High uric acid promotes dysfunction in pancreatic β cells by blocking IRS2/AKT signalling

Hu, Yaqiu; Zhao, Hairong; Lu, Jiaming; Xie, De; Wang, Qiang; Huang, Tianliang; Xin, Hancheng; Hisatome, Ichiro; Yamamoto, Tetsuya; Wang, Wei

doi:10.1016/j.mce.2020.111070

Cited by 17 publications

(13 citation statements)

References 54 publications

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“…Accumulating evidence from clinical observational studies suggests the involvement of asymptomatic hyperuricemia, independent of crystal formation, in hypertension, atherosclerosis, acute and chronic kidney disease, obesity, metabolic syndrome, fatty liver, insulin resistance (IR), and diabetes ( 3 – 5 ). Our previous studies also confirmed that hyperuricemia induced an IR state in several peripheral tissues ( 6 – 8 ), including the liver, myocardium, skeletal muscles, and adipose tissue as well as pancreatic β cells ( 9 ), and was a strong risk factor for type 2 diabetes mellitus (T2DM).…”

Section: Introductionsupporting

confidence: 77%

“…Hyperuricemia is also associated with chronic low-grade tissue inflammation, manifested as elevated serum chemokine ligand 2 levels, increased monocyte recruitment ( 26 ), and chronic inflammatory cell infiltration into the kidney ( 26 ). Clinical studies and our experiments have found associations between serum UA levels and the development of IR ( 27 , 28 ); however, whether macrophages infiltrate the liver and lead to intrinsic IR and the underlying mechanisms of the process remain unknown. In the current study, we constructed a mouse model of UOX knockout (UOX-KO) to investigate the role of high UA (HUA) in hepatic macrophage recruitment and IR.…”

Section: Introductionmentioning

confidence: 84%

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Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation

Zhao

et al. 2022

Front. Immunol.

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AimNumerous reports have demonstrated the key importance of macrophage-elicited metabolic inflammation in insulin resistance (IR). Our previous studies confirmed that hyperuricemia or high uric acid (HUA) treatment induced an IR state in several peripheral tissues to promote the development of type 2 diabetes mellitus (T2DM). However, the effect of HUA on glucose uptake and the insulin sensitivity of macrophages and its mechanism is unclear.MethodsTo assess systemic IR, we generated hyperuricemic mice by urate oxidase knockout (UOX-KO). Then, glucose/insulin tolerance, the tissue uptake of 18F-fluorodeoxyglucose, body composition, and energy balance were assessed. Glucose uptake of circulating infiltrated macrophages in the liver was evaluated by glucose transporter type 4 (GLUT-4) staining. Insulin sensitivity and the insulin signaling pathway of macrophages were demonstrated using the 2-NBDG kit, immunoblotting, and immunofluorescence assays. The immunoprecipitation assay and LC-MS analysis were used to determine insulin receptor substrate 2 (IRS2) levels and its interacting protein enrichment under HUA conditions.ResultsCompared to WT mice (10 weeks old), serum uric acid levels were higher in UOX-KO mice (WT, 182.3 ± 5.091 μM versus KO, 421.9 ± 45.47 μM). Hyperuricemic mice with metabolic disorders and systemic IR showed inflammatory macrophage recruitment and increased levels of circulating proinflammatory cytokines. HUA inhibited the nuclear translocation of GLUT-4 in hepatic macrophages, restrained insulin-induced glucose uptake and glucose tolerance, and blocked insulin IRS2/PI3K/AKT signaling. Meanwhile, HUA mediated the IRS2 protein degradation pathway and activated AMPK/mTOR in macrophages. LC-MS analysis showed that ubiquitination degradation could be involved in IRS2 and its interacting proteins to contribute to IR under HUA conditions.ConclusionThe data suggest that HUA-induced glucose intolerance in hepatic macrophages contributed to insulin resistance and impaired the insulin signaling pathway via IRS2-proteasome degradation

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Section: Introductionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 84%

Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation

Zhao

et al. 2022

Front. Immunol.

