Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man

被引：262

作者：

Jais, Alexander ^{[1
]}

Einwallner, Elisa ^{[1
]}

Sharif, Omar ^{[1
,2
]}

Gossens, Klaus ^{[3
]}

Lu, Tess Tsai-Hsiu ^{[3
]}

Soyal, Selma M. ^{[4
]}

Medgyesi, David ^{[3
,5
]}

Neureiter, Daniel ^{[4
]}

Paier-Pourani, Jamile ^{[6
]}

Dalgaard, Kevin ^{[3
]}

Duvigneau, J. Catharina ^{[7
]}

Lindroos-Christensen, Josefine ^{[1
]}

Zapf, Thea-Christin ^{[1
]}

Amann, Sabine ^{[1
]}

Saluzzo, Simona ^{[1
,2
]}

Jantscher, Florian ^{[1
]}

Stiedl, Patricia ^{[8
]}

Todoric, Jelena ^{[1
]}

Martins, Rui ^{[1
,2
]}

Oberkofler, Hannes ^{[4
]}

Mueller, Simone ^{[7
]}

Hauser-Kronberger, Cornelia ^{[4
]}

Kenner, Lukas ^{[1
,7
,8
]}

Casanova, Emilio ^{[1
,8
]}

Sutterluety-Fall, Hedwig ^{[1
]}

Bilban, Martin ^{[1
]}

Miller, Karl ^{[9
]}

Kozlov, Andrey V. ^{[6
]}

Krempler, Franz ^{[9
]}

Knapp, Sylvia ^{[1
,2
]}

Lumeng, Carey N. ^{[10
]}

Patsch, Wolfgang ^{[4
]}

Wagner, Oswald ^{[1
]}

Pospisilik, J. Andrew ^{[3
]}

Esterbauer, Harald ^{[1
]}

机构：

[1] Med Univ Vienna, A-1090 Vienna, Austria

[2] Austrian Acad Sci, Res Ctr Mol Med, CeMM, A-1090 Vienna, Austria

[3] Max Planck Inst Immunobiol & Epigenet, D-79108 Freiburg, Germany

[4] Paracelsus Med Univ, A-5020 Salzburg, Austria

[5] Univ Freiburg, BIOSS Ctr Biol Signalling Studies, D-79104 Freiburg, Germany

[6] Ludwig Boltzmann Inst Expt & Clin Traumatol, A-1200 Vienna, Austria

[7] Univ Vet Med Vienna, A-1210 Vienna, Austria

[8] Ludwig Boltzmann Inst Canc Res, A-1090 Vienna, Austria

[9] Gen Hosp Hallein, A-5400 Hallein, Austria

[10] Univ Michigan, Ann Arbor, MI 48109 USA

来源：

CELL | 2014年 / 158卷 / 01期

基金：

奥地利科学基金会; 美国国家卫生研究院;

关键词：

ADIPOSE-TISSUE; UP-REGULATION; IKK-BETA; MACROPHAGE POLARIZATION; MITOCHONDRIAL-FUNCTION; COBALT PROTOPORPHYRIN; METABOLIC HOMEOSTASIS; GENE-EXPRESSION; OBESITY; INFLAMMATION;

D O I：

10.1016/j.cell.2014.04.043

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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

引用

页码：25 / 40

页数：16

共 59 条

[1]

Pharmacological and clinical aspects of heme oxygenase [J].