Abstract
Uridine is a pyrimidine nucleoside that exerts restorative functions in tissues under stress. Short-term co-administration of uridine with multiple unrelated drugs prevents drug-induced liver lipid accumulation. Uridine has the ability to modulate liver metabolism; however, the precise mechanism has not been delineated. In this study, long-term effects of uridine on liver metabolism were examined in both HepG2 cell cultures and C57BL/6J mice. We report that uridine administration was associated with O-GlcNAc modification of FOXO1, increased gluconeogenesis, reduced insulin signaling activity, and reduced expression of a liver-specific fatty acid binding protein FABP1. Long-term uridine feeding induced systemic glucose intolerance and severe liver lipid accumulation in mice. Our findings suggest that the therapeutic potentials of uridine should be designed for short-term acute administration.
Highlights
Uridine is a biologically active pyrimidine with multiple therapeutic potentials
We further investigate the effects of long-term uridine supplementation on liver lipid and glucose metabolism
Using 1D Western blot and an antibody that recognizes Ser-O-GlcNAc and ThrO-GlcNAc, total cellular protein from HepG2 cells treated with uridine exhibited a significantly higher protein O-linked glycosylation profile compared to untreated HepG2 cells (Fig 1A)
Summary
Uridine is a biologically active pyrimidine with multiple therapeutic potentials. Uridine reduces cytotoxicity on non-cancerous cells due to the administration of anti-cancer drug 5-fluorouracil [1]. Uridine mitigates lipodystrophy associated with the usage of nucleoside reverse transcriptase inhibitors for HIV treatment [2]. Uridine is a nutrient critical for phosphatidylcholine biosynthesis and synapse formation [3]. Uridine improves neurophysiological functions in patients with diabetic neuropathy [4]. Uridine has been shown to suppress hepatic steatosis induced by the usage of drugs in mice including zalcitabine [5], fenofibrate [6], and tamoxifen [7]. Uridine triacetate (Xuriden), an orally active prodrug of uridine, has recently received an orphan drug designation by the FDA to treat hereditary orotic aciduria
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