Gout‐induced endothelial impairment: The role of SREBP2 transactivation of YAP

Zhao, Zunlan; Zhao, Yingshuai; Zhang, Yuqing; Shi, Weili; Li, Xiqing; Shyy, John Y.‐J.; He, Ming; Wang, Liuyi

doi:10.1096/fj.202100337r

Cited by 11 publications

(15 citation statements)

References 51 publications

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“…We found that both the Bifidobacteriales order and Bifidobacteriaceae family had a protective effect on urate metabolism partially through DHA level, whereas rs182549 in MCM6 was the most predominant variant. MCM6 could be activated by both DHA supplements in the human body and hyperuricemia status in mice ( 49 , 50 ). The complex MCM6/LCT variation also participated in several diseases’ progress such as obesity, lactose intolerance, and irritable bowel syndrome ( 51 , 52 ).…”

Section: Discussionmentioning

confidence: 99%

Dissecting the causal effect between gut microbiota, DHA, and urate metabolism: A large-scale bidirectional Mendelian randomization

et al. 2023

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ObjectivesOur aim was to investigate the interactive causal effects between gut microbiota and host urate metabolism and explore the underlying mechanism using genetic methods.MethodsWe extracted summary statistics from the abundance of 211 microbiota taxa from the MiBioGen (N =18,340), 205 microbiota metabolism pathways from the Dutch Microbiome Project (N =7738), gout from the Global Biobank Meta-analysis Initiative (N =1,448,128), urate from CKDGen (N =288,649), and replication datasets from the Global Urate Genetics Consortium (N gout =69,374; N urate =110,347). We used linkage disequilibrium score regression and bidirectional Mendelian randomization (MR) to detect genetic causality between microbiota and gout/urate. Mediation MR and colocalization were performed to investigate potential mediators in the association between microbiota and urate metabolism.ResultsTwo taxa had a common causal effect on both gout and urate, whereas the Victivallaceae family was replicable. Six taxa were commonly affected by both gout and urate, whereas the Ruminococcus gnavus group genus was replicable. Genetic correlation supported significant results in MR. Two microbiota metabolic pathways were commonly affected by gout and urate. Mediation analysis indicated that the Bifidobacteriales order and Bifidobacteriaceae family had protective effects on urate mediated by increasing docosahexaenoic acid. These two bacteria shared a common causal variant rs182549 with both docosahexaenoic acid and urate, which was located within MCM6/LCT locus.ConclusionsGut microbiota and host urate metabolism had a bidirectional causal association, implicating the critical role of host-microbiota crosstalk in hyperuricemic patients. Changes in gut microbiota can not only ameliorate host urate metabolism but also become a foreboding indicator of urate metabolic diseases.

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Section: Discussionmentioning

confidence: 99%

Dissecting the causal effect between gut microbiota, DHA, and urate metabolism: A large-scale bidirectional Mendelian randomization

et al. 2023

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“…In recent years, the incidence of HUA and gout has continued to increase worldwide, which may be related to changes in lifestyle, such as the prevalence of a high-purine diet, fructose beverages, and alcohol consumption ( Kolasinski, 2014 ; Jakše et al., 2019 ; Yokose et al., 2021 ). HUA and gout cause increased oxidative stress, endothelial dysfunction, inflammation, platelet adhesion and aggregation, and vasoconstriction ( Macfarlane et al., 1983 ; Krishnan, 2010 ; Feig, 2014 ; So and Martinon, 2017 ; Zhao et al., 2021 ). HUA and gout are also independent risk factors for cardiovascular disease, metabolic syndrome, and acute kidney injury ( Thottam et al., 2017 ; Bardin and Richette, 2017 ; Abeles and Pillinger, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Gut microbiota remodeling: A promising therapeutic strategy to confront hyperuricemia and gout

Wang

Liao

et al. 2022

Front. Cell. Infect. Microbiol.

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The incidence of hyperuricemia (HUA) and gout continuously increases and has become a major public health problem. The gut microbiota, which colonizes the human intestine, has a mutually beneficial and symbiotic relationship with the host and plays a vital role in the host’s metabolism and immune regulation. Structural changes or imbalance in the gut microbiota could cause metabolic disorders and participate in the synthesis of purine-metabolizing enzymes and the release of inflammatory cytokines, which is closely related to the occurrence and development of the metabolic immune disease HUA and gout. The gut microbiota as an entry point to explore the pathogenesis of HUA and gout has become a new research hotspot. This review summarizes the characteristics of the gut microbiota in patients with HUA and gout. Meanwhile, the influence of different dietary structures on the gut microbiota, the effect of the gut microbiota on purine and uric acid metabolism, and the internal relationship between the gut microbiota and metabolic endotoxemia/inflammatory factors are explored. Moreover, the intervention effects of probiotics, prebiotics, and fecal microbial transplantation on HUA and gout are also systematically reviewed to provide a gut flora solution for the prevention and treatment of related diseases.

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“…SREBP1 has previously been identified as an intracellular cholesterol sensors located in the endoplasmic reticulum that provide feedback regulation of intracellular cholesterol. Recently it has been reported that UA could cause endothelial dysfunction via SREBP2 transactivation of YAP [41]. But it remains unclear whether UA regulate the SREBP1 pathway and cause dysregulated FFA metabolism.…”

Section: Discussionmentioning

confidence: 99%

Increased circulating uric acid aggravates heart failure via impaired fatty acid metabolism

Lou

Ott

et al. 2023

J Transl Med

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Background Increased circulating uric acid (UA) concentration may disrupt cardiac function in heart failure patients, but the specific mechanism remains unclear. Here, we postulate that hyperuremia induces sterol regulatory element binding protein 1 (SREBP1), which in turn activate hepatic fatty acid biosynthesis response, leading to cardiac dysfunction. Methods and results Increased circulating uric acid was observed in heart failure patients and inversely correlated to cardiac function. Besides, uric acid correlated to circulating lipids profile based on metabolomics in heart failure patients. Using cultured human hepatoellular carcinomas (HepG2) and Tg(myl7:egfp) zebrafish, we demonstrated that UA regulated fatty acid synthase (FASN) via SREBP1 signaling pathway, leading to FFA accumulation and impaired energy metabolism, which could be rescued via SREBP1 knockdown. In ISO treated zebrafish, UA aggravated heart failure via increased cardiovascular cavity size, decreased heart beats, pericardial edema and long-stretched heart deformation. Conclusions Our findings suggest that UA-SREBP1-FASN signaling exacerbates cardiac dysfunction during FFA accumulation. Identification of this mechanism may help in treatment and prevention of heart failure.

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Gout‐induced endothelial impairment: The role of SREBP2 transactivation of YAP

Cited by 11 publications

References 51 publications

Dissecting the causal effect between gut microbiota, DHA, and urate metabolism: A large-scale bidirectional Mendelian randomization

Dissecting the causal effect between gut microbiota, DHA, and urate metabolism: A large-scale bidirectional Mendelian randomization

Gut microbiota remodeling: A promising therapeutic strategy to confront hyperuricemia and gout

Increased circulating uric acid aggravates heart failure via impaired fatty acid metabolism

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