Lauric acid impairs insulin-induced Akt phosphorylation by upregulating SELENOP expression via HNF4α induction.
Am J Physiol Endocrinol Metab
; 2022 May 02.
Article
em En
| MEDLINE
| ID: mdl-35499234
ABSTRACT
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 4α (HNF4α) binding site in the SELENOP promoter. A chromatin immunoprecipitation (ChIP) assay showed that lauric acid increased the binding of HNF4α to the SELENOP promoter. The knockdown of Hnf4α using siRNA canceled the upregulation of lauric acid-induced Selenop. Thus, the lauric acid-induced impairment of Akt phosphorylation brought about by insulin was rescued by the knockdown of either Hnf4α 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.
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Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article