Homocysteine Induces Monocyte Chemoattractant Protein-1 Expression in Hepatocytes Mediated via Activator Protein-1 Activation

Woo, Connie W.; Siow, Yaw L.; Karmin, O

doi:10.1074/jbc.m707886200

Cited by 32 publications

(34 citation statements)

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“…In another set of experiments, a membrane-permeable SOD mimetic, 4-hydroxy-tetramethyl-piperidine-1-oxyl (TEMPO), was injected (1.5 mmol/kg ip) into rats fed a control or a high-methionine diet 6 h before euthanasia (18). Results from our previous studies demonstrated that hyperhomocysteinemia could be induced in rats by feeding a high-methionine diet (20,48,49). Serum and liver Hcy concentrations were measured by using the IMx Hcy assay based on the fluorescence polarization immunoassay technology (Abbott Diagnostics Division, Abbott Park, IL) (47,48).…”

Section: Methodsmentioning

confidence: 99%

“…Results from our previous studies demonstrated that hyperhomocysteinemia could be induced in rats by feeding a high-methionine diet (20,48,49). Serum and liver Hcy concentrations were measured by using the IMx Hcy assay based on the fluorescence polarization immunoassay technology (Abbott Diagnostics Division, Abbott Park, IL) (47,48). Liver function was examined by measuring the activity of alanine aminotransferase (ALT) in serum samples with an enzymatic kit (Diagnostic Chemical Limited, Charlottetown, PE).…”

Section: Methodsmentioning

confidence: 99%

“…Nuclear proteins were prepared from rat liver as previously described (4,48). Nuclear proteins (10 g) were incubated with excess 32 P-end-labeled oligonucleotides containing a consensus sequence specific for NF-B/DNA binding site (5Ј-AGTTGAGGG-GACTTTCCCAGGC-3Ј) (Promega, Madison, WI).…”

Section: Methodsmentioning

confidence: 99%

“…However, most of reported studies conducted in animal models were focused on its chronic effects in which induction of hyperhomocysteinemia ranges from a few weeks to months (4,5,20,40,44,48). Little information is available regarding the pathophysiological impact during the initial phase of hyperhomocysteinemia.…”

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confidence: 99%

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Induction of hepatic cyclooxygenase-2 by hyperhomocysteinemia via nuclear factor-κB activation

Siow

Karmin

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Wu N, Siow YL, O K. Induction of hepatic cyclooxygenase-2 by hyperhomocysteinemia via nuclear factor-B activation. Am J Physiol Regul Integr Comp Physiol 297: R1086 -R1094, 2009. First published August 5, 2009 doi:10.1152/ajpregu.00293.2009.-Hyperhomocysteinemia, an elevation of blood homocysteine (Hcy), is a metabolic disorder associated with dysfunction of multiple organs. Apart from endothelial dysfunction, Hcy can cause hepatic lipid accumulation and liver injury. However, the mechanism responsible for Hcy-induced liver injury is poorly understood. The aim of this study was to investigate the regulation of cyclooxygenase-2 (COX-2), a proinflammatory factor, expression in the liver during the initial phase of hyperhomocysteinemia. Sprague-Dawley rats were fed a high-methionine diet for 1 or 4 wk. Serum and liver concentrations of Hcy were significantly elevated after 1 or 4 wk of dietary treatment. COX-2 mRNA and protein levels were significantly elevated in the liver of hyperhomocysteinemic rats. The induction of COX-2 expression was more prominent in 1-wk hyperhomocysteinemic rats than that in the 4-wk group. EMSA revealed an activation of NF-B in the same liver tissue in which COX-2 was induced. Administration of a NF-B inhibitor to hyperhomocysteinemic rats effectively abolished hepatic COX-2 expression, inhibited the formation of inflammatory foci, and improved liver function. Further investigation revealed that oxidative stress due to increased superoxide generation was responsible for increased phosphorylation and degradation of IB␣ leading to NF-B activation in the liver. Administration of 4-hydroxy-tetramethyl-piperidine-1-oxyl, an SOD mimetic, to hyperhomocysteinemic rats not only inhibited NF-B activation but also prevented hepatic COX-2 induction and improved liver function. These results suggest that hyperhomocysteinemia-induced COX-2 expression is mediated via NF-B activation. Increased oxidative stress and inflammatory response may contribute to liver injury associated with hyperhomocysteinemia.homocysteine; oxidative stress; inflammatory response; liver injury HYPERHOMOCYSTEINEMIA IS A metabolic disorder characterized by an elevation of total plasma homocysteine (Hcy) levels (26). Epidemiological studies indicate that hyperhomocysteinemia is associated with dysfunction of multiple systems, including cardiovascular and cerebrovascular disease, osteoporosis, glomerulosclerosis, and fatty liver (15,23,33,41,42,50). Hcy is an intermediate amino acid produced in cells through metabolism of methionine to cysteine. The cellular homeostasis of Hcy is tightly regulated and any perturbation of Hcy metabolism causes an increase in its cellular concentrations, leading to hyperhomocysteinemia. Moderately fatty liver (lipid accumulation) has been observed in the autopsy of pediatric patients with hyperhomocysteinemia (25). Hcy, at elevated levels, causes abnormal lipid metabolism, endoplasmic reticulum stress, and oxidative stress in hyperhomocysteinemic rodents (45,46,49). It is increasingly recognized t...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Induction of hepatic cyclooxygenase-2 by hyperhomocysteinemia via nuclear factor-κB activation

