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      Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

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          Abstract

          Metabolomics studies hold promise for discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. A metabolomics approach was used to generate unbiased small molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine, namely choline, trimethylamine N-oxide (TMAO), and betaine, were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted up-regulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases (FMOs), an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidemic mice. Discovery of a relationship between gut flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for development of both novel diagnostic tests and therapeutic approaches for atherosclerotic heart disease.

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          Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

          Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
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            An integrative genomics approach to infer causal associations between gene expression and disease.

            A key goal of biomedical research is to elucidate the complex network of gene interactions underlying complex traits such as common human diseases. Here we detail a multistep procedure for identifying potential key drivers of complex traits that integrates DNA-variation and gene-expression data with other complex trait data in segregating mouse populations. Ordering gene expression traits relative to one another and relative to other complex traits is achieved by systematically testing whether variations in DNA that lead to variations in relative transcript abundances statistically support an independent, causative or reactive function relative to the complex traits under consideration. We show that this approach can predict transcriptional responses to single gene-perturbation experiments using gene-expression data in the context of a segregating mouse population. We also demonstrate the utility of this approach by identifying and experimentally validating the involvement of three new genes in susceptibility to obesity.
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              Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages.

              Modification of low density lipoprotein (LDL) can result in the avid uptake of these lipoproteins via a family of macrophage transmembrane proteins referred to as scavenger receptors (SRs). The genetic inactivation of either of two SR family members, SR-A or CD36, has been shown previously to reduce oxidized LDL uptake in vitro and atherosclerotic lesions in mice. Several other SRs are reported to bind modified LDL, but their contribution to macrophage lipid accumulation is uncertain. We generated mice lacking both SR-A and CD36 to determine their combined impact on macrophage lipid uptake and to assess the contribution of other SRs to this process. We show that SR-A and CD36 account for 75-90% of degradation of LDL modified by acetylation or oxidation. Cholesteryl ester derived from modified lipoproteins fails to accumulate in macrophages taken from the double null mice, as assessed by histochemistry and gas chromatography-mass spectrometry. These results demonstrate that SR-A and CD36 are responsible for the preponderance of modified LDL uptake in macrophages and that other scavenger receptors do not compensate for their absence.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                4 March 2011
                7 April 2011
                7 October 2011
                : 472
                : 7341
                : 57-63
                Affiliations
                [1 ]Department of Cell Biology, Cleveland Clinic, Cleveland, OH 44195
                [2 ]Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, OH 44195
                [3 ]Department of Medicine/Division of Cardiology, BH-307 Center for the Health Sciences, University of California, Los Angeles, CA 90095
                [4 ]Department of Mathematics, Cleveland State University, Cleveland, OH 44115
                [5 ]Bariatric and Metabolic Institute, Cleveland Clinic, Cleveland, OH 44195
                [6 ]Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195
                [7 ]Department of Preventive Medicine and Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089
                Author notes
                [8 ]To whom correspondence should be addressed: Cleveland Clinic, 9500 Euclid Avenue, NE-10, Cleveland, OH 44195 Tel: 216-445-9763, Fax: 216-636-0392, hazens@ 123456ccf.org
                Article
                nihpa271797
                10.1038/nature09922
                3086762
                21475195
                9c0a22e0-1a34-4b91-8b61-811d25ab31c8

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Center for Research Resources : NCRR
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: UL1 RR024989-05 ||RR
                Funded by: National Center for Research Resources : NCRR
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: T32 DK007789-10 ||DK
                Funded by: National Center for Research Resources : NCRR
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 HL103931-02 ||HL
                Funded by: National Center for Research Resources : NCRR
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 HL103866-02 ||HL
                Funded by: National Center for Research Resources : NCRR
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 DK080732-02 ||DK
                Funded by: National Center for Research Resources : NCRR
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: P01 HL098055-02 ||HL
                Funded by: National Center for Research Resources : NCRR
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: P01 HL087018-02 ||HL
                Funded by: National Center for Research Resources : NCRR
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: P01 HL076491-05 ||HL
                Funded by: National Center for Research Resources : NCRR
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: P01 HL030568-27 ||HL
                Funded by: National Center for Research Resources : NCRR
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: P01 HL028481-26A1 ||HL
                Funded by: National Center for Research Resources : NCRR
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: K99 HL102223-01A1 ||HL
                Categories
                Article

                Uncategorized
                choline,diet,phospholipid,intestinal microbiota,atherosclerosis,metabolomics
                Uncategorized
                choline, diet, phospholipid, intestinal microbiota, atherosclerosis, metabolomics

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