High uric acid directly inhibits insulin signalling and induces insulin resistance

Yang, Zhu; Hu, Yaqiu; Huang, Tianliang; Zhang, Yongneng; Li, Zhi; Luo, Chaohuan; Luo, Yinfeng; Yuan, Huier; Hisatome, Ichiro; Yamamoto, Tetsuya; Cheng, Juei‐Tang

doi:10.1016/j.bbrc.2014.04.080

Cited by 241 publications

(209 citation statements)

References 35 publications

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“…It has previously been observed that LA activates eNOS by activating Akt signaling (34). By contrast, inhibition of Akt signaling by high levels of UA may be associated with UA-induced insulin resistance, indicating that Akt signaling serves an essential role in endothelial cell function (35). Collectively, the results of the present study demonstrate that LA exerts protective effects in hyperuricemic rats by activating Akt signaling.…”

Section: Discussionsupporting

confidence: 63%

Protective role of α-lipoic acid in hyperuricemia-induced endothelial dysfunction

Zou

Wang

Liu

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The aim of the current study was to determine the effects of α-lipoic acid (LA) on hyperuricemia and endothelial dysfunction, and to uncover the underlying mechanism of its action. A hyperuricemic rat model was established by administration of uric acid (UA) and the rats were orally fed with 2 g/kg/day LA or phosphate-buffered saline. Primary rat aortic endothelial cells were subsequently isolated, and a cell viability assay, apoptosis assay, enzyme nitric oxide synthase (eNOS) activity assay and mitochondrial function assay were all performed. For the in vitro study, human umbilical vein endothelial cells were used and western blotting was performed to assess Akt signaling activity. The results of the current study indicated that LA inhibited apoptosis, enhanced eNOS activity and production of nitric oxide (NO), and rescued mitochondrial mass and function in uric acid (UA)-treated endothelial cells. LA activated Akt signaling and inhibition of Akt signaling abolished the effects of LA on cell viability, NO production, ROS production and ATP levels in UA-treated endothelial cells. Therefore, the current study demonstrated that LA attenuated oxidant stress and inhibited apoptosis in UA-treated endothelial cells by activating Akt signaling. The results indicate that LA may serve as a therapeutic approach to treat hyperuricemia-induced endothelial dysfunction.

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Section: Discussionsupporting

confidence: 63%

Protective role of α-lipoic acid in hyperuricemia-induced endothelial dysfunction

Zou

Wang

Liu

et al. 2017

Experimental and Therapeutic Medicine

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“…AKT has also been studied in relation to uric acid effects in a model of potassium oxonate-induced hyperuricemia in mice. AKT phosphorylation was inhibited by uric acid, and this diminished insulin sensitivity in cardiomyocytes (32) and in liver cells (26) through an ROS-dependent pathway. In our experimental setup, uric acid potently inhibited ROS production ( Fig.…”

Section: Discussionmentioning

confidence: 98%

“…AKT has been associated previously with effects of uric acid, such as oxidative stress and AKT inhibition, which could be an explanation for reduced IL-1Ra (26). Uric acid has also been linked to AMP-activated protein kinase (AMPK) inhibition through reactive oxygen species (ROS) induction, and this effect was described as inducing mTOR (27).…”

Section: Akt Is Phosphorylated In Uric Acid-primed Monocytes In the Amentioning

confidence: 99%

Uric acid priming in human monocytes is driven by the AKT–PRAS40 autophagy pathway

