Lauric acid impairs insulin-induced Akt phosphorylation by upregulatin SELENOP expression via HNF4 alpha induction

Selenoprotein P (SeP; encoded by SELENOP in humans, Selenop in rodents) is a hepatokine that is upregulated in the liver of humans with type 2 diabetes. Excess SeP contributes to the onset of insulin resistance and various type 2 diabetes-related complications. We have previously reported that the long-chain saturated fatty acid, palmitic acid, upregulates Selenop expression, whereas the polyunsaturated fatty acids (PUFAs) downregulate it in hepatocytes. However, the effect of medium-chain fatty acids (MCFAs) on Selenop is unknown. Here, we report novel mechanisms that underlie the lauric acid-mediated Selenop gene regulation in hepatocytes. Lauric acid upregulated Selenop expression in Hepa1-6 hepatocytes and mice liver. A luciferase promoter assay and computational analysis of transcription factor-binding sites identified the hepatic nuclear factor 4 alpha (HNF4 alpha) binding site in the SELENOP promoter. A chromatin immunoprecipitation (ChIP) assay showed that lauric acid increased the binding of HNF4 alpha to the SELENOP promoter. The knockdown of Hnf4 alpha using siRNA canceled the upregulation of lauric acid-induced Selenop. The lauric acid-induced impairment of Akt phosphorylation brought about by insulin was rescued by the knockdown of either Hnf4 alpha or Selenop. These results provide new insights into the regulation of SeP by fatty acids and suggest that SeP may mediate MCFA-induced hepatic insulin signal reduction. NEW & NOTEWORTHY Lauric acid induces hepatic insulin resistance by upregulating Selenop. These findings caution the metabolic risk of excessive lauric acid intake, especially in people with hepatic insulin resistance associated with type 2 diabetes.