Hepcidin in morbidly obese women with non-alcoholic fatty liver disease

Auguet, Teresa; Aragonès, Gemma; Berlanga, Alba; Martínez, Salomé; Sabench, Fàtima; Binetti, Jessica; Aguilar, Carmen; Porras, José Antonio; López, Alicia Molina; Castillo, Daniel Del; Richart, C

doi:10.1371/journal.pone.0187065

Cited by 24 publications

(26 citation statements)

References 54 publications

(70 reference statements)

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“…The increase in hepcidin we observed is consistent with previous studies in models with chronic inflammation such as obese mice 44 . This finding is supported by previous research indicating that in morbidity obese women with non-alcoholic fatty liver disease, the hepatic mRNA expressions of hepcidin and FPN were significantly greater than in obese women with normal liver 45 . Although FPN inactivation by hepcidin results in displacement from the cellular membrane into the cytosol 46 , the activity of FPN may not coincide with the amount of FPN.…”

Section: Discussionsupporting

confidence: 88%

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice

Lee

Choi

et al. 2020

Sci Rep

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Leptin-deficient and leptin-resistant mice manifest obesity, insulin resistance, and left ventricular hypertrophy (LVH); however, LVH's mechanisms are not fully understood. Cardiac iron dysregulation has been recently implicated in cardiomyopathy. Here we investigated the protective effects of caloric restriction on cardiac remodeling in impaired leptin signaling obese mice. RNA-seq analysis was performed to assess the differential gene expressions in the heart of wild-type and ob/ob mice. In particular, to investigate the roles of caloric restriction on iron homeostasis-related gene expressions, 10-week-old ob/ob and db/db mice were assigned to ad libitum or calorie-restricted diets for 12 weeks. Male ob/ob mice exhibited LVH, cardiac inflammation, and oxidative stress. Using RNA-seq analysis, we identified that an iron uptake-associated gene, transferrin receptor, was upregulated in obese ob/ob mice with LVH. Caloric restriction attenuated myocyte hypertrophy, cardiac inflammation, fibrosis, and oxidative stress in ob/ob and db/db mice. Furthermore, we found that caloric restriction reversed iron homeostasis-related lipocalin 2, divalent metal transporter 1, transferrin receptor, ferritin, ferroportin, and hepcidin expressions in the heart of ob/ob and db/db mice. These findings demonstrate that the cardioprotective effects of caloric restriction result from the cellular regulation of iron homeostasis, thereby decreasing oxidative stress, inflammation, and cardiac remodeling. We suggest that decreasing iron-mediated oxidative stress and inflammation offers new therapeutic approaches for obesityinduced cardiomyopathy.Disruption of leptin signaling leads to obesity-induced cardiac remodeling 1,2 , and this progression of cardiac hypertrophy to heart failure is a major contributor to morbidity and mortality in obese patients 3 . Although the pathophysiology of cardiac remodeling in obesity is complex, leptin-deficient (ob/ob) and leptin-resistant (db/ db) signaling serve an important role in obesity-associated left ventricular hypertrophy (LVH) 1,2,4 . The cardiomyopathy that stems from disruption of leptin signaling is due to several factors including insulin resistance, myocardial steatosis, inflammation, oxidative stress, and direct effects of deficiencies in leptin or leptin receptors 1,5,6 . However, the precise role of leptin on obesity-induced cardiomyopathy is not completely understood.Effect of CR on cardiac iron uptake in ob/ob and db/db mice. Due to our observation of elevated cardiac ferrous iron levels in ob/ob mice (Fig. 2f), we examined regulation of iron uptake-related genes via qRT-PCR. LCN2, DMT1, Tfrc, and L-ferritin mRNA levels were significantly lower in ob/ob+CR mice relative to ob/ob and db/db mice fed ad libitum (Figs. S6 and S8). Although the level of 24p3R mRNA in the hearts of ob/ob mice was significantly reduced by CR, we did not observe the same pattern in db/db mice (Figs. S6b and S8b). In addition, CR did not cause the change of iron uptake-related genes in WT and db/m mice ( Figs. S...

