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      PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis

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          Abstract

          In mammals, the liver plays a central role in maintaining carbohydrate and lipid homeostasis by acting both as a major source and a major sink of glucose and lipids. In particular, when dietary carbohydrates are in excess, the liver converts them to lipids via de novo lipogenesis. The molecular checkpoints regulating the balance between carbohydrate and lipid homeostasis, however, are not fully understood. Here we identify PPP2R5C, a regulatory subunit of PP2A, as a novel modulator of liver metabolism in postprandial physiology. Inactivation of PPP2R5C in isolated hepatocytes leads to increased glucose uptake and increased de novo lipogenesis. These phenotypes are reiterated in vivo, where hepatocyte specific PPP2R5C knockdown yields mice with improved systemic glucose tolerance and insulin sensitivity, but elevated circulating triglyceride levels. We show that modulation of PPP2R5C levels leads to alterations in AMPK and SREBP-1 activity. We find that hepatic levels of PPP2R5C are elevated in human diabetic patients, and correlate with obesity and insulin resistance in these subjects. In sum, our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state.

          Author Summary

          After a meal, dietary glucose travels through the hepatic portal vein to the liver. A substantial part of this glucose is taken up by liver, which converts it to glycogen which is stored, and lipids which are in part stored and in part secreted as VLDL particles. The rest of the organs receive whatever glucose the liver leaves in circulation, plus the secreted lipids. Hence the liver plays a crucial role in determining the balance of sugar versus lipids in the body after a meal. This balance is very important, because too much glucose in circulation leads to diabetic complications whereas too much VLDL increases risk of atherosclerosis. Little is known about how the liver strikes this balance. We identify here a phosphatase—the PP2A holoenzyme containing the PPP2R5C regulatory subunit—as a regulator of this process. We find that knockdown of PPP2R5C in mouse liver specifically causes it to uptake elevated levels of glucose, and secrete elevated levels of VLDL into circulation. This leads to a phenotype of improved glucose tolerance and insulin sensitivity. The prediction from these functional studies in mice is that elevated levels of PPP2R5C expression should lead to insulin resistance. Indeed, we find that PPP2R5C expression levels are elevated in diabetic patients, or healthy controls with visceral obesity, raising the possibility that dysregulation of PPP2R5C expression in humans may contribute towards metabolic dysfunction.

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          Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy.

          Tissues from rhesus monkeys were screened by PCR for the presence of sequences homologous to known adeno-associated virus (AAV) serotypes 1-6. DNA spanning entire rep-cap ORFs from two novel AAVs, called AAV7 and AAV8, were isolated. Sequence comparisons among these and previously described AAVs revealed the greatest divergence in capsid proteins. AAV7 and AAV8 were not neutralized by heterologous antisera raised to the other serotypes. Neutralizing antibodies to AAV7 and AAV8 were rare in human serum and, when present, were low in activity. Vectors formed with capsids from AAV7 and AAV8 were generated by using rep and inverted terminal repeats (ITRs) from AAV2 and were compared with similarly constructed vectors made from capsids of AAV1, AAV2, and AAV5. Murine models of skeletal muscle and liver-directed gene transfer were used to evaluate relative vector performance. AAV7 vectors demonstrated efficiencies of transgene expression in skeletal muscle equivalent to that observed with AAV1, the most efficient known serotype for this application. In liver, transgene expression was 10- to 100-fold higher with AAV8 than observed with other serotypes. This improved efficiency correlated with increased persistence of vector DNA and higher number of transduced hepatocytes. The efficiency of AAV8 vector for liver-directed gene transfer of factor IX was not impacted by preimmunization with the other AAV serotypes. Vectors based on these novel, nonhuman primate AAVs should be considered for human gene therapy because of low reactivity to antibodies directed to human AAVs and because gene transfer efficiency in muscle was similar to that obtained with the best known serotype, whereas, in liver, gene transfer was substantially higher than previously described.
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            Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome--an allostatic perspective.

