Adiponectin-Mediated Heme Oxygenase-1 Induction Protects Against Iron-Induced Liver Injury via a PPARα-Dependent Mechanism

Lin, Heng; Yu, Chun Hsien; Jen, Chih Yu; Cheng, Ching Feng; Chou, Ying-Hsiang; Chang, Chih Cheng; Juan, Shu Hui

doi:10.2353/ajpath.2010.090789

Cited by 50 publications

(48 citation statements)

References 49 publications

(53 reference statements)

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“…Considering the importance of AMPK and C/EBP␤ in hepatocyte survival, it is predicted that AMPK-dependent C/EBP␤ activation may contribute to the ability of CDCA to maintain hepatocyte viability. This concept is in line with the previous findings that AMPK activation induces HO-1 via peroxisome proliferatoractivated receptor ␣ activation in the liver and protects cells from oxidative stress (Shin and Kim, 2009;Lin et al, 2010).…”

Section: Noh Et Alsupporting

confidence: 80%

Farnesoid X Receptor Activation by Chenodeoxycholic Acid Induces Detoxifying Enzymes through AMP-Activated Protein Kinase and Extracellular Signal-Regulated Kinase 1/2-Mediated Phosphorylation of CCAAT/Enhancer Binding Protein β

Noh

Kim

et al. 2011

Drug Metab Dispos

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Section: Noh Et Alsupporting

confidence: 80%

Farnesoid X Receptor Activation by Chenodeoxycholic Acid Induces Detoxifying Enzymes through AMP-Activated Protein Kinase and Extracellular Signal-Regulated Kinase 1/2-Mediated Phosphorylation of CCAAT/Enhancer Binding Protein β

Noh

Kim

et al. 2011

Drug Metab Dispos

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“…NRF2 activators have been demonstrated to prevent iron-or diet-induced NASH (22,30). Additionally, heme oxygenase-1 has also been shown to play a protective role in concert with adiponectin against iron-induced injury in hepatocytes (15). Furthermore, the mRNA levels of XBP1, the UPR regulator, were downregulated in the DI mice.…”

Section: Discussionmentioning

confidence: 79%

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

117

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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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“…For adenoassociated virus-ADIPOQ (AAV-ADIPOQ) and adenovirus-ADIPOQ (Adv-ADIPOQ) construction, full-length ADIPOQ cDNA was respectively cloned into the pAAV8-cytomegalovirus (CMV)-multiple cloning sites vector, and a human phosphoglycerate kinase (HPGK) promoter was used to drive ADIPOQ expression. The experimental protocol has been described in detail in prior studies (Lin et al, 2002(Lin et al, , 2010. The recombinant AAV-ADIPOQ (with 1 Â 10 12 viral particles in 50 ml of saline) was injected into a mouse tail vein (i.v.)…”

Section: Ironmentioning

confidence: 99%

“…Although iron chelation therapy is widely used to treat iron-overload conditions, recent data have shown that iron-overload cardiomyopathy is the primary determinant of cardiac complications and survival in these patients (Fraga and Oteiza, 2002). Lin et al (2010) demonstrated that adiponectin exerts its protective effects against iron-induced liver injury through peroxisome proliferator-activated receptor (PPAR)a-dependent heme oxygenase-1 (HO-1) induction. Cheng et al (2012) demonstrated a similar mechanism in which adiponectin exerts a protective effect against acute renal ischemia-reperfusion (I/R) injury through the prostacyclin-PPARa-HO-1 signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Adiponectin Ameliorates Iron-Overload Cardiomyopathy through the PPARα–PGC-1–Dependent Signaling Pathway

et al. 2013

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Adiponectin is a circulating adipose-derived cytokine that may act as an antioxidative and anti-inflammatory protein. Although adiponectin has been reported to exert cytoprotective effects in acute cardiac diseases, its effects on chronic heart failure are less clear. Therefore, we aimed to investigate whether adiponectin would have a beneficial effect in iron-induced chronic heart failure and to elucidate its regulation in cardiomyocytes. Mice were first treated with iron dextran for 4 weeks to induce iron-overload cardiomyopathy. They exhibited decreased survival with impaired left ventricle contractility and decreased serum adiponectin levels. In vivo cardiac adiponectin gene (ADIPOQ) overexpression with adenoassociated virus (AAV)-ADIPOQ ameliorated cardiac iron deposition and restored cardiac function in iron-overloaded mice. In addition, AAV-ADIPOQ-treated iron-overload mice had lower expression of inflammatory markers, including myeloperoxidase activity, monocyte chemotactic protein-1, tumor necrosis factor-a, interleukin-6, and intercellular adhesion molecule-1, than iron-overloaded mice not treated with AAV-ADIPOQ. Our in vitro study showed that adiponectin induced heme oxygenase-1 (HO-1) expression through the peroxisome proliferator-activated receptor (PPAR)a-HO-1 signaling pathway. Furthermore, the adiponectin-mediated beneficial effects were PPARa-dependent as the adiponectinmediated attenuation of iron deposition was abolished in PPARa-knockout mice. Finally, PPARa-HO-1 signaling involved PPARa and peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) binding and nuclear translocation, and their levels were increased by adiponectin therapy. Together, these findings suggest that adiponectin acts as an antiinflammatory signaling molecule and induces the expression of HO-1 through the PPARa-PGC-1 complex-dependent pathway in cardiomyocytes, resulting in the attenuation of iron-induced cardiomyopathy. Using adiponectin for adjuvant therapies in iron-overload cardiac dysfunction may be an option in the future.

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Adiponectin-Mediated Heme Oxygenase-1 Induction Protects Against Iron-Induced Liver Injury via a PPARα-Dependent Mechanism

Cited by 50 publications

References 49 publications

Farnesoid X Receptor Activation by Chenodeoxycholic Acid Induces Detoxifying Enzymes through AMP-Activated Protein Kinase and Extracellular Signal-Regulated Kinase 1/2-Mediated Phosphorylation of CCAAT/Enhancer Binding Protein β

Farnesoid X Receptor Activation by Chenodeoxycholic Acid Induces Detoxifying Enzymes through AMP-Activated Protein Kinase and Extracellular Signal-Regulated Kinase 1/2-Mediated Phosphorylation of CCAAT/Enhancer Binding Protein β

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

Adiponectin Ameliorates Iron-Overload Cardiomyopathy through the PPARα–PGC-1–Dependent Signaling Pathway

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