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Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man.

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-?B amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease.

SUBMITTER: Jais A

PROVIDER: S-EPMC5749244 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man.

Jais Alexander A Einwallner Elisa E Sharif Omar O Gossens Klaus K Lu Tess Tsai-Hsiu TT Soyal Selma M SM Medgyesi David D Neureiter Daniel D Paier-Pourani Jamile J Dalgaard Kevin K Duvigneau J Catharina JC Lindroos-Christensen Josefine J Zapf Thea-Christin TC Amann Sabine S Saluzzo Simona S Jantscher Florian F Stiedl Patricia P Todoric Jelena J Martins Rui R Oberkofler Hannes H Müller Simone S Hauser-Kronberger Cornelia C Kenner Lukas L Casanova Emilio E Sutterlüty-Fall Hedwig H Bilban Martin M Miller Karl K Kozlov Andrey V AV Krempler Franz F Knapp Sylvia S Lumeng Carey N CN Patsch Wolfgang W Wagner Oswald O Pospisilik J Andrew JA Esterbauer Harald H

Cell 20140701 1

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 obes ...[more]

PMID: 24995976

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Project description:Atypical hemolytic uremic syndrome (aHUS) is a severe disease characterized by microvascular endothelial cell (EC) lesions leading to thrombi formation, mechanical hemolysis and organ failure, predominantly renal. Complement system overactivation is a hallmark of aHUS. To investigate this selective susceptibility of the microvascular renal endothelium to complement attack and thrombotic microangiopathic lesions, we compared complement and cyto-protection markers on EC, from different vascular beds, in in vitro and in vivo models as well as in patients. No difference was observed for complement deposits or expression of complement and coagulation regulators between macrovascular and microvascular EC, either at resting state or after inflammatory challenge. After prolonged exposure to hemolysis-derived heme, higher C3 deposits were found on glomerular EC, in vitro and in vivo, compared with other EC in culture and in mice organs (liver, skin, brain, lungs and heart). This could be explained by a reduced complement regulation capacity due to weaker binding of Factor H and inefficient upregulation of thrombomodulin (TM). Microvascular EC also failed to upregulate the cytoprotective heme-degrading enzyme heme-oxygenase 1 (HO-1), normally induced by hemolysis products. Only HUVEC (Human Umbilical Vein EC) developed adaptation to heme, which was lost after inhibition of HO-1 activity. Interestingly, the expression of KLF2 and KLF4-known transcription factors of TM, also described as possible transcription modulators of HO-1- was weaker in micro than macrovascular EC under hemolytic conditions. Our results show that the microvascular EC, and especially glomerular EC, fail to adapt to the stress imposed by hemolysis and acquire a pro-coagulant and complement-activating phenotype. Together, these findings indicate that the vulnerability of glomerular EC to hemolysis is a key factor in aHUS, amplifying complement overactivation and thrombotic microangiopathic lesions.

Dataset Information

Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man.

Publications

Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man.

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