Serum Levels of Hepcidin in Patients with Biopsy-Proven Nonalcoholic Fatty Liver Disease

Şenateş, Ebubekir; Yılmaz, Yusuf; Çolak, Yaşar; Öztürk, Oğuzhan; Altunöz, Mustafa Erhan; Kurt, Ramazan; Özkara, Selvinaz; Aksaray, Sebahat; Tuncer, İlyas; Övünç, Ayşe Oya Kurdaş

doi:10.1089/met.2010.0121

Cited by 52 publications

(52 citation statements)

References 22 publications

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“…This predominantly hepatic RES deposition in response to 2% carbonyl iron is consistent with a previous report (5). Increased serum hepcidin has also been associated with metabolic syndrome in humans (29). We also observed that the hepatic and adipose lipid metabolism was impaired in our DI mice.…”

Section: Discussionsupporting

confidence: 93%

Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice

Handa

Morgan-Stevenson

Maliken³

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

116

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MM, Kowdley KV. Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice. Am J Physiol Gastrointest Liver Physiol 310: G117-G127, 2016. First published November 12, 2015; doi:10.1152/ajpgi.00246.2015.-The aim of this study was to determine the effect of iron overload in the development of nonalcoholic steatohepatitis (NASH) in a genetically obese mouse model (Lepr db/db ). Leptin receptor-deficient mice were fed a normal or an iron-supplemented chow for 8 wk and switched to normal chow for 8 wk. All dietary iron (DI)-fed mice developed hepatic iron overload predominantly in the reticuloendothelial system. Hepatocellular ballooning injury was observed in the livers of 85% of DI mice, relative to 20% of chow-fed Lepr db/db . Hepatic malonyldialdehyde levels and mRNA levels of antioxidant genes (Nrf2, Gpx1, and Hmox1) were significantly increased in the DI mice. Hepatic mRNA levels of mitochondrial biogenesis regulators Pgc1␣, Tfam, Cox4, and Nrf1 were diminished in the DI mice. In addition, gene expression levels of cytokines (Il6, Tnf␣) and several innate and adaptive immune cell markers such as Tlr4, Inos, CD11c, CD4, CD8, and Ifn␥ were significantly increased in livers of the DI group. Strikingly, Nlrp3, a component of the inflammasome and Il18, a cytokine elicited by inflammasome activation, were significantly upregulated in the livers of DI mice. In addition, RAW 264.7 macrophages loaded with exogenous iron showed significantly higher levels of inflammatory markers (Inos, Tnf␣, Mcp1, Tlr4). Thus dietary iron excess leads to hepatic oxidative stress, inflammasome activation, induction of inflammatory and immune mediators, hepatocellular ballooning injury, and therefore NASH in this model. Taken together, these studies indicate a multifactorial role for iron overload in the pathogenesis of NASH in the setting of obesity and metabolic syndrome. iron excess; hepatocellular ballooning; inflammasome; immune cell activation; reticuloendothelial system NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) is the most prevalent chronic liver disease in the world and is strongly associated with obesity and the attendant metabolic syndrome (17

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Section: Discussionsupporting

confidence: 93%

Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice

Handa

Morgan-Stevenson

Maliken³

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

116

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“…A few recent studies have investigated hepcidin gene expression and/or circulating hepcidin levels in a small number of NAFLD patients with or without iron [33][34][35][36][37]. Bekri et al, found increased adipose (but not hepatic) tissue hepcidin mRNA levels were observed in obese individuals and correlated with IL-6 and CRP mRNA levels, suggesting that hepcidin was an adipokine upregulated in the chronic inflammatory state associated with obesity, however hepcidin expression was not different among obese subjects with NASH or diabetes [35].…”

Section: Hepcidin Is a Central Regulator Of Iron Homeostasismentioning

confidence: 99%

“…Aigner et al, showed that hepatic hepcidin expression was significantly higher in NAFLD subjects with hepatic iron staining compared to NAFLD subjects without iron and that hepcidin expression positively correlated with hepatic TNF-α expression and body mass index [33]. Several studies have investigated either urinary [34], plasma [37] or serum [36] hepcidin levels in patients with NAFLD compared to patients with other liver diseases or healthy controls. Subjects with Dysmetabolic Hepatic Iron Overload (DHIO, characterized by hepatic iron loading and features of the metabolic syndrome; 21/25 or 84% also had NAFLD) had significantly higher urinary hepcidin levels compared to NAFLD patients without hepatic iron, which the authors postulate may explain the predominantly mixed RES/HC iron distribution in this group [34].…”

Section: Hepcidin Is a Central Regulator Of Iron Homeostasismentioning

confidence: 99%

Iron Metabolism in Nonalcoholic Fatty Liver Disease

Nelson

Klintworth

Kowdley

2011

Curr Gastroenterol Rep

106

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Non-Alcoholic Fatty Liver Disease (NAFLD) is a common worldwide clinical and major public health problem affecting both adults and children in developed nations. Increased hepatic iron stores are observed in about one-third of adult NAFLD patients. Iron deposition may occur in parenchymal and/or non-parenchymal cells of the reticuloendothelial system (RES). Similar patterns of iron deposition have been associated with increased severity of other chronic liver diseases including HCV infection and dysmetabolic iron overload, suggesting there may be a common mechanism for hepatic iron deposition in these diseases. In NAFLD, iron may potentiate the onset and progression of disease by increasing oxidative stress and altering insulin signaling and lipid metabolism. The impact of iron in these processes may depend upon the sub-cellular location of iron deposition in hepatocytes or RES cells. Iron depletion therapy has shown efficacy at reducing serum aminotransferase levels and improving insulin sensitivity in subjects with NAFLD.

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“…GH patients also display impaired hepcidin expression [33] . Although changes in both serum and liver hepcidin expression levels have been reported in NAFLD/NASH patients [14,[34][35][36][37][38] , the significance of hepcidin in disease pathogenesis is unknown. Our findings in this study with Hamp1 knockout mice administered a high fat diet for different time points suggest a role for hepcidin in NAFLD/NASH pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver

Bennett

Kharbanda

et al. 2016

WJH

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Serum Levels of Hepcidin in Patients with Biopsy-Proven Nonalcoholic Fatty Liver Disease

Abstract: Although subject to future confirmation, our data suggest that hepcidin levels are elevated in NAFLD and could be associated with lipid parameters in this setting.

Cited by 52 publications

References 22 publications

Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice

Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice

Iron Metabolism in Nonalcoholic Fatty Liver Disease

Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver

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