Iron Overload Causes Oxidative Stress and Impaired Insulin Signaling in AML-12 Hepatocytes

Messner, Donald J.; Rhieu, Byung Han; Kowdley, Kris V.

doi:10.1007/s10620-013-2648-3

Cited by 41 publications

(27 citation statements)

References 48 publications

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“…Iron overload increased both glucose and insulin levels in a mouse model [22]. Iron overload caused oxidative stress and impaired insulin signaling in hepatocytes [23,24]. A close relationship has been observed between insulin resistance and iron overload with regard to ROS generation [25].…”

Section: Discussionmentioning

confidence: 98%

Effect of excess iron on oxidative stress and gluconeogenesis through hepcidin during mitochondrial dysfunction

Lee

Choi

Lee

et al. 2015

The Journal of Nutritional Biochemistry

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Section: Discussionmentioning

confidence: 98%

Effect of excess iron on oxidative stress and gluconeogenesis through hepcidin during mitochondrial dysfunction

Lee

Choi

Lee

et al. 2015

The Journal of Nutritional Biochemistry

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“…Insulin resistance is associated with the development of NAFLD (276,282) and evidence from in vitro analysis also supports a role for reduced insulin sensitivity with iron loading and the combination of FFA and iron loading (155). This study has demonstrated that FFA and iron loading alone do not have a significant effect on insulin signalling but the co-administration of fat and iron loading significantly reduces insulin sensitivity.…”

Section: Inflammation Drives Changes Of Arsg Gpld1 and Ifi27l2b In Hsupporting

confidence: 53%

“…There was also an upregulation of genes from the cytochrome P450 family which are upregulated in response to oxidative stress (182) in another study in Hfe -/-mice. Additional evidence for a role of oxidative stress comes from a study of iron and fat loading in vitro where AML12 hepatocytes developed insulin resistance associated with the development of oxidative stress, and the blunted response to insulin stimulus was reversed with the administration of an antioxidant, curcumin (155). A similar observation was evidenced in Hfe -/-mice which developed steatohepatitis when fed a high calorie diet and steatotic injury was reduced when mice were supplemented with dietary curcumin.…”

Section: Oxidative Stressmentioning

confidence: 80%

“…Iron has been shown to activate phosphatidylinositol-3-kinase (PI3K) mediated activation of inflammatory signalling in macrophages in vitro (154). In another in vitro study, iron accumulation was shown to reduce insulin sensitivity which was reversed by administration of an antioxidant (155). Hepatic stellate cell activation has also been induced by hepatic iron loading in haemochromatosis and this phenotype was reversed after iron removal by phlebotomy (156).…”

Section: Iron Mediated Pathogenesismentioning

confidence: 99%

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Hfe-associated steatohepatitis: expression profiling and identifying the molecular basis of liver injury

Santrampurwala¹

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Non-alcoholic fatty liver disease (NAFLD) is an increasingly common clinical diagnosis and is predicted to become the leading indication for liver transplantation within a decade. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD with a fibro-inflammatory phenotype and can lead to liver cirrhosis. Although the factors responsible for progression from simple steatosis to NASH are unknown, there has been a particular interest in the role of ironinduced oxidative stress in this transition. The HFE protein plays a vital role in maintaining systemic iron homeostasis and a gene mutation in HFE is causative of haemochromatosis. In HFE-haemochromatosis, steatosis is associated with increased liver fibrosis. In keeping with these results, research from our laboratory has previously shown altered lipid metabolism and greater severity of injury in Hfe -/-mice fed a high calorie diet (HCD), which represents a western diet.The primary aim of this project was to enhance the understanding of disease progression inHfe-associated steatohepatitis through the identification and characterisation of genes that are differentially expressed. A gene expression profile was generated by high throughput sequencing of messenger RNA isolated from livers of Hfe -/-mice fed a chow diet and those fed a HCD. Subsequent bioinformatics analysis revealed a list of genes that were significantly altered in response to HCD-induced steatohepatitis. Among the genes that were upregulated are lipid droplet proteins, Perilipin 2 (Plin2) and Cell death inducing DFFA-like effector c (Cidec) which have been previously associated with the development of liver steatosis.Glycosylphosphatidylinositol phospholipase D1 (Gpld1), a high-density lipoprotein, was decreased in NASH livers and was the focus of this study because of the contrary upregulation observed in patients with NAFLD. Arylsulfatase G (Arsg) and Interferon, alpha-inducible protein 27 like 2B (Ifi27l2b) were identified as genes without a previously recognised role in the development of liver injury or fat accumulation and the work in this thesis has primarily focussed on elucidating the underlying roles of these genes in liver injury.To further investigate these genes an in vitro model of hepatocyte fat and iron loading was developed. This model showed gene expression which indicated increased, mitochondrial β-oxidation and reduced fatty acid storage in cells with concomitant free fatty acid (FFA) and iron loading. These changes were also associated with an increase in the pro-inflammatory In this thesis, Gpld1 expression was consistently reduced in AML12 hepatocytes, with all external stimuli, FFA and iron, insulin and inflammation. This downregulation was similar to its expression in rodent NASH livers from transcriptomics analysis and suggests that Gpld1 may influence the extent of injury in iron related steatohepatitis. To the best of my knowledge this is the first study to describe a role for Arsg in response to lipid droplet accumulation and inflammation in hepatocyte...

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“…In vitro studies show that curcumin is able to reduce induced lipid accumulation by downregulating lipogenic proteins and upregulating the expression of fatty acid β-oxidation-related genes as PPARα, via AMPK phosphorylation [108]. Moreover, this polyphenol seems to protect hepatocytes from lipoapoptosis [109] and iron-induced insulin resistance and oxidative stress in cells treated with stearic acid, probably reducing phosphorylated JNK levels [110].…”

Section: Fig (2)mentioning

confidence: 99%

Flavonoids and Related Compounds in Non-Alcoholic Fatty Liver Disease Therapy

Pisonero-Vaquero¹,

González‐Gallego²,

Sánchez-Campos³

et al. 2015

CMC

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Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is one of the most common chronic liver diseases, which may progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD is characterized by the accumulation of lipids in the liver arising from multiple factors: increased fatty acid uptake, increased de novo lipogenesis, reduced fatty acid oxidation and very low density lipoproteins (VLDL) secretion. Most therapeutic approaches for this disease are often directed at reducing body mass index and improving insulin resistance through lifestyle modifications, bariatric surgery and pharmacological treatments. Nevertheless, there is increasing evidence that the use of natural compounds, as polyphenols, exert multiple benefits on the disorders associated with NAFLD. These molecules seem to be able to regulate the expression of genes mainly involved in de novo lipogenesis and fatty acid oxidation, which contributes to their lipid-lowering effect in the liver. Their antioxidant, anti-inflammatory, antifibrogenic and antilipogenic properties seem to confer on them a great potential as strategy for preventing NAFLD progression. In this review, we summarized the effects of these compounds, especially flavonoids, and their mechanisms of action, that have been reported in several studies carried out in in vitro and in vivo models of NAFLD.

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Iron Overload Causes Oxidative Stress and Impaired Insulin Signaling in AML-12 Hepatocytes

Cited by 41 publications

References 48 publications

Effect of excess iron on oxidative stress and gluconeogenesis through hepcidin during mitochondrial dysfunction

Effect of excess iron on oxidative stress and gluconeogenesis through hepcidin during mitochondrial dysfunction

Hfe-associated steatohepatitis: expression profiling and identifying the molecular basis of liver injury

Flavonoids and Related Compounds in Non-Alcoholic Fatty Liver Disease Therapy

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