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

Handa, Priya; Morgan-Stevenson, Vicki; Maliken, Bryan D.; Nelson, James E.; Washington, Shenna; Westerman, Mark; Yeh, Matthew M.; Kowdley, Kris V.

doi:10.1152/ajpgi.00246.2015

Cited by 117 publications

(100 citation statements)

References 34 publications

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“…Only levels of more than 300 mg/kg iron in liver tissue may be referred to as high [31]. Tissue injury due to excess iron eventually leads to organ dysfunction [32, 33]. In general, liver damage (hepatic fibrosis, cirrhosis) occurs when liver iron concentration increases to more than 10-times the normal level [34].…”

Section: Discussionmentioning

confidence: 99%

Fat content, fatty acid pattern and iron content in livers of turkeys with hepatic lipidosis

Visscher

Middendorf

Gunther³

et al. 2017

Lipids Health Dis

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BackgroundThe so-called “hepatic lipidosis” in turkeys is an acute progressive disease associated with a high mortality rate in a very short time. Dead animals show a massive fatty degeneration of the liver. The cause is still unclear. Previous findings suggest that there may be parallels to human non-alcoholic fatty liver disease. The object of the study was to examine the changes in the fat contents, the fatty acid composition and the iron content in livers of animals, which have died from hepatic lipidosis.MethodsThe conspicuous livers (n = 85) were collected from 20 flocks where the phenomenon of massive increased animal losses accompanied by marked macroscopically visible pathological liver steatosis suddenly occurred. For comparison and as a reference, livers (n = 16) of two healthy flocks were taken. Healthy and diseased flocks were fed identical diets concerning official nutrient recommendations and were operating under standardized, comparable conventional conditions.ResultsCompared to livers of healthy animals, in the livers of turkeys died from hepatic lipidosis there were found massively increased fat levels (130 ± 33.2 vs. 324 ± 101 g/kg dry matter-DM). In all fatty livers, different fatty acids concentrations were present in significantly increased concentrations compared to controls (palmitic acid: 104 g/kg DM, +345%; palmitoleic acid: 18.0 g/kg DM, + 570%; oleic acid: 115 g/kg DM, +437%). Fatty acids concentrations relevant for liver metabolism and inflammation were significantly reduced (arachidonic acid: 2.92 g/kg DM, −66.6%; eicosapentaenoic acid: 0.141 g/kg DM, −78.3%; docosahexaenoic acid: 0.227 g/kg DM, −90.4%). The ratio of certain fatty acids to one another between control and case livers changed analogously to liver diseases in humans (e.g.: C18:0/C16:0 – 0.913 against 0.311; C16:1n7/C16:0 – 0.090 against 0.165; C18:1/C18:0 – 0.938 against 4.03). The iron content in the liver tissue also increased massively (271 ± 51.5 vs 712 ± 214 mg/kg DM).ConclusionThe hepatic lipidosis has a massive impact on the lipid content, the lipid composition and the iron content in the liver. The character of the metabolic disorder includes parallels to the non-alcoholic steatohepatitis in humans.

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Section: Discussionmentioning

confidence: 99%

Fat content, fatty acid pattern and iron content in livers of turkeys with hepatic lipidosis

Visscher

Middendorf

Gunther³

et al. 2017

Lipids Health Dis

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show abstract

“…Excessive hepatic iron accumulation causes oxidative stress and promotes chronic liver damage in patients with genetic hemochromatosis associated with HFE variants, especially C282Y (rs1800562) and H63D (rs1799945). In mouse, iron-induced inflammatory activation may contribute to the necroinflammation, while the iron-mediated downregulation M2 pathway in macrophages has an impact on fibrogenesis in NASH (58), which supports for a mechanistic role for iron in NASH. HFE is characterized by the enhanced absorption of dietary iron that results in progressive deposition of metal in the liver.…”

