathogenesis of insulin resistance and associated metabolic failures in humans through its potent and selective inhibitory effect on tyrosine kinase activity of insulin receptor, however, no reports related to its implication in equine metabolic syndrome onset have been published yet. In this investigation, the effect of FBXW7 E3 ligase on the Fetuin-A/INSR axis has been evaluated. EMS affected liver tissue exhibited significant elevated Fetuin-A levels at protein and mRNA level over lean samples. Moreover, increased Fetuin-A was accompanied by augmentation of circulating levels of IL-1β and TNF-α pro-inflammatory cytokines. Interestingly, liver FBXW7 levels inversely correlated with high Fetuin-A concentrations, and was sensibly downregulated under EMS condition. Treatment of liver explants with exogenous FBXW7 protein resulted in a marked depletion in total Fetuin-A protein expression, which subsequently restored insulin signal transduction via increased INSR phosphorylation. Conclusion: On the whole, EMS affected horses display abnormal high Fetuin-A levels and suppressed FBXW7 expression, which could serve as a new potential therapeutic target for insulin sensitivity restoration in EMS
FBXW7 is an F-box protein that acts as a substrate recognition component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex. By selectively targeting many oncoproteins for proteasome-mediated degradation, FBXW7 acts as a typical tumor suppressor.
FBXW7 also recognizes non-canonical substrates, such as XRCC4 or γ-catenin, for polyubiquitylation via the K63 linkage, not for degradation, but for functional modulation. Moreover, FBXW7 binds to a pseudo-substrate LSD, not for degradation, rather being self-degraded.
EMS is a disorder associated with inappropriate blood insulin levels and fat deposition. It often affects “thrifty” equids such as ponies, donkeys, Arabians, and mustangs. EMS can cause laminitis, a serious condition that requires emergency veterinary intervention.
Fetuin-A is a multifactorial glycoprotein predominantly produced by liver but also found in adipose tissue. It has been implicated in the pathogenesis of insulin resistance and associated metabolic failures in humans through its potent and selective inhibitory effect on tyrosine kinase activity of insulin receptor.
The abstract you shared suggests that FBXW7 E3 ligase regulates Fetuin-A expression and function in EMS-affected liver tissue. It also proposes that FBXW7 could be a new potential therapeutic target for insulin sensitivity restoration in EMS.
