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Multicenter study: The enzyme HO-1 makes all the difference.

(Vienna, 3 July 2014) Around every one in five Austrians is regarded as being very overweight (obese), and this trend is growing. Three-quarters of those affected suffer with associated conditions such as diabetes, cardiovascular disease or even cancer. A quarter of them are basically healthy, however, despite being very overweight – and often remain so. Working groups of the Clinical Institute of Laboratory Medicine at the MedUni Vienna, the Max Planck Institute for Immunobiology and Epigenetics in Freiburg and the Paracelsus Private Medical University in Salzburg have now discovered the cause of this: the enzyme HO-1, which makes all the difference. People with low HO-1 levels stay healthier despite being overweight. This discovery could generally facilitate healthier ageing, since HO-1 is believed to play a role in many age-related inflammatory conditions.
The teams, led by Harald Esterbauer (Clinical Institute of Laboratory Medicine at the MedUni Vienna), used various models to investigate which factors distinguish between obesity that makes people ill and obesity that doesn't. Together with the working group led by Wolfgang Patsch (Paracelsus Private Medical University in Salzburg), it was demonstrated that the enzyme HO-1 (heme oxygenase-1) is able to predict with a high degree of certainty the risk of type 2 diabetes and fatty liver. If the HO-1 levels in the liver and in the fatty tissue were high, then numerous known indicators of insulin resistance were also markedly raised, i.e. in the pathological range. This predictive ability of HO-1 was independent of body weight, waist size or proportion of abdominal fat.

“HO-1’s predictive ability, regardless of body weight and build, is completely surprising. This led us to suspect that we are on the trail of a new risk factor for unhealthy obesity,” says Esterbauer. It was still unclear, however, whether the HO-1 enzyme was only a new indicator of pathological obesity or was actually involved as a causative factor in the development of type 2 diabetes and fatty liver. To answer these questions, the Vienna researchers joined forces with the working group led by Andrew Pospisilik (Max Planck Institute for Immunobiology and Epigenetics in Freiburg) and switched off the enzyme in various organs central to the metabolism in a mouse model. Switching off the enzyme in the liver cells and in the scavenger cells, or macrophages, yielded positive effects.
HO-1 as a driver for diabetes
The central result of the study, which has now been published in the highly respected journal “Cell”, was that the mice continued to gain weight after HO-1 was switched off and became fat with fatty food, but developed scarcely any associated illnesses. The development of pathological fatty liver was delayed or completely prevented, for example, and liver damage was also greatly reduced. The cells remain sensitive to insulin, despite the severe obesity. Says Esterbauer: “This strongly indicates that HO-1 acts as a completely new and central key player at the interface between obesity and its associated diseases.”

The researchers were also able to refute one of the central dogmas of HO-1 research that has prevailed for years: until now, it was assumed that the enzyme inhibits inflammation. In fact, the opposite is true. HO-1 promotes chronic, cold inflammatory processes in the body, i.e. inflammations without fever. And it promotes insulin resistance and therefore diabetes mellitus and fatty liver.

Therapeutic approach for healthier ageing
These types of chronic inflammation are generally risk factors. Not just for diabetes and cardiovascular disease, but also for neurodegenerative conditions such as Parkinson's or Alzheimer's, as well as cancer. Says Esterbauer: “As a result, our discovery could ultimately lead to HO-1 inhibition, as a highly attractive target for therapeutic approaches, generally contributing to facilitating healthier ageing. After all, we were also able to demonstrate that the mitochondria, the cells’ powerhouses, also work much, much better without the HO-1 enzyme.”

Treating obesity as a condition is possible
Agents that work in this direction are already available, explains Esterbauer: “And in fact they are used for the treatment of the very common condition of jaundice in newborn babies.” Despite this strong base for the development of pharmaceutical agents, it will still be around ten years after the clinical studies that are now needed until the new findings relating to HO-1 can be used for therapeutic purposes and in clinical situations, according to estimates by the teams from Vienna and Freiburg.

In June 2013, the American Medical Association decided to classify obesity as a disease. Since obesity is not necessarily associated with negative effects on the metabolism, this decision is not uncontroversial. The results