Section: Iron Overload and Hemochromatosis (Hfe)mentioning

confidence: 72%

“…Among the candidate factors of oxidative stress, iron is a notable pro-oxidant and acts through the Fenton reaction to generate hydroxyl radicals (58). Excessive hepatic iron accumulation causes oxidative stress and promotes chronic liver damage in patients with genetic hemochromatosis associated with HFE variants, especially C282Y (rs1800562) and H63D (rs1799945).…”

Section: Iron Overload and Hemochromatosis (Hfe)mentioning

confidence: 99%

Development of gene polymorphisms in meditators of nonalcoholic fatty liver disease

Wang

Gong

2017

Biomedical Reports

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Abstract. Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, the morbidity of which closely correlates with diversity of ethnicity, minority, family and location. Its histology spans from simple steatosis, to nonalcoholic steatohepatitis, which ultimately results in fibrosis, cirrhosis and hepatocellular carcinoma. The accelerating prevalence of NAFLD is due to an incremental incidence of metabolic syndrome that is distinguished by dyslipidemia, glucose impairment, obesity, excessive oxidative stress and adipocytokine impairment. Additionally, the pathogenesis of NAFLD is thought to be a multifactorial and complicated disease associated with lifestyle habits, nutritional factors and genetics. However, the pathogenesis and underlying mechanism in the development of NAFLD caused by genetics remains unclear. People have been increasingly emphasizing on the relationship between NAFLD and gene polymorphisms in recent years, with the aim of having a comprehensive elucidation of associated gene polymorphisms influencing the pathogenesis of the disease. In the current article, the authors attempted to critically summarize the most recently identified gene polymorphisms from the facets of glucose metabolism, fatty acid metabolism, oxidative stress and related cytokines in NAFLD that contribute to promoting the progression of the disease.

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“…2a) on either control diet (lab chow; contains 280 ppm iron) or high-iron diet (fortified with 2% carbonyl iron, 20,000 ppm) which has been used to induce iron overload (Handa et al 2016). Lcn2KO mice on control diet gained significantly more body weight compared to all other groups, but this phenotype is lost in Lcn2KO mice fed on high-iron diet.…”

Section: Resultsmentioning

confidence: 99%

Lipocalin 2 alleviates iron toxicity by facilitating hypoferremia of inflammation and limiting catalytic iron generation

et al. 2016

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Iron is an essential transition metal ion for virtually all aerobic organisms, yet its dysregulation (iron overload or anemia) is a harbinger of many pathologic conditions. Hence, iron homeostasis is tightly regulated to prevent the generation of catalytic iron (CI) which can damage cellular biomolecules. In this study, we investigated the role of iron-binding/trafficking innate immune protein, lipocalin 2 (Lcn2, aka siderocalin) on iron and CI homeostasis using Lcn2 knockout (KO) mice and their WT littermates. Administration of iron either systemically or via dietary intake strikingly upregulated Lcn2 in the serum, urine, feces, and liver of WT mice. However, similarly-treated Lcn2KO mice displayed elevated CI, augmented lipid peroxidation and other indices of organ damage markers, implicating that Lcn2 responses may be protective against iron-induced toxicity. Herein, we also show a negative association between serum Lcn2 and CI in the murine model of dextran sodium sulfate (DSS)-induced colitis. The inability of DSS-treated Lcn2KO mice to elicit hypoferremic response to acute colitis, implicate the involvement of Lcn2 in iron homeostasis during inflammation. Using bone marrow chimeras, we further show that Lcn2 derived from both immune and non-immune cells participate in CI regulation. Remarkably, exogenous rec-Lcn2 supplementation suppressed CI levels in Lcn2KO serum and urine. Collectively, our results suggest that Lcn2 may facilitate hypoferremia, suppress CI generation and prevent iron-mediated adverse effects.

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

Cited by 117 publications

References 34 publications

Fat content, fatty acid pattern and iron content in livers of turkeys with hepatic lipidosis

Fat content, fatty acid pattern and iron content in livers of turkeys with hepatic lipidosis

Development of gene polymorphisms in meditators of nonalcoholic fatty liver disease

Lipocalin 2 alleviates iron toxicity by facilitating hypoferremia of inflammation and limiting catalytic iron generation

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