Cellular methylation processes enable expression of gluconeogenic
enzymes and metabolism of the nutrient
selenium.
Selenium status has been proposed to relate to type II diabetes risk, and plasma levels of
selenoprotein P (SEPP1) have been positively correlated with
insulin resistance. Increased expression of gluconeogenic
enzymes glucose-6-phosphatase (G6PC) and
phosphoenolpyruvate carboxykinase 1 (PCK1) has negative consequences for
blood glucose management in type II diabetics. Transcriptional regulation of SEPP1 is directed by the same
transcription factors that control the expression of G6PC and PCK1, and these factors are activated by methylation of
arginine residues. We sought to determine whether expression of SEPP1 and the aforementioned glucoconeogenic
enzymes are regulated by
protein methylation, the levels of which are reliant upon adequate
S-adenosylmethionine (SAM) and inhibited by
S-adenosylhomocysteine (SAH). We treated a human hepatocyte cell line, HepG2, with inhibitors of adenosylhomocysteine
hydrolase (AHCY) known to increase concentration of SAH before analysis of G6PC, PCK1, and SEPP1 expression. Increasing SAH decreased 1) the SAM/SAH ratio, 2)
protein-
arginine methylation, and 3) expression of SEPP1, G6PC, and PCK1 transcripts. Furthermore,
hormone-dependent induction of gluconeogenic
enzymes was reduced by inhibition of
protein methylation. When
protein-arginine methyltransferase 1 expression was reduced by
siRNA treatment, G6PC expression was inhibited. These findings demonstrate that hepatocellular SAM-dependent
protein methylation is required for both SEPP1 and gluconeogenic
enzyme expression and that inhibition of
protein arginine methylation might provide a route to therapeutic interventions in type II diabetes.