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“…Ferroptosis is a newly discovered type of regulated cell death mainly mediated by iron-dependent lipid peroxidation and has contributed to many pathological processes including ASVD, cancer development, neurodegenerative disease, and acute kidney injury [ 11 , 26 , 38 , 39 ]. Accumulating evidence suggests that HUA can promote oxidative activity and increase the production of ROS [ 37 , 57 ]. Therefore, we speculated that HUA may promote the progression of atherosclerosis by regulating ferroptosis in foam cells.…”

Section: Discussionmentioning

confidence: 99%

High Level of Uric Acid Promotes Atherosclerosis by Targeting NRF2-Mediated Autophagy Dysfunction and Ferroptosis

Liu

Xie

et al. 2022

Oxidative Medicine and Cellular Longevity

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Atherosclerotic vascular disease (ASVD) is the leading cause of death worldwide. Hyperuricemia is the fourth risk factor for atherosclerosis after hypertension, diabetes, and hyperlipidemia. The mechanism of hyperuricemia affecting the occurrence and development of atherosclerosis has not been fully elucidated. Mononuclear macrophages play critical roles in all stages of atherosclerosis. Studies have confirmed that both hyperuricemia and ferroptosis promote atherosclerosis, but whether high level of uric acid (HUA) promotes atherosclerosis by regulating ferroptosis in macrophages remains unclear. We found that HUA significantly promoted the development of atherosclerotic plaque and downregulated the protein level of the NRF2/SLC7A11/GPX4 signaling pathway in ApoE−/− mice. Next, we evaluated the effect of HUA and ferroptosis inhibitor ferrostatin-1 (Fer-1) treatment on the formation of macrophage-derived foam cells. HUA promoted the formation of foam cells, decreased cell viability, and increased iron accumulation and lipid peroxidation in macrophages treated with oxidized low-density lipoprotein (oxLDL); these effects were reversed by Fer-1 treatment. Mechanistically, HUA significantly inhibited autophagy and the protein level of the NRF2/SLC7A11/GPX4 signaling pathway. Fer-1 activated autophagy and upregulated the level of ferroptosis-associated proteins. Moreover, an NRF2 inducer (tertbutyl hydroquinone (TBHQ)) and autophagy activator (rapamycin (RAPA)) could reverse the inhibitory effect of HUA on foam cell survival. Our results suggest that HUA-induced ferroptosis of macrophages is involved in the formation of atherosclerotic plaques. More importantly, enhancing autophagy and inhibiting ferroptosis by activating NRF2 may alleviate HUA-induced atherosclerosis. These findings might contribute to a deeper understanding of the role of HUA in the pathogenesis of atherosclerosis and provide a therapeutic target for ASVD associated with hyperuricemia.

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“…However, uric acid was also reported to suppress Akt. Uric acid was suggested to be involved in the progression of atherosclerosis via insulin resistance induced by the suppression of Akt [83].…”

Section: Pi3k-akt Pathwaymentioning

confidence: 99%

Uric Acid in Inflammation and the Pathogenesis of Atherosclerosis

Kimura

Tsukui

Kono

2021

IJMS

124

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Hyperuricemia is a common metabolic syndrome. Elevated uric acid levels are risk factors for gout, hypertension, and chronic kidney diseases. Furthermore, various epidemiological studies have also demonstrated an association between cardiovascular risks and hyperuricemia. In hyperuricemia, reactive oxygen species (ROS) are produced simultaneously with the formation of uric acid by xanthine oxidases. Intracellular uric acid has also been reported to promote the production of ROS. The ROS and the intracellular uric acid itself regulate several intracellular signaling pathways, and alterations in these pathways may result in the development of atherosclerotic lesions. In this review, we describe the effect of uric acid on various molecular signals and the potential mechanisms of atherosclerosis development in hyperuricemia. Furthermore, we discuss the efficacy of treatments for hyperuricemia to protect against the development of atherosclerosis.

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High uric acid promotes dysfunction in pancreatic β cells by blocking IRS2/AKT signalling

Cited by 17 publications

References 54 publications

Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation

Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation

High Level of Uric Acid Promotes Atherosclerosis by Targeting NRF2-Mediated Autophagy Dysfunction and Ferroptosis

Uric Acid in Inflammation and the Pathogenesis of Atherosclerosis

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