Siow

Karmin

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Hyperhomocysteinemia produces complex alterations in the blood vessels including oxidative stress, endothelial dysfunction and inflammatory response via the activation of transcription factor such as nuclear factor-kB (NF-kB) or activiator protein-1(AP-1). Homocysteiene upregulate E-selectin, P-selectin, ICAM-1, V-CAM-1, MCP-1 via activation of NF-kB, and AP-1 Woo et al, 2008). No study has yet evaluated the morphological characteristics of the folate-deficient hippocampus after transient forebrain ischemia.…”

Section: Introductionmentioning

confidence: 99%

Folate Deficiency Enhances Delayed Neuronal Death in the Hippocampus After Transient Cerebral Ischemia

Yoo¹

2012

Advances in the Preclinical Study of Ischemic Stroke

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An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: Regulation of proinflammatory cytokines and hepatic steatosis in mice

Mandrekar¹,

Ambade²,

Lim³

et al. 2011

Hepatology

263

209

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Background and Aims The importance of chemokines in alcoholic liver injury has been implicated. The role of chemokine, monocyte chemoattractant protein-1 (MCP-1) elevated in patients with alcoholic liver disease is not yet understood. Here we evaluate the pathophysiological significance of MCP-1 and its receptor CCR2 in alcoholic liver injury. Methods Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) and MCP-1 deficient (KO) mice for 5 weeks. In vivo and in vitro assays were performed to study the role of MCP-1 in alcoholic liver injury. Results MCP-1 was increased in Kupffer cells as well as hepatocytes of alcohol-fed mice. Alcohol feeding increased serum ALT, in WT and CCR2KO but not MCP-1KO mice. Alcohol-induced liver steatosis and triglyceride was attenuated in alcohol-fed MCP-1KO but high in CCR2KO compared to WT, whereas serum endotoxin was high in alcohol-fed WT and MCP-1KO mice. Expression of liver pro-inflammatory cytokines TNFα, IL-1β, IL-6, KC/IL-8, ICAM-1 and CD68 was induced in alcohol-fed WT mice but inhibited in MCP-1KO, independent of NFκB activation in Kupffer cells. Oxidative stress, but not CYP2E1, was prevented in chronic alcohol-fed MCP-1KO mice compared to WT. Increased expression of PPARα and PPARγ, was accompanied by nuclear translocation, DNA binding and induction of fatty acid metabolism genes, ACOX and CPT-1, in livers of alcohol-fed MCP-1KO mice compared to WT controls. In vitro assays uncovered an inhibitory effect of recombinant MCP-1 on PPARα mRNA and PPRE binding in hepatocytes, independent of CCR2. Conclusion Deficiency of MCP-1 protects mice against alcoholic liver injury, independent of CCR2, by inhibition of pro-inflammatory cytokines and induction of genes related to fatty acid oxidation, linking chemokines to hepatic lipid metabolism.

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Homocysteine Induces Monocyte Chemoattractant Protein-1 Expression in Hepatocytes Mediated via Activator Protein-1 Activation

Cited by 32 publications

References 55 publications

Induction of hepatic cyclooxygenase-2 by hyperhomocysteinemia via nuclear factor-κB activation

Induction of hepatic cyclooxygenase-2 by hyperhomocysteinemia via nuclear factor-κB activation

Folate Deficiency Enhances Delayed Neuronal Death in the Hippocampus After Transient Cerebral Ischemia

An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: Regulation of proinflammatory cytokines and hepatic steatosis in mice

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