Urolithin A, C, and D, but not iso‐urolithin A and urolithin B, attenuate triglyceride accumulation in human cultures of adipocytes and hepatocytes

Kang, Inhae; Kim, YongEun; Tomás-Barberán, Francisco A.; Espı́n, Juan Carlos; Chung, Soonkyu

doi:10.1002/mnfr.201500796

Cited by 92 publications

(81 citation statements)

References 48 publications

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“…In this context, we recently showed that urolithins are able to reduce the pro-inflammatory response to high glucose levels in cultured neonatal cardiomyocytes and fibroblasts [13], suggesting that they can prevent the diabetes-induced microenvironmental changes triggering myocardial inflammation and functional impairment in the diabetic heart. These findings confirmed previous in vitro studies demonstrating the positive role of urolithin supplementation in different cell models, including anti-inflammatory activity in endothelial cells and macrophages [15, 32–36] and beneficial effects on lipid metabolism in adipocytes and hepatocytes [37]. However, the biological effects of in vivo urolithin administration in the setting of diabetes, as well as in other pathological conditions, remain to be characterized [38].…”

Section: Discussionsupporting

confidence: 87%

In vivo administration of urolithin A and B prevents the occurrence of cardiac dysfunction in streptozotocin-induced diabetic rats

Savi

Bocchi

Mena

et al. 2017

Cardiovasc Diabetol

109

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BackgroundEmerging evidence suggests that specific (poly)phenols may constitute new preventative strategies to counteract cell oxidative stress and myocardial tissue inflammation, which have a key role in the patho-physiology of diabetic cardiomyopathy. In a rat model of early diabetes, we evaluated whether in vivo administration of urolithin A (UA) or urolithin B (UB), the main gut microbiota phenolic metabolites of ellagitannin-rich foods, can reduce diabetes-induced microenvironmental changes in myocardial tissue, preventing cardiac functional impairment.MethodsAdult Wistar rats with streptozotocin-induced type-1 diabetes (n = 29) were studied in comparison with 10 control animals. Diabetic rats were either untreated (n = 9) or subjected to daily i.p. injection of UA (n = 10) or UB (n = 10). After 3 weeks of hyperglycaemia, hemodynamics, cardiomyocyte contractile properties and calcium transients were measured to assess cardiac performance. The myocardial expression of the pro-inflammatory cytokine fractalkine and proteins involved in calcium dynamics (sarcoplasmic reticulum calcium ATPase, phospholamban and phosphorylated phospholamban) were evaluated by immunoblotting. Plasma, urine and tissue distribution of UA, UB and their phase II metabolites were determined.ResultsIn vivo urolithin treatment reduced by approximately 30% the myocardial expression of the pro-inflammatory cytokine fractalkine, preventing the early inflammatory response of cardiac cells to hyperglycaemia. The improvement in myocardial microenvironment had a functional counterpart, as documented by the increase in the maximal rate of ventricular pressure rise compared to diabetic group (+18% and +31% in UA and UB treated rats, respectively), and the parallel reduction in the isovolumic contraction time (−12%). In line with hemodynamic data, both urolithins induced a recovery of cardiomyocyte contractility and calcium dynamics, leading to a higher re-lengthening rate (+21%, on average), lower re-lengthening times (−56%), and a more efficient cytosolic calcium clearing (−32% in tau values). UB treatment also increased the velocity of shortening (+27%). Urolithin metabolites accumulated in the myocardium, with a higher concentration of UB and UB-sulphate, potentially explaining the slightly higher efficacy of UB administration.ConclusionsIn vivo urolithin administration may be able to prevent the initial inflammatory response of myocardial tissue to hyperglycaemia and the negative impact of the altered diabetic milieu on cardiac performance.

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Section: Discussionsupporting

confidence: 87%

In vivo administration of urolithin A and B prevents the occurrence of cardiac dysfunction in streptozotocin-induced diabetic rats

Savi

Bocchi

Mena

et al. 2017

Cardiovasc Diabetol

109

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“…Previously, we demonstrated that UroA decreased TG accumulation in human hepatocytes . To determine whether UroA injection recapitulates these results in vivo , we investigated hepatic TG regulation.…”

Section: Resultsmentioning

confidence: 93%

“…Our laboratory has previously demonstrated the role of UroA in reducing lipogenesis by using primary cultures of human adipocytes in vitro . In this study, we collected eWAT from mice to validate the physiological function of UroA in adipose tissue.…”

Section: Resultsmentioning

confidence: 99%

Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity Through Augmentation of Mitochondrial Function and Biogenesis

