Oxidative stress-associated rise of hepatic protein glycation increases inflammatory liver injury in uncoupling protein-2 deficient mice

Kuhla, Angela; Hettwer, Christina; Menger, Michael D.; Vollmar, Brigitte

doi:10.1038/labinvest.2010.84

Cited by 20 publications

(16 citation statements)

References 56 publications

(57 reference statements)

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“…UCP2, a mitochondrial anion carrier protein [39], plays a key role as a moderator of ROS production in hepatic metabolism [40, 41]. Accordingly, UCP2 −/− mice showed increased ROS formation [42]. In ACE2 −/y mice, an increase in intracellular lipids in the liver may lead to a mitochondria overload, followed by an increase in ROS production during the β -oxidation of lipids, which in turn stimulates the expression of UCP2 to combat this imbalance.…”

Section: Discussionmentioning

confidence: 99%

CD36/Sirtuin 1 Axis Impairment Contributes to Hepatic Steatosis in ACE2‐Deficient Mice

Nunes-Souza

Alenina

Qadri

et al. 2016

Oxidative Medicine and Cellular Longevity

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Background and Aims. Angiotensin converting enzyme 2 (ACE2) is an important component of the renin-angiotensin system. Since angiotensin peptides have been shown to be involved in hepatic steatosis, we aimed to evaluate the hepatic lipid profile in ACE2-deficient (ACE2−/y) mice. Methods. Male C57BL/6 and ACE2−/y mice were analyzed at the age of 3 and 6 months for alterations in the lipid profiles of plasma, faeces, and liver and for hepatic steatosis. Results. ACE2−/y mice showed lower body weight and white adipose tissue at all ages investigated. Moreover, these mice had lower levels of cholesterol, triglycerides, and nonesterified fatty acids in plasma. Strikingly, ACE2−/y mice showed high deposition of lipids in the liver. Expression of CD36, a protein involved in the uptake of triglycerides in liver, was increased in ACE2−/y mice. Concurrently, these mice exhibited an increase in hepatic oxidative stress, evidenced by increased lipid peroxidation and expression of uncoupling protein 2, and downregulation of sirtuin 1. ACE2−/y mice also showed impairments in glucose metabolism and insulin signaling in the liver. Conclusions. Deletion of ACE2 causes CD36/sirtuin 1 axis impairment and thereby interferes with lipid homeostasis, leading to lipodystrophy and steatosis.

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Section: Discussionmentioning

confidence: 99%

CD36/Sirtuin 1 Axis Impairment Contributes to Hepatic Steatosis in ACE2‐Deficient Mice

Nunes-Souza

Alenina

Qadri

et al. 2016

Oxidative Medicine and Cellular Longevity

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“…Additionally, emerging evidence suggests that the up-regulation of mitochondrial UCPs may provide another means of constraining oxidant production during mitochondrial respiration 11,27-29. Li et al30 reported that overexpression of UCP2 is associated with protection from ROS-induced toxicity in pancreatic β-cells.…”

Section: Discussionmentioning

confidence: 99%

Role of UCP2 Expression after Hepatic Warm Ischemia-Reperfusion in the Rat

Ninomiya¹,

Shirabe²,

Shimada³

et al. 2011

Gut Liver

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Background/AimsThe role of uncoupling protein-2 (UCP2) in the liver is currently unclear. Emerging evidence suggests a relationship between UCP2 and oxidative stress. In the present study, we tested the hypothesis that UCP2 expression in the liver might change during warm ischemia-reperfusion (I/R) according to oxidative stress.MethodsWistar rats were subjected to 40 (short ischemia) or 90 (long ischemia) minutes of partial lobar ischemia followed by 4 hours of reperfusion. UCP2 expression in the ischemic and nonischemic lobes was assessed using reverse transcription-polymerase chain reaction and immunohistochemistry. Malondialdehyde concentrations in the liver tissue were also compared.ResultsMalondialdehyde concentrations in the ischemic lobes were significantly higher in the long ischemia group. In the ischemic lobes of the short ischemia group, UCP2 protein expression was induced in hepatocytes, which did not express the protein prior to treatment, and the expression levels were higher than in the long ischemia group. The intralobular distribution of UCP2 seemed to correlate inversely with that of the necrotic area. UCP2 expression was observed, even in nonischemic lobes with similar intralobular heterogeneity.ConclusionsUCP2 was induced in hepatocytes after warm I/R. Although the primitive role of UCP2 expression may be cytoprotective in nature, its actual protective effect in hepatic I/R may be minimal

