A critical role for hepatic protein arginine methyltransferase 1 isoform 2 in glycemic control.

Appropriate control of hepatic gluconeogenesis is essential for the organismal survival upon prolonged fasting and maintaining systemic homeostasis under metabolic stress. Here, we show protein arginine methyltransferase 1 (PRMT1), a key enzyme that catalyzes the protein arginine methylation process, particularly the isoform encoded byPrmt1variant 2 (PRMT1V2),is critical in regulating gluconeogenesis in the liver. Liver-specific deletion ofPrmt1reduced gluconeogenic capacity in cultured hepatocytes and in the liver.Prmt1v2was expressed at a higher level compared toPrmt1v1in hepatic tissue and cells. Gain-of-function of PRMT1V2 clearly activated the gluconeogenic program in hepatocytes via interactions with PGC1 alpha, a key transcriptional coactivator regulating gluconeogenesis, enhancing its activity via arginine methylation, while no effects of PRMT1V1 were observed. Similar stimulatory effects of PRMT1V2 in controlling gluconeogenesis were observed in human HepG2 cells. PRMT1, specifically PRMT1V2, was stabilized in fasted liver and hepatocytes treated with glucagon, in a PGC1 alpha-dependent manner. PRMT1, particularlyPrmt1v2, was significantly induced in the liver of streptozocin-induced type 1 diabetes and high fat diet-induced type 2 diabetes mouse models and liver-specificPrmt1deficiency drastically ameliorated diabetic hyperglycemia. These findings reveal that PRMT1 modulates gluconeogenesis and mediates glucose homeostasis under physiological and pathological conditions, suggesting that deeper understanding how PRMT1 contributes to the coordinated efforts in glycemic control may ultimately present novel therapeutic strategies that counteracts hyperglycemia in disease settings.