Toney

Fan

Xian

et al. 2019

Obesity

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Objective Urolithin A (UroA) is a major metabolite of ellagic acid produced following microbial catabolism in the gut. Emerging evidence has suggested that UroA modulates energy metabolism in various cells. However, UroA’s physiological functions related to obesity and insulin resistance remain unclear. Methods Male mice were intraperitoneally administrated either UroA or dimethyl sulfoxide (vehicle) along with a high‐fat diet for 12 weeks. Insulin sensitivity was evaluated via glucose and insulin tolerance tests and acute insulin signaling. The effects of UroA on hepatic triglyceride accumulation, adipocyte size, mitochondrial DNA content, and proinflammatory gene expressions were determined. The impact of UroA on macrophage polarization and mitochondrial respiration were assessed in bone marrow–derived macrophages. Results Administration of UroA (1) improved systemic insulin sensitivity, (2) attenuated triglyceride accumulation and elevated mitochondrial biogenesis in the liver, (3) reduced adipocyte hypertrophy and macrophage infiltration into the adipose tissue, and (4) altered M1/M2 polarization in peritoneal macrophages. In addition, UroA favored macrophage M2 polarization and mitochondrial respiration in bone marrow‐derived macrophages. Conclusions UroA plays a direct role in improving systemic insulin sensitivity independent of its parental compounds. This work supports UroA’s role in the metabolic benefits of ellagic acid–rich foods and highlights the significance of its microbial transformation in the gut.

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“…In a series of gut microbiota‐mediated reactions, ellagitannins are hydrolysed yielding ellagic acid, which is converted to urolithins through the loss of one of its two lactones and by successive removal of hydroxyl groups (Espín et al, ). This process leads to the production of urolithin A, urolithin B, urolithin C, and urolithin D. Urolithins have been shown to regulate cellular processes involved in normal and pathological conditions (Espín et al, ; Kang, Kim, Tomás‐Barberán, Espín, & Chung, ; Tang et al, ). A few recent studies have also reported that administration and consumption of these colonic metabolites, in particular urolithin A, promote positive health outcomes in animal models (Ryu et al, ; Savi et al, ; Tang et al, ).…”

Section: Discussionmentioning

confidence: 99%

The ellagitannin metabolite urolithin C is a glucose‐dependent regulator of insulin secretion through activation of L‐type calcium channels

Bayle

Neasta

Dall’Asta

et al. 2019

British J Pharmacology

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Background and Purpose The pharmacology of polyphenol metabolites on beta‐cell function is largely undetermined. We sought to identify polyphenol metabolites that enhance the insulin‐secreting function of beta‐cells and to explore the underlying mechanisms. Experimental Approach INS‐1 beta‐cells and rat isolated islets of Langerhans or perfused pancreas preparations were used for insulin secretion experiments. Molecular modelling, intracellular Ca2+ monitoring, and whole‐cell patch‐clamp recordings were used for mechanistic studies. Key Results Among a set of polyphenol metabolites, we found that exposure of INS‐1 beta‐cells to urolithins A and C enhanced glucose‐stimulated insulin secretion. We further characterized the activity of urolithin C and its pharmacological mechanism. Urolithin C glucose‐dependently enhanced insulin secretion in isolated islets of Langerhans and perfused pancreas preparations. In the latter, enhancement was reversible when glucose was lowered from a stimulating to a non‐stimulating concentration. Molecular modelling suggested that urolithin C could dock into the Cav1.2 L‐type Ca2+ channel. Calcium monitoring indicated that urolithin C had no effect on basal intracellular Ca2+ but enhanced depolarization‐induced increase in intracellular Ca2+ in INS‐1 cells and dispersed cells isolated from islets. Electrophysiology studies indicated that urolithin C dose‐dependently enhanced the L‐type Ca2+ current for levels of depolarization above threshold and shifted its voltage‐dependent activation towards more negative potentials in INS‐1 cells. Conclusion and Implications Urolithin C is a glucose‐dependent activator of insulin secretion acting by facilitating L‐type Ca2+ channel opening and Ca2+ influx into pancreatic beta‐cells. Our work paves the way for the design of polyphenol metabolite‐inspired compounds aimed at ameliorating beta‐cell function.

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Urolithin A, C, and D, but not iso‐urolithin A and urolithin B, attenuate triglyceride accumulation in human cultures of adipocytes and hepatocytes

Abstract: Taken together, our results demonstrated that UroA, UroC, and UroD, but not isoUroA and UroB, reduce TG accumulation and increase FA oxidation in adipocytes as well as hepatocytes.

Cited by 92 publications

References 48 publications

In vivo administration of urolithin A and B prevents the occurrence of cardiac dysfunction in streptozotocin-induced diabetic rats

In vivo administration of urolithin A and B prevents the occurrence of cardiac dysfunction in streptozotocin-induced diabetic rats

Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity Through Augmentation of Mitochondrial Function and Biogenesis

The ellagitannin metabolite urolithin C is a glucose‐dependent regulator of insulin secretion through activation of L‐type calcium channels

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