Is the iron regulatory hormone hepcidin a risk factor for alcoholic liver disease?

Harrison-Findik, Duygu Dee

doi:10.3748/wjg.15.1186

Cited by 43 publications

(37 citation statements)

References 117 publications

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“…38 Paradoxically, ethanol-induced disruption of several molecules involved in the iron metabolism, such as ferritin, hepcidin, and iron, seems mediated via LCN2 independent manners (Supplemental Figure S4, B and C). Additional studies addressing the roles of LCN2-24p3R axis in regulating iron metabolism and its involvement in pathogenesis of alcoholic liver disease are needed.…”

Section: Discussionmentioning

confidence: 99%

The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

Cai

Jogasuria

Yin

et al. 2016

The American Journal of Pathology

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We have previously shown that the ethanol-mediated elevation of lipocaline-2 (LCN2) is closely associated with the development of alcoholic fatty liver disease (AFLD) in mice. Herein, we aimed to understand the functional significance of LCN2 induction by ethanol and to explore its underlying mechanisms. We evaluated the effects of LCN2 in an in vitro cellular alcoholic steatosis model and in an animal study using wild-type and LCN2 knockout mice fed for 4 weeks with an ethanol-supplemented Lieber-DeCarli diet. In the cellular model of alcoholic steatosis, recombinant LCN2 or overexpression of LCN2 exacerbated ethanol-induced fat accumulation, whereas knocking down LCN2 prevented steatosis in hepatocytes exposed to ethanol. Consistently, removal of LCN2 partially but significantly alleviated alcoholic fatty liver injury in mice. Mechanistically, LCN2 mediates detrimental effects of ethanol in the liver via disrupted multiple signaling pathways, including aberrant nicotinamide phosphoribosyltransferaseesirtuin 1 axis, perturbed endocrine metabolic regulatory fibroblast growth factor 15/19 signaling, and impaired chaperone-mediated autophagy. Finally, compared with healthy human livers, liver samples from patients with AFLD had lower gene expression of several LCN2-regualted molecules. Our study demonstrated a pivotal and causal role of LCN2 in the development of AFLD and suggested that targeting the LCN2 could be of great value for the treatment of human AFLD. (Am J Pathol 2016 http://dx

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Section: Discussionmentioning

confidence: 99%

The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

Cai

Jogasuria

Yin

et al. 2016

The American Journal of Pathology

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“…So, hepcidin is negative iron regulator, mainly through regulating intestinal iron uptake and release of iron from macrophages (Laftah et al, 2004). Inhibition of hepcidin expression was considered as one cause of alcohol-induced liver injuries (Harrison-Findik, 2009). In this research, alcohol down-regulated mice hepcidin expression in liver, leading to elevated expression of the Fpn1 and DMT1 in the duodenum.…”

Section: Discussionmentioning

confidence: 99%

Vitamin C protective role for alcoholic liver disease in mice through regulating iron metabolism

Guo

Xin

et al. 2010

Toxicol Ind Health

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Alcoholic liver disease (ALD) is a major medical complication of drinking alcohol, and commonly accompanied with hepatic iron overload and liver injuries. Oxidative stress plays an important role in pathogenesis of ALD and also leads to iron-metabolic disorders. In this study, the effects of vitamin C (Vc) on iron metabolism-related genes expression and liver protection from drinking in mice were investigated. Twenty-four male kunming mice were divided into four groups (six mice per group): control (water drinking); alcohol group (20% alcohol drinking), alcohol + low Vc group (adding 50 mg/kg Vc daily) and alcohol + high Vc group (adding 100 mg/kg Vc daily). All these mice were sacrificed after 7 days. Vc can ameliorate the increase of sera alanine aminotransferase (ALT) activity and hepatic iron overload of drinking alcohol in mice. Vc increases the expression of the iron-regulated hormone hepcidin and decreases transferrin receptor 1 (TfR1) expression in liver. Vc also down-regulates the expression of ferroportin 1 (Fpn1) in the intestine and decreases the iron release to blood. In conclusion, Vc ameliorated the alcoholic liver injuries through regulating the iron metabolism-related genes expression.

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“…C/ebp α is a transcription factor in the liver that has a positive effect on Hamp promoter activity [20]. Alcoholic and viral liver cell damage both reduce hepcidin expression, a reduction which is mediated by ROS via C/ebp α [40,41]. Reduction in hepatic C/ebp α mRNA expression in renocardiac failure may associate with hepatic oxidative stress [42].…”

Section: Discussionmentioning

confidence: 99%

Cardiac Hepcidin Expression Associates with Injury Independent of Iron

et al. 2016

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Background: Hepcidin regulates systemic iron homeostasis by downregulating the iron exporter ferroportin. Circulating hepcidin is mainly derived from the liver but hepcidin is also produced in the heart. We studied the differential and local regulation of hepcidin gene expression in response to myocardial infarction (MI) and/or chronic kidney disease (CKD). We hypothesized that cardiac hepcidin gene expression is induced by and regulated to severity of cardiac injury, either through direct (MI) or remote (CKD) stimuli, as well as through increased local iron content. Methods: Nine weeks after subtotal nephrectomy (SNX) or sham surgery (CON), rats were subjected to coronary ligation (CL) or sham surgery to realize 4 groups: CON, SNX, CL and SNX + CL. In week 16, the gene expression of hepcidin, iron and damage markers in cardiac and liver tissues was assessed by quantitative polymerase chain reaction and ferritin protein expression was studied by immunohistochemistry. Results: Cardiac hepcidin messenger RNA (mRNA) expression was increased 2-fold in CL (p = 0.03) and 3-fold in SNX (p = 0.01). Cardiac ferritin staining was not different among groups. Cardiac hepcidin mRNA expression correlated with mRNA expression levels of brain natriuretic peptide (β = 0.734, p < 0.001) and connective tissue growth factor (β = 0.431, p = 0.02). In contrast, liver hepcidin expression was unaffected by SNX and CL alone, while it had decreased 50% in SNX + CL (p < 0.05). Hepatic ferritin immunostaining was not different among groups. Conclusions: Our data indicate differences in hepcidin regulation in liver and heart and suggest a role for injury rather than iron as the driving force for cardiac hepcidin expression in renocardiac failure.

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Is the iron regulatory hormone hepcidin a risk factor for alcoholic liver disease?

Abstract: Despite heavy consumption over a long period of time,

Cited by 43 publications

References 117 publications

The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

Vitamin C protective role for alcoholic liver disease in mice through regulating iron metabolism

Cardiac Hepcidin Expression Associates with Injury Independent of Iron

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