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Yi P.,Molecular and Cellular Physiology | Pang J.,Microbiology and Immunology | Alexander J.S.,Molecular and Cellular Physiology | Rivera C.,Review Centre
BMC Physiology | Year: 2013

Background: Postprandial lipidemia is important in the development of coronary artery disease (CAD). Consumption of a meal high in monounsaturated fat was correlated with acute impairment of endothelial function. However, the mechanisms underlying impaired endothelial function in the postprandial state have not yet been elucidated. The effects of polyunsaturated fat (corn oil) and monounsaturated fat (olive oil) on vascular dysfunction in intestinal postcapillary venules and arterioles were examined in wild-type (WT) mice, mice genetically deficient in TLR4 (TLR4§ssup§-/-§esup§) and mice pre-treated with antibiotics by intravital microscopy which was performed 1.0, 1.5, 2.0, 2.5 hours after oil administration. After intravital microscopy, samples of jejunum were therefore collected to test TLR4, pNF-kB p65 and SIRT1 protein expression by western blotting. Results: Our findings showed that feeding mono-unsaturated olive oil or polyunsaturated corn oil promoted leukocyte and platelet trafficking in the gut microvasculature, and impaired endothelium-dependent arteriolar vasodilator responses during postprandial lipidemia. The expression of TLR4, pNF-kB p65 was significantly increased in mice gavaged with olive oil at 2 h and was significantly reduced in mice gavaged for 7 days with antibiotics and in TLR4 knockout (TLR4§ssup§-/- §esup§) mice. At the same time, SIRT1 protein expression is diminished by feeding olive oil for 2 h, a phenomenon that is attenuated in mice pre-treated with antibiotics and in TLR4§ssup§-/-§esup§ mice. Corn oil treated mice exhibited a pattern of response similar to olive oil. Conclusions: Dietary oils may be negative regulators of SIRT1 which activate the innate immune response through the endotoxin/TLR4 axis. Our findings establish a link between innate immunity (i.e. the endotoxin/TLR4 axis) and epigenetic controls mediated by SIRT1 in the genesis of diet associated vascular stress. © 2013 Yi et al.; licensee BioMed Central Ltd. Source

Pandey S.,Texas Tech University Health Sciences Center | Simmons G.E.,University of Texas Southwestern Medical Center | Malyarchuk S.,Molecular and Cellular Physiology | Calhoun T.N.,Molecular and Cellular Physiology | Pruitt K.,Texas Tech University Health Sciences Center
Genes and Cancer | Year: 2015

Methyl-CpG-binding protein-2 (MeCP2) regulates gene expression by recruiting SWI/SNF DNA helicase/ATPase (ATRX) and Histone Deacetylase-1 (HDAC1) to methylated gene regions and modulates heterochromatin association by interacting with Heterochromatin protein-1. As MeCP2 contributes to tumor suppressor gene silencing and its mutation causes Rett Syndrome, we investigated how novel posttranslational- modification contributes to its function. Herein we report that upon pharmacological inhibition of SIRT1 in RKO colon and MCF-7 breast cancer cells, endogenous MeCP2 is acetylated at sites critical for binding to DNA and transcriptional regulators. We created an acetylation mimetic mutation in MeCP2 and found it to possess decreased binding to ATRX and HDAC1. Conditions inducing MeCP2 acetylation do not alter its promoter occupancy at a subset of target genes analyzed, but do cause decreased binding to ATRX and HDAC1. We also report here that a specific inhibitor of SIRT1, IV, can be used to selectively decrease H3K27me3 repressive marks on a subset of repressed target gene promoters analyzed. Lastly, we show that RKO cells over-expressing MeCP2 mutant show reduced proliferation compared to those overexpressing MeCP2-wildtype. Our study demonstrates the importance of acetylated lysine residues and suggests their key role in regulating MeCP2 function and its ability to bind transcriptional regulators. © 2015, Impact Journals LLC. All rights reserved. Source

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