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      Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis

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          Abstract

          Despite the well-documented association between insulin resistance and cardiovascular disease, the key targets of insulin relevant to the development of cardiovascular disease are not known. Here, using non-biased profiling methods, we identify the enzyme flavin-containing monooxygenase 3 ( Fmo3) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans. We show that FMO3 is suppressed by insulin in vitro, increased in obese/insulin resistant male mice and increased in obese/insulin-resistant humans. Knockdown of FMO3 in insulin-resistant mice suppresses FoxO1, a central node for metabolic control, and entirely prevents the development of hyperglycaemia, hyperlipidemia and atherosclerosis. Taken together, these data indicate that FMO3 is required for FoxO1 expression and the development of metabolic dysfunction.

          Abstract

          The hepatic enzyme FMO3 has been linked to atherosclerosis. Here the authors show that FMO3 is upregulated in various models of diabetes and link FMO3 with key transcriptional regulators of hepatic glucose and cholesterol synthesis, thus proposing a mechanistic connection between diabetes and atherosclerosis.

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          Most cited references32

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          Cardiovascular morbidity and mortality associated with the metabolic syndrome.

          To estimate the prevalence of and the cardiovascular risk associated with the metabolic syndrome using the new definition proposed by the World Health Organization A total of 4,483 subjects aged 35-70 years participating in a large family study of type 2 diabetes in Finland and Sweden (the Botnia study) were included in the analysis of cardiovascular risk associated with the metabolic syndrome. In subjects who had type 2 diabetes (n = 1,697), impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) (n = 798) or insulin-resistance with normal glucose tolerance (NGT) (n = 1,988), the metabolic syndrome was defined as presence of at least two of the following risk factors: obesity, hypertension, dyslipidemia, or microalbuminuria. Cardiovascular mortality was assessed in 3,606 subjects with a median follow-up of 6.9 years. In women and men, respectively, the metabolic syndrome was seen in 10 and 15% of subjects with NGT, 42 and 64% of those with IFG/IGT, and 78 and 84% of those with type 2 diabetes. The risk for coronary heart disease and stroke was increased threefold in subjects with the syndrome (P < 0.001). Cardiovascular mortality was markedly increased in subjects with the metabolic syndrome (12.0 vs. 2.2%, P < 0.001). Of the individual components of the metabolic syndrome, microalbuminuria conferred the strongest risk of cardiovascular death (RR 2.80; P = 0.002). The WHO definition of the metabolic syndrome identifies subjects with increased cardiovascular morbidity and mortality and offers a tool for comparison of results from diferent studies.
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            Diabetes and Cardiovascular Disease: A Statement for Healthcare Professionals From the American Heart Association

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              Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance.

              Animal cells control their membrane lipid composition within narrow limits, but the sensing mechanisms underlying this control are largely unknown. Recent studies disclosed a protein network that controls the level of one lipid-cholesterol. This network resides in the endoplasmic reticulum (ER). A key component is Scap, a tetrameric ER membrane protein that binds cholesterol. Cholesterol binding prevents Scap from transporting SREBPs to the Golgi for activation. Using a new method to purify ER membranes from cultured cells, we show that Scap responds cooperatively to ER cholesterol levels. When ER cholesterol exceeds 5% of total ER lipids (molar basis), SREBP-2 transport is abruptly blocked. Transport resumes when ER cholesterol falls below the 5% threshold. The 5% threshold is lowered to 3% when cells overexpress Insig-1, a Scap-binding protein. Cooperative interactions between cholesterol, Scap, and Insig create a sensitive switch that controls the cholesterol composition of cell membranes with remarkable precision.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                07 April 2015
                : 6
                : 6498
                Affiliations
                [1 ]Division of Endocrinology, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts, USA
                [2 ]Isis Pharmaceuticals , Carlsbad, California, USA
                [3 ]Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts, USA
                [4 ]Metabolic Disease Program and Diabetes and Obesity Center, Sanford-Burnham Medical Research Institute , Orlando, Florida, USA
                [5 ]Broad Institute , Cambridge, Massachusetts, USA
                [6 ]Department of Endocrinology and Nutrition, Hospital Carlos III , Madrid 28029, Spain
                [7 ]Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ) , Madrid 28046, Spain
                [8 ]Department of Endocrinology and Nutrition, Hospital Clínico San Carlos , Madrid, 28040, Spain
                [9 ]Medical School, Complutense University , Madrid, 28040, Spain
                [10 ]Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdiSSC) , Madrid, 28040, Spain
                [11 ]Department of Surgery. Hospital Clínico San Carlos , Madrid, 28040, Spain
                [12 ]List of members and affiliations appears at the end of the paper.
                Author notes
                [*]

                Present address: Department of Microbiology, Hospital Universitario Ramón y Cajal-IRYCIS & CIBERESP, Madrid 28034, Spain

                [†]

                Present address: Department of Endocrinology and Nutrition, Hospital Universitario La Paz, Madrid 28046, Spain

                Article
                ncomms7498
                10.1038/ncomms7498
                4391288
                25849138
                1b85222a-46fd-4f46-abde-12c18e2f2e69
                Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 01 December 2014
                : 03 February 2015
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