Endothelial dysfunction is defined as impairment of the balance between endothelium-dependent vasodilation and constriction. Despite evidence of uric acid-induced endothelial dysfunction, a relationship with insulin resistance has not been clearly established. In this study, we investigated the role of vascular insulin resistance in uric acid-induced endothelial dysfunction. Uric acid inhibited insulin-induced endothelial nitric oxide synthase (eNOS) phosphorylation and NO production more substantially than endothelin-1 expression in HUVECs, with IC50 of 51.0, 73.6, and 184.2, respectively. Suppression of eNOS phosphorylation and NO production by uric acid was PI3K/Akt-dependent, as verified by the transfection with p110. Treatment of rats with the uricase inhibitor allantoxanamide induced mild hyperuricemia and increased mean arterial pressure by 25%. While hyperuricemic rats did not show systemic insulin resistance, they showed impaired vasorelaxation induced by insulin by 56%. A compromised insulin response in terms of the Akt/eNOS pathway was observed in the aortic ring of hyperuricemic rats. Coadministration with allopurinol reduced serum uric acid levels and blood pressure and restored the effect of insulin on Akt-eNOS pathway and vasorelaxation. Taken together, uric acid induced endothelial dysfunction by contributing to vascular insulin resistance in terms of insulin-induced NO production, potentially leading to the development of hypertension.-Choi, Y.-J., Yoon, Y., Lee, K.-Y., Hien, T. T., Kang, K. W., Kim, K.-C., Lee, J., Lee, M.-Y., Lee, S. M., Kang, D.-H., Lee, B.-H. Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the impairment of nitric oxide synthesis.

Non-alcoholic fatty liver disease is associated with inhibited AMP-activated kinase (AMPK) and activation of sterol regulatory element binding protein 1 (SREBP-1). AMPK phosphorylation inhibits SREBP-1, a major transcription factor of de novo lipogenesis, by inhibiting the liver X receptor (LXR) or by direct phosphorylation. Resveratrol, a polyphenol, has regulatory effects on hepatic lipid metabolism as a potent AMPK activator. In this study, we evaluated the anti-steatogenic effects of resveratrol and its derivatives and identified the molecular mechanism in vitro and in vivo. Resveratrol and its derivatives decreased lipid accumulation by free fatty acids (FFA mixture; 0.5 mM, oleic acid:palmitic acid = 2: 1) in H4IIEC3 cells. Synthesized derivatives of resveratrol had lower cytotoxicity than the parental molecule with similar potency. SY-102 suppressed SREBP-1 maturation by T0901317, an LXR agonist, and decreased SRE luciferase activity and the mRNA levels of lipogenic genes. Inhibition of AMPK by pre-treatment with compound C completely blocked the effects of SY-102. To evaluate their efficacy in vivo, mice were fed a high-fat diet for 5 days, and resveratrol or SY-102 was administered orally for the last 2 days. Oral administration of the SY-102 increased AMPK phosphorylation, followed by reduced hepatic triglyceride accumulation to a similar extent as resveratrol. These data demonstrate that SY-102, a synthesized derivative of resveratrol, might provide a promising therapeutic effect against fatty liver disease.

Orotic acid (OA) is an intermediate of pyrimidine nucleotide biosynthesis. Hereditary deficiencies in some enzymes associated with pyrimidine synthesis or the urea cycle induce OA accumulation, resulting in orotic aciduria. A link between patients with orotic aciduria and hypertension has been reported; however, the molecular mechanisms remain elusive. In this study, to elucidate the role of OA in vascular insulin resistance, we investigated whether OA induced endothelial dysfunction and hypertension. OA inhibited insulin- or metformin-stimulated nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation in human umbilical vein endothelial cells. A decreased insulin response by OA was mediated by impairment of the insulin-stimulated phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) signaling pathway in cells overexpressing the p110-PI3K catalytic subunit. Impaired effects of metformin on eNOS phosphorylation and NO production were reversed in cells transfected with constitutively active AMP-activated protein kinase. Moreover, experimental induction of orotic aciduria in rats caused insulin resistance, measured as a 125% increase in the homeostasis model assessment, and hypertension, measured as a 25% increase in systolic blood pressure. OA increased the plasma concentration of endothelin-1 by 201% and significantly inhibited insulin- or metformin-induced vasodilation. A compromised insulin or metformin response on the Akt/eNOS and AMP-activated protein kinase/eNOS pathway was observed in aortic rings of OA-fed rats. Taken together, we showed that OA induces endothelial dysfunction by contributing to vascular and systemic insulin resistance that affects insulin- or metformin-induced NO production, leading to the development of hypertension.