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Section: Discussionsupporting

confidence: 88%

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice

Lee

Choi

et al. 2020

Sci Rep

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“…DOI: 10.1159/000497228 ies have reported a relationship between serum ferritin and NAFLD, the connection was still disputable [11,12,14]. In the present study, we found that patients with NAFLD had higher serum ferritin levels than control subjects, and an elevated level of serum ferritin was associated with a significantly increased risk of NAFLD (OR = 1.679, 95% CI 1.189-2.371).…”

Section: Discussion/conclusionmentioning

confidence: 40%

“…Several human studies have elucidated the role of hepcidin in iron overload and chronic liver disease [21,22], but its effect on NAFLD is controversial. In the study by Auguet et al [11], the plasma levels of hepcidin among women with morbidly obesity were not significantly different between NAFLD patients and those with normal liver; however, Demircioğlu et al [16] reported that among children with obesity, hepcidin levels were significantly higher in NAFLD patients than in controls. In the present study, we found that serum hepcidin levels were not associated with NAFLD risk, but may have augmented the risk effect of central obesity on NAFLD (p = 0.04).…”

Section: Discussion/conclusionmentioning

confidence: 92%

“…Some authors have reported that serum ferritin is frequently increased in NAFLD patients, and its level is related to the severity of liver fibrosis [11,12], while others have not made this finding [13,14]. Hepcidin is the principal regulator of systemic iron homeostasis, secreted mainly by hepatocytes in response to iron perturbations, inflammation, and hypoxia [15].…”

Section: Introductionmentioning

confidence: 99%

“…Hepcidin is the principal regulator of systemic iron homeostasis, secreted mainly by hepatocytes in response to iron perturbations, inflammation, and hypoxia [15]. However, the role of hepcidin in the pathogenesis of NAFLD is controversial [11,16,17]. The reasons for these inconsistent results are unclear, but may relate to patient selection/study design, or competing factors that may influence serum levels of ferritin and hepcidin.…”

Section: Introductionmentioning

confidence: 99%

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Circulating Iron Levels Interaction with Central Obesity on the Risk of Nonalcoholic Fatty Liver Disease: A Case–Control Study in Southeast China

et al. 2019

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Objectives: We aimed to evaluate the associations between body iron stores and the risk of nonalcoholic fatty liver disease (NAFLD) in a Chinese population and explore whether this effect may be modified by other factors. Methods: A 1: 1 frequency-matched case–control study was conducted, including 482 NAFLD cases and 490 gender- and age-matched controls. Serum levels of ferritin, hepcidin, and C-reactive protein were measured. Results: Multivariate logistic regression analysis showed that hepcidin was not associated with NAFLD risk; however, elevated serum ferritin was significantly associated with increased risk of NAFLD (adjusted OR 1.619, 95% CI 1.158–2.267), and hepcidin:ferritin ratio was significantly associated with decreased risk of NAFLD (OR_adjusted 0.702, 95% CI 0.501–0.984). When stratified by gender, a significant association was found between elevated serum ferritin and hepcidin:ferritin ratio and NAFLD only for women (OR_adjusted 2.131, 95% CI 1.151–3.944 and OR_adjusted 0.414, 95% CI 0.219–0.781, respectively). A significant multiplicative interaction between central obesity and elevated serum hepcidin was observed (p < 0.05). Conclusions: Elevated serum ferritin and hepcidin:ferritin ratio are associated with NAFLD in a Chinese population. Although serum hepcidin is not associated with NAFLD, it may augment the risk effect of central obesity on NAFLD.

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Role of microRNA‐122 in microcystin‐leucine arginine‐induced dysregulation of hepatic iron homeostasis in mice

Wang

Liu

et al. 2020

Environmental Toxicology

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Microcystin‐leucine arginine (MC‐LR) is a cyclic heptapeptide hepatotoxin produced by cyanobacteria. MicroRNA‐122 (miR‐122) is specifically expressed in the liver. This study focuses on the role of miR‐122 in MC‐LR‐induced dysregulation of hepatic iron homeostasis in C57BL/6 mice. The thirty mice were randomly divided into five groups (Control, 12.5 μg/kg·BW MC‐LR, 25 μg/kg·BW MC‐LR, Negative control agomir and 25 μg/kg·BW MC‐LR + miR‐122 agomir). The results show that MC‐LR decreases the expressions of miR‐122, Hamp, and its related regulators, while increasing the content of hepatic iron and the expressions of FPN1 and Tmprss6. Furthermore, miR‐122 agomir pretreatment improves MC‐LR induced dysregulation of hepatic iron homeostasis by arousing the related regulators and reducing the expression of Tmprss6. These results suggest that miR‐122 agomir can prevent the accumulation of hepatic iron induced by MC‐LR, which may be related to the regulation of hepcidin by BMP/SMAD and IL‐6/STAT signaling pathways.

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Hepcidin in morbidly obese women with non-alcoholic fatty liver disease

Cited by 24 publications

References 54 publications

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice

Circulating Iron Levels Interaction with Central Obesity on the Risk of Nonalcoholic Fatty Liver Disease: A Case–Control Study in Southeast China

Role of microRNA‐122 in microcystin‐leucine arginine‐induced dysregulation of hepatic iron homeostasis in mice

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