Metabolomic analysis revealed the role of DNA methylation in the balance of arachidonic acid metabolism and endothelial activation

Xue, Shanshan; He, Jinlong; Zhang, Xu; Liu, Yajin; Xue, Fengxia; Ai, Ding; Zhu, Yi

doi:10.1016/j.bbalip.2015.07.001

Cited by 15 publications

(16 citation statements)

References 36 publications

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“…The residue was dissolved in 100 μL of 30% acetonitrile. Ultra‐high‐performance liquid chromatography (Waters, Milford, MA) involved a 5500 QTRAP hybrid triple‐quadruple linear ion‐trap mass spectrometer (AB Sciex, Foster City, CA) equipped with a Turbo Ion Spray electrospray ionization source (liquid chromatography/tandem mass spectrometry) as described …”

Section: Methodsmentioning

confidence: 99%

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Hyperhomocysteinemia activates the aryl hydrocarbon receptor/CD36 pathway to promote hepatic steatosis in mice

et al. 2016

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Hyperhomocysteinemia (HHcy) is associated with liver diseases such as fatty liver and hepatic fibrosis; however, the underlying mechanism is still largely unknown. The current study aimed to explore the signaling pathway involved in HHcyinduced hepatic steatosis (HS). C57BL/6 mice were fed a high-methionine diet (HMD) for 4 and 8 weeks to establish the HHcy mouse model. Compared to a chow diet, the HMD induced hepatic steatosis and elevated hepatic expression of CD36, a fatty acid transport protein. The increased CD36 expression was associated with activation of the aryl hydrocarbon receptor (AHR). In primary cultured hepatocytes, high levels of homocysteine (Hcy) treatment up-regulated CD36 and increased subsequent lipid uptake; both were significantly attenuated by small interfering RNA (siRNA) knockdown of CD36 and AHR. Chromatin immunoprecipitation assay revealed that Hcy promoted binding of AHR to the CD36 promoter, and transient transfection assay demonstrated markedly increased activity of the AHR response element by Hcy, which was ligand dependent. Mass spectrometry revealed significantly increased hepatic content of lipoxin A 4 (LXA 4 ), a metabolite of arachidonic acid, in HMD-fed mice. Furthermore, overexpression of 15-oxoprostaglandin 13-reductase 1, a LXA 4 inactivation enzyme, inhibited Hcy-induced AHR activation, lipid uptake, and lipid accumulation. Moreover, LXA 4 -induced up-regulation of CD36 and lipid uptake was inhibited by AHR siRNA in vitro in hepatocytes. Finally, treatment with an AHR antagonist reversed HHcy-induced lipid accumulation by inhibiting the AHR-CD36 pathway in mice. Conclusion: HHcy activates the AHR-CD36 pathway by increasing hepatic LXA 4 content, which results in hepatic steatosis. (HEPATOLOGY 2016;64:92-105) N onalcoholic fatty liver disease (NAFLD) is an increasingly recognized disease status that involves a spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Obesity, type 2 diabetes mellitus, and hyperlipidemia are important risk factors of NAFLD, but the pathogenesis of NAFLD is poorly understood. (1) Homocysteine (Hcy) is a toxic Abbreviations: 15d-PGJ2, 15-deoxy-D12,14-prostaglandin J2; 15-oxo-ETE, 15-oxo-eicosatetraenoic acid; 3-MC, 3

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Section: Methodsmentioning

confidence: 99%

“…Several metabolites of arachidonic acids (AAs) have been identified as novel endogenous ligands of AHR . Our previous studies showed that HHcy was associated with AA metabolism . AHR activation has a wide variety of toxic and biological effects.…”

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Hyperhomocysteinemia activates the aryl hydrocarbon receptor/CD36 pathway to promote hepatic steatosis in mice

et al. 2016

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“…Metabolomics can be a useful tool in studying AAP‐induced side effects due to its ability to represent the echo of complex lifestyles of individuals interacting with genetic and environmental factors such as medications . The changes in the metabolome secondary to AAP‐induced insulin resistance may be the functional consequence of epigenetic changes, and therefore combining these two molecular approaches may aid in understanding the pathways involved in AAP‐induced insulin resistance …”

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confidence: 99%

Gene‐specific DNA methylation may mediate atypical antipsychotic‐induced insulin resistance

et al. 2016

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Objectives Atypical Antipsychotics (AAPs) carry a significant risk of cardiometabolic side effects including insulin resistance. It is thought that the insulin resistance resulting from the use of AAP may be associated with changes in DNA methylation. We aimed to identify and validate a candidate gene associated with AAP-induced insulin resistance by using a multi-step approach that included an epigenome-wide association study (EWAS) and validation with site-specific methylation and metabolomics data. Methods Bipolar subjects treated with AAPs or lithium monotherapy were recruited for a cross-sectional visit to analyze peripheral blood DNA methylation and insulin resistance. Epigenome-wide DNA methylation was analyzed in a discovery sample (n=48) using the Illumina 450K BeadChip. Validation analyses of the epigenome-wide findings occurred in a separate sample (n=72) using site-specific methylation with pyrosequencing and untargeted metabolomics data. Regression analyses were conducted controlling for known confounders in all analyses and a mediation analysis was performed to investigate if AAP-induced insulin resistance occurs through changes in DNA methylation. Results A differentially methylated probe associated with insulin resistance was discovered and validated in the Fatty Acyl CoA Reductase 2 (FAR2) gene of Chromosome 12. Functional associations of this DNA methylation site on untargeted phospholipid-related metabolites were also detected. Our results identified a mediating effect of this FAR2 methylation site on AAP-induced insulin resistance. Conclusions Going forward, prospective, longitudinal studies assessing comprehensive changes in FAR2 DNA methylation, expression, and lipid metabolism before and after AAP treatment are required to assess its potential role in the development of insulin resistance.

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“…Real‐time PCR with primers was conducted as previously described (Xue et al, ). Total RNA from cells or mouse tissues was isolated by use of RNAiso Plus reagent (Takara Bio, Japan) as instructed and reverse‐transcribed by using the first‐strand cDNA synthesis kit (Thermo Scientific, Rockford, IL, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis was performed as described previously (Xue et al, ). Cell lysates were resolved by 10% SDS‐PAGE, then transferred to a PVDF membrane, which was incubated with primary antibodies, then horseradish peroxidase‐conjugated secondary antibody.…”

Section: Methodsmentioning

confidence: 99%

Metabolic profiling of murine plasma reveals eicosapentaenoic acid metabolites protecting against endothelial activation and atherosclerosis

Liu

Fang

Zhang

et al. 2017

British J Pharmacology

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Metabolomic analysis revealed the role of DNA methylation in the balance of arachidonic acid metabolism and endothelial activation

Cited by 15 publications

References 36 publications

Hyperhomocysteinemia activates the aryl hydrocarbon receptor/CD36 pathway to promote hepatic steatosis in mice

Hyperhomocysteinemia activates the aryl hydrocarbon receptor/CD36 pathway to promote hepatic steatosis in mice

Gene‐specific DNA methylation may mediate atypical antipsychotic‐induced insulin resistance

Metabolic profiling of murine plasma reveals eicosapentaenoic acid metabolites protecting against endothelial activation and atherosclerosis

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