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“…Kuhla and colleagues showed that mice deficient in Uncoupling Protein 2 (UCP2) demonstrated increased oxidative stress (as determined by lower ratio of GSH to GSSG) [47]. In parallel, increased oxidative stress was linked to reduced activity of glyoxalase 1 (Glo1); Glo1 is a chief enzyme responsible for the detoxification of major AGE precursors methylglyoxal and glyoxal [48].…”

Section: Rage and Oxidative Stress: Evidence From In Vivo Modelsmentioning

confidence: 99%

“…In parallel, increased oxidative stress was linked to reduced activity of glyoxalase 1 (Glo1); Glo1 is a chief enzyme responsible for the detoxification of major AGE precursors methylglyoxal and glyoxal [48]. The authors showed that AGE and RAGE levels in the livers of UCP2 null mice were increased and that levels of the soluble RAGE decoy, soluble RAGE (sRAGE), were greatly reduced in these animals compared to the wild-type control mice [47]. When liver injury was induced in these animals, administration of recombinant soluble RAGE exerted protection.…”

Section: Rage and Oxidative Stress: Evidence From In Vivo Modelsmentioning

confidence: 99%

“…Such release and availability of these RAGE ligands may further amplify RAGE-dependent oxidative stress. Furthermore, as illustrated by enlightening experiments in UCP2 null mice discussed above, oxidative stress may beget further AGE production [47], thereby fueling the engines of oxidative and cellular stress and tissue damage. Additional evidence supporting this premise is deduced from the work of Anderson and Heinecke in which they showed that phagocyte-derived oxidants from NADPH oxidase are required for the production of CML AGEs during inflammation [67].…”

Section: Summary and Perspectivesmentioning

confidence: 99%

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Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond

Daffu

Pozo

O’Shea

et al. 2013

IJMS

178

138

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Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE) mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS) and consequent downstream signal transduction and regulation of gene expression. The primary mechanism by which RAGE generates oxidative stress is via activation of NADPH oxidase; amplification mechanisms in the mitochondria may further drive ROS production. Recent studies indicating that the cytoplasmic domain of RAGE binds to the formin mDia1 provide further support for the critical roles of this pathway in oxidative stress; mDia1 was required for activation of rac1 and NADPH oxidase in primary murine aortic smooth muscle cells treated with RAGE ligand S100B. In vivo, in multiple distinct disease models in animals, RAGE action generates oxidative stress and modulates cellular/tissue fate in range of disorders, such as in myocardial ischemia, atherosclerosis, and aneurysm formation. Blockade or genetic deletion of RAGE was shown to be protective in these settings. Indeed, beyond cardiovascular disease, evidence is accruing in human subjects linking levels of RAGE ligands and soluble RAGE to oxidative stress in disorders such as doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, diabetes, preeclampsia, rheumatoid arthritis and pulmonary fibrosis. Blockade of RAGE signal transduction may be a key strategy for the prevention of the deleterious consequences of oxidative stress, particularly in chronic disease.

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Oxidative stress-associated rise of hepatic protein glycation increases inflammatory liver injury in uncoupling protein-2 deficient mice

Cited by 20 publications

References 56 publications

CD36/Sirtuin 1 Axis Impairment Contributes to Hepatic Steatosis in ACE2‐Deficient Mice

CD36/Sirtuin 1 Axis Impairment Contributes to Hepatic Steatosis in ACE2‐Deficient Mice

Role of UCP2 Expression after Hepatic Warm Ischemia-Reperfusion in the Rat

Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond

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