Abstract
Selenoprotein P (SeP) was recently identified as a hepatokine that induces insulin resistance (IR) in rodents and humans. Recent clinical trials have shown that salsalate, a prodrug of salicylate, significantly lowers blood glucose levels and increases adiponectin concentrations. We examined the effects of salsalate and full length-adiponectin (fAd) on the expression of SeP under hyperlipidemic conditions and explored their regulatory mechanism on SeP. In palmitate-treated HepG2 cells as well as high fat diet (HFD)-fed male Spraque Dawley (SD) rats and male db/db mice, SeP expression and its regulatory pathway, including AMPK-FOXO1α, were evaluated after administration of salsalate and salicylate. Palmitate treatment significantly increased SeP expression and aggravated IR, while knock-down of SeP by siRNA restored these changes in HepG2 cells. Palmitate-induced SeP expression was inhibited by both salsalate and salicylate, which was mediated by AMPK activation, and was blocked by AMPK siRNA or an inhibitor of AMPK. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift (EMSA) assay showed that salsalate suppressed SeP expression by AMPK-mediated phosphorylation of FOXO1α. Moreover, fAd also reduced palmitate-induced SeP expression through the activation of AMPK, which results in improved IR. Both salsalate and salicylate treatment significantly improved glucose intolerance and insulin sensitivity, accompanied by reduced SeP mRNA and protein expression in HFD-fed rats and db/db mice, respectively. Taken together, we found that salsalate and adiponectin ameliorated palmitate-induced IR in hepatocytes via SeP inhibition through the AMPK-FOXO1α pathway. The regulation of SeP might be a novel mechanism mediating the anti-diabetic effects of salsalate and adiponectin.
Highlights
The liver is a pivotal organ in the regulation of glucose homeostasis and may modulate insulin resistance (IR) via the production of secreted proteins termed hepatokines [1]
Selenoprotein P (SeP) is Involved in Palmitate-induced IR in HepG2 Cells We evaluated the role of SeP in insulin signaling in hepatocytes
With palmitate, the suppression of SeP expression by siRNA improved insulin signaling in HepG2 cells (Figure 1)
Summary
The liver is a pivotal organ in the regulation of glucose homeostasis and may modulate insulin resistance (IR) via the production of secreted proteins termed hepatokines [1]. SeP administration aggravated IR and glucose metabolism in both hepatocytes and myocytes. Both genetic deletion and RNA interference-mediated knockdown of SeP in mice led to an improvement in systemic IR and glucose tolerance [1]. The metabolic effects of SeP were mediated by the inhibition of adenosine monophosphate-activated protein kinase (AMPK) [1]. Circulating SeP levels were positively correlated with fasting plasma glucose and negatively associated with adiponectin in patients with type 2 diabetes mellitus (T2DM) [2]. Serum SeP concentrations were significantly higher in patients with T2DM or prediabetes compared to those with normal glucose tolerance [3]. Circulating SeP levels were associated with various cardiometabolic parameters including IR, inflammation, and atherosclerosis [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