Crişan

Cleophas

Novakovic

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

113

105

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Metabolic triggers are important inducers of the inflammatory processes in gout. Whereas the high serum urate levels observed in patients with gout predispose them to the formation of monosodium urate (MSU) crystals, soluble urate also primes for inflammatory signals in cells responding to gout-related stimuli, but also in other common metabolic diseases. In this study, we investigated the mechanisms through which uric acid selectively lowers human blood monocyte production of the natural inhibitor IL-1 receptor antagonist (IL-1Ra) and shifts production toward the highly inflammatory IL-1β. Monocytes from healthy volunteers were first primed with uric acid for 24 h and then subjected to stimulation with lipopolysaccharide (LPS) in the presence or absence of MSU. Transcriptomic analysis revealed broad inflammatory pathways associated with uric acid priming, with NF-κB and mammalian target of rapamycin (mTOR) signaling strongly increased. Functional validation did not identify NF-κB or AMP-activated protein kinase phosphorylation, but uric acid priming induced phosphorylation of AKT and proline-rich AKT substrate 40 kDa (PRAS 40), which in turn activated mTOR. Subsequently, Western blot for the autophagic structure LC3-I and LC3-II (microtubule-associated protein 1A/1B-light chain 3) fractions, as well as fluorescence microscopy of LC3-GFPoverexpressing HeLa cells, revealed lower autophagic activity in cells exposed to uric acid compared with control conditions. Interestingly, reactive oxygen species production was diminished by uric acid priming. Thus, the Akt-PRAS40 pathway is activated by uric acid, which inhibits autophagy and recapitulates the uric acid-induced proinflammatory cytokine phenotype.uric acid | interleukin-1 | interleukin-1 receptor antagonist | AKT | autophagy

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“…ROS are generally believed to be harmful to cells and tissues [13]. HUA levels increase oxidative stress in multiple cells [14][15][16][17][18] and cause damaged endothelia, renal injury, insulin resistance and inflammation. The three members of the mitogen-activated protein kinase (MAPK) family, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38, regulate a variety of physiological processes, such as cell growth, metabolism, differentiation and cell death.…”

Section: Introductionmentioning

confidence: 99%

High Uric Acid Inhibits Cardiomyocyte Viability Through the ERK/P38 Pathway via Oxidative Stress

Shen

Chen³

et al. 2018

Cell Physiol Biochem

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Background/Aims:Clinical studies have shown that hyperuricaemia is strongly associated with cardiovascular disease. However, the molecular mechanisms of high uric acid (HUA) associated with cardiovascular disease remain poorly understood. In this study, we investigated the effect of HUA on cardiomyocytes. Methods: We exposed H9c2 cardiomyocytes to HUA, then cell viability was determined by MTT assay, and reactive oxygen species' (ROS) production was detected by a fluorescence assay. Western blot analysis was used to examine phosphorylation of extracellular signal-regulated kinase (ERK), p38, phosphatidylinositol 3-kinase (PI3K) and Akt. We monitored the impact of HUA on phospho-ERK and phospho-p38 levels in myocardial tissue from an acute hyperuricaemia mouse model established by potassium oxonate treatment. Results: HUA decreased cardiomyocyte viability and increased ROS production in cardiomyocytes; pre-treatment with N-acetyl-L-cysteine, a ROS scavenger, and PD98059, an ERK inhibitor, reversed HUA-inhibited viability of cardiomyocytes. Further examination of signal transduction pathways revealed HUA-induced ROS involved in activating ERK/P38 and inhibiting PI3K/Akt in cardiomyocytes. Furthermore, the acute hyperuricaemic mouse model showed an increased phospho-ERK/p38 level in myocardial tissues. Conclusion: HUA induced oxidative damage and inhibited the viability of cardiomyocytes by activating ERK/p38 signalling, for a novel potential mechanism of hyperuricaemic-related cardiovascular disease.

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High uric acid directly inhibits insulin signalling and induces insulin resistance

Cited by 241 publications

References 35 publications

Protective role of α-lipoic acid in hyperuricemia-induced endothelial dysfunction

Protective role of α-lipoic acid in hyperuricemia-induced endothelial dysfunction

Uric acid priming in human monocytes is driven by the AKT–PRAS40 autophagy pathway

High Uric Acid Inhibits Cardiomyocyte Viability Through the ERK/P38 Pathway via Oxidative Stress

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