Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity

Cimini, Flavia Agata; Arena, Andrea; Barchetta, Ilaria; Tramutola, Antonella; Ceccarelli, Valentina; Lanzillotta, Chiara; Fontana, Mario; Bertoccini, Laura; Leonetti, Frida; Capoccia, Danila; Silecchia, Gianfranço; Cristofano, Claudio Di; Chiappetta, Caterina; Domenico, Fabio Di; Baroni, Marco Giorgio; Perluigi, Marzia; Cavallo, Maria Gisella; Barone, Eugenio

doi:10.1016/j.bbadis.2019.02.021

Cited by 30 publications

(28 citation statements)

References 67 publications

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“…Visceral fat releases greater amounts of damaging adipokines (TNFα), which can result in insulin resistance and inflammation [10,11,46,47]. In humans, lower BVRA levels are found in obesity and contribute to the metabolic syndrome and visceral adipose tissue inflammation [18]. Not surprisingly, BVRA has anti-inflammatory actions via inhibition of toll-like receptor 4 (TLR4) and NF-κB [48][49][50][51][52].…”

Section: Discussionmentioning

confidence: 99%

“…Given the importance of this pathway to the actions of insulin, Zhang et al proposed activation of AKT as a novel strategy to treat insulin resistance [56]. One of the primary regulators of AKT activity and insulin signaling is BVRA [18,57]. Studies by Miralem et al elegantly demonstrated that BVRA modulates AKT activity by aiding the formation of a complex with phosphatidylinositol-dependent kinase 1 (PDK1) [12].…”

Section: Discussionmentioning

confidence: 99%

“…Others have shown that the loss of BVRA in the brain causes insulin-resistance that occurs in Alzheimer's disease [60][61][62]. However, the loss of BVRA in obesity can result in hyperactivation of insulin signaling [18]. These conflicting results highlight the lack of consensus in the field.…”

Section: Discussionmentioning

confidence: 99%

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Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

et al. 2020

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Biliverdin reductase (BVR) is an enzymatic and signaling protein that has multifaceted roles in physiological systems. Despite the wealth of knowledge about BVR, no data exist regarding its actions in adipocytes. Here, we generated an adipose-specific deletion of biliverdin reductase-A (BVRA) (BlvraFatKO) in mice to determine the function of BVRA in adipocytes and how it may impact adipose tissue expansion. The BlvraFatKO and littermate control (BlvraFlox) mice were placed on a high-fat diet (HFD) for 12 weeks. Body weights were measured weekly and body composition, fasting blood glucose and insulin levels were quantitated at the end of the 12 weeks. The data showed that the percent body fat and body weights did not differ between the groups; however, BlvraFatKO mice had significantly higher visceral fat as compared to the BlvraFlox. The loss of adipocyte BVRA decreased the mitochondrial number in white adipose tissue (WAT), and increased inflammation and adipocyte size, but this was not observed in brown adipose tissue (BAT). There were genes significantly reduced in WAT that induce the browning effect such as Ppara and Adrb3, indicating that BVRA improves mitochondria function and beige-type white adipocytes. The BlvraFatKO mice also had significantly higher fasting blood glucose levels and no changes in plasma insulin levels, which is indicative of decreased insulin signaling in WAT, as evidenced by reduced levels of phosphorylated AKT (pAKT) and Glut4 mRNA. These results demonstrate the essential role of BVRA in WAT in insulin signaling and adipocyte hypertrophy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

et al. 2020

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“…BVR-A was shown to be a Ser/Thr/Tyr kinase able to regulate a number of pathways involved in cell growth, differentiation and survival [1,3,12]. In particular, BVR-A was identified as a novel regulator of the insulin/IGF1 signaling in vitro [13][14][15] and recent studies showing that loss of BVR-A impairs insulin signaling activation and cell metabolism also in vivo support this hypothesis [16][17][18][19].…”

Section: Introductionmentioning

confidence: 96%

BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain—Implications for Neurodegeneration

et al. 2020

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Biliverdin reductase-A (BVR-A) impairment is associated with increased accumulation of oxidatively-damaged proteins along with the impairment of autophagy in the brain during neurodegenerative disorders. Reduced autophagy inhibits the clearance of misfolded proteins, which then form neurotoxic aggregates promoting neuronal death. The aim of our study was to clarify the role for BVR-A in the regulation of the mTOR/autophagy axis by evaluating age-associated changes (2, 6 and 11 months) in cerebral cortex samples collected from BVR-A knock-out (BVR-A−/−) and wild-type (WT) mice. Our results show that BVR-A deficiency leads to the accumulation of oxidatively-damaged proteins along with mTOR hyper-activation in the cortex. This process starts in juvenile mice and persists with aging. mTOR hyper-activation is associated with the impairment of autophagy as highlighted by reduced levels of Beclin-1, LC3β, LC3II/I ratio, Atg5–Atg12 complex and Atg7 in the cortex of BVR-A−/− mice. Furthermore, we have identified the dysregulation of AMP-activated protein kinase (AMPK) as a critical event driving mTOR hyper-activation in the absence of BVR-A. Overall, our results suggest that BVR-A is a new player in the regulation of autophagy, which may be targeted to arrive at novel therapeutics for diseases involving impaired autophagy.

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“…Indeed, there has been a correlation showing that plasma bilirubin levels are lower in obese humans [3][4][5]. The enzyme that produces bilirubin, BVRA [6,7], is also reduced in obese humans compared to lean matched controls [8]. Studies indicate that bilirubin levels might increase with exercise [9,10] and fasting [11][12][13][14], implying a possible role for metabolic regulation.…”

Section: Introductionmentioning

confidence: 99%

Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1

et al. 2020

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Exercise in humans and animals increases plasma bilirubin levels, but the mechanism by which this occurs is unknown. In the present study, we utilized rats genetically selected for high capacity running (HCR) and low capacity running (LCR) to determine pathways in the liver that aerobic exercise modifies to control plasma bilirubin. The HCR rats, compared to the LCR, exhibited significantly higher levels of plasma bilirubin and the hepatic enzyme that produces it, biliverdin reductase-A (BVRA). The HCR also had reduced expression of the glucuronyl hepatic enzyme UGT1A1, which lowers plasma bilirubin. Recently, bilirubin has been shown to activate the peroxisome proliferator-activated receptor-α (PPARα), a ligand-induced transcription factor, and the higher bilirubin HCR rats had significantly increased PPARα-target genes Fgf21, Abcd3, and Gys2. These are known to promote liver function and glycogen storage, which we found by Periodic acid–Schiff (PAS) staining that hepatic glycogen content was higher in the HCR versus the LCR. Our results demonstrate that exercise stimulates pathways that raise plasma bilirubin through alterations in hepatic enzymes involved in bilirubin synthesis and metabolism, improving liver function, and glycogen content. These mechanisms may explain the beneficial effects of exercise on plasma bilirubin levels and health in humans.

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Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity

Cited by 30 publications

References 67 publications

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

BVR-A Deficiency Leads to Autophagy Impairment through the Dysregulation of AMPK/mTOR Axis in the Brain—Implications for Neurodegeneration

Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1

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