            While the link between obesity and type 2 diabetes is clear on an epidemiological level, the underlying mechanism linking these two common disorders is not as clearly understood. One hypothesis linking obesity to type 2 diabetes is the adipose tissue expandability hypothesis. The adipose tissue expandability hypothesis states that a failure in the capacity for adipose tissue expansion, rather than obesity per se is the key factor linking positive energy balance and type 2 diabetes. All individuals possess a maximum capacity for adipose expansion which is determined by both genetic and environmental factors. Once the adipose tissue expansion limit is reached, adipose tissue ceases to store energy efficiently and lipids begin to accumulate in other tissues. Ectopic lipid accumulation in non-adipocyte cells causes lipotoxic insults including insulin resistance, apoptosis and inflammation. This article discusses the links between adipokines, inflammation, adipose tissue expandability and lipotoxicity. Finally, we will discuss how considering the concept of allostasis may enable a better understanding of how diabetes develops and allow the rational design of new anti diabetic treatments. Copyright (c) 2009 Elsevier B.V. All rights reserved.
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              Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome.

              Insulin resistance is a key feature of the metabolic syndrome and often progresses to type 2 diabetes. Both insulin resistance and type 2 diabetes are characterized by dyslipidemia, which is an important and common risk factor for cardiovascular disease. Diabetic dyslipidemia is a cluster of potentially atherogenic lipid and lipoprotein abnormalities that are metabolically interrelated. Recent evidence suggests that a fundamental defect is an overproduction of large very low-density lipoprotein (VLDL) particles, which initiates a sequence of lipoprotein changes, resulting in higher levels of remnant particles, smaller LDL, and lower levels of high-density liporotein (HDL) cholesterol. These atherogenic lipid abnormalities precede the diagnosis of type 2 diabetes by several years, and it is thus important to elucidate the mechanisms involved in the overproduction of large VLDL particles. Here, we review the pathophysiology of VLDL biosynthesis and metabolism in the metabolic syndrome. We also review recent research investigating the relation between hepatic accumulation of lipids and insulin resistance, and sources of fatty acids for liver fat and VLDL biosynthesis. Finally, we briefly discuss current treatments for lipid management of dyslipidemia and potential future therapeutic targets.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                6 October 2015
                October 2015
                : 11
                : 10
                : e1005561
                Affiliations
                [1 ]German Cancer Research Center (DKFZ), Heidelberg, Germany
                [2 ]Department of Medicine, University of Leipzig, Leipzig, Germany
                [3 ]Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili. Universitat, Rovira i Virgili, CIBERDEM, Tarragona, Spain
                [4 ]Hospital Universitari de Tarragona Joan XXIII. Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgili, CIBERDEM, Tarragona, Spain
                [5 ]Institute for Research in Biomedicine (IRB Barcelona), Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, and CIBERDEM, Barcelona, , Spain
                [6 ]Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany, and Joint Heidelberg-IDC Translational Diabetes Program, University Hospital Heidelberg, Heidelberg, Germany
                [7 ]Chair Molecular Metabolic Control, Medical Faculty, Technical University Munich, Germany
                UCSF Diabetes Center, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YSC MB SH MBD AAT. Performed the experiments: YSC OS NK AD KS SFV JJV AZ MB SH MBD AAT. Analyzed the data: YSC OS NK AD KS SFV JJV AZ MB SH MBD AAT. Contributed reagents/materials/analysis tools: YSC OS NK AD KS SFV JJV AZ MB SH MBD AAT. Wrote the paper: YSC AZ SH MBD AAT.

                ‡ ABD and AAT are joint senior co-authors.

                Article
                PGENETICS-D-15-00084
                10.1371/journal.pgen.1005561
                4595073
                26440364
                02b1875c-6c5b-41ff-972f-9c888c15fecd
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 13 January 2015
                : 10 September 2015
                Page count
                Figures: 7, Tables: 0, Pages: 27
                Funding
                This work was supported in part by a Fritz Thyssen Stiftung grant (10.10.2.158) to AAT, a Deutsche Forschungsgemeinschaft grant (He3260/4-2) to SH, a joint Helmholtz Portfolio Topic grant “Metabolic Dysfunction” to SH and AAT, and the SFB 1118 funded by the Deutsche Forschungsgemeinschaft. The Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM) (CB07708/0012) is an initiative of the Instituto de Salud Carlos III. SFV acknowledges support from the “Miguel Servet” tenure-track program (CP10/00438) from the Fondo de Investigación Sanitaria (FIS) co-financed by the European Regional Development Fund (ERDF) and from from the Spanish Ministry of Economy and Competitiveness (SAF2012-36186). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Genetics
                Genetics

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