| Literature DB >> 24995976 |
Alexander Jais1, Elisa Einwallner1, Omar Sharif2, Klaus Gossens3, Tess Tsai-Hsiu Lu3, Selma M Soyal4, David Medgyesi5, Daniel Neureiter4, Jamile Paier-Pourani6, Kevin Dalgaard3, J Catharina Duvigneau7, Josefine Lindroos-Christensen1, Thea-Christin Zapf1, Sabine Amann1, Simona Saluzzo2, Florian Jantscher1, Patricia Stiedl8, Jelena Todoric1, Rui Martins2, Hannes Oberkofler4, Simone Müller7, Cornelia Hauser-Kronberger4, Lukas Kenner9, Emilio Casanova10, Hedwig Sutterlüty-Fall1, Martin Bilban1, Karl Miller11, Andrey V Kozlov6, Franz Krempler11, Sylvia Knapp2, Carey N Lumeng12, Wolfgang Patsch4, Oswald Wagner1, J Andrew Pospisilik13, Harald Esterbauer14.
Abstract
Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and the molecular determinants of "healthy" versus "unhealthy" obesity remain ill-defined. Chronic metabolic inflammation (metaflammation) is believed to be pivotal. Here, we tested a hypothesized anti-inflammatory role for heme oxygenase-1 (HO-1) in the development of metabolic disease. Surprisingly, in matched biopsies from "healthy" versus insulin-resistant obese subjects we find HO-1 to be among the strongest positive predictors of metabolic disease in humans. We find that hepatocyte and macrophage conditional HO-1 deletion in mice evokes resistance to diet-induced insulin resistance and inflammation, dramatically reducing secondary disease such as steatosis and liver toxicity. Intriguingly, cellular assays show that HO-1 defines prestimulation thresholds for inflammatory skewing and NF-κB amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease.Entities:
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Year: 2014 PMID： 24995976 PMCID： PMC5749244 DOI： 10.1016/j.cell.2014.04.043
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582