Abstract
Purines and pyrimidines are complementary bases of the genetic code. The roles of purines and their derivatives in cellular signal transduction and energy metabolism are well-known. In contrast, the roles of pyrimidines and their derivatives in cellular function remain poorly understood. In this study, the roles of uridine, a pyrimidine nucleoside, in liver metabolism are examined in mice. We report that short-term uridine administration in C57BL/6J mice increases liver protein glycosylation profiles, reduces phosphorylation level of insulin signaling proteins, and activates the HRI-eIF-2α-ATF4 heme-deficiency stress response pathway. Short-term uridine administration is also associated with reduced liver hemin level and reduced ability for insulin-stimulated blood glucose removal during an insulin tolerance test. Some of the short-term effects of exogenous uridine in C57BL/6J mice are conserved in transgenic UPase1 −/− mice with long-term elevation of endogenous uridine level. UPase1 −/− mice exhibit activation of the liver HRI-eIF-2α-ATF4 heme-deficiency stress response pathway. UPase1 −/− mice also exhibit impaired ability for insulin-stimulated blood glucose removal. However, other short-term effects of exogenous uridine in C57BL/6J mice are not conserved in UPase1 −/− mice. UPase1 −/− mice exhibit normal phosphorylation level of liver insulin signaling proteins and increased liver hemin concentration compared to untreated control C57BL/6J mice. Contrasting short-term and long-term consequences of uridine on liver metabolism suggest that uridine exerts transient effects and elicits adaptive responses. Taken together, our data support potential roles of pyrimidines and their derivatives in the regulation of liver metabolism.
Highlights
Uridine is a pyrimidine nucleoside that has the ability to affect liver energy metabolism
We report that uridine administration in C57BL/ 6J mice increases liver protein glycosylation profiles, reduces phosphorylation level of liver insulin signaling proteins, and activates the HRI-eukaryotic translation initiation factor 2a (eIF-2a)-activating transcription factor 4 (ATF4) heme-deficiency stress response pathway
Uridine administration is associated with reduced ability to remove blood glucose during a glucose tolerance test and insensitivity to insulin-stimulated blood glucose removal during an insulin tolerance test
Summary
Uridine is a pyrimidine nucleoside that has the ability to affect liver energy metabolism. Uridine is produced via several reversible reactions including de-phosphorylation of a uridine monophosphate, de-amination of a cytidine, or combination of a uracil and a ribose-1-phosphate [1]. Uridine homeostasis is regulated in part by uridine phosphorylase, an enzyme that catalyzes the reversible conversion of uridine to uracil [2]. UPase1-TG mice with ubiquitous genetic knock-in of a gene encoding for UPase exhibit depleted plasma and liver uridine concentration [3]. UPase1-TG mice exhibit intrinsic liver lipid accumulation [3,4]. UPase12/2 mice with ubiquitous genetic knock-out of a gene encoding for UPase exhibit elevated plasma and liver uridine concentration [5,6]. UPase12/2 mice are protected against fatty liver condition induced by a number of drugs with different acting mechanisms [7,8,9]. Uridine exerts protective effects against liver lipid accumulation; the underlying mechanisms have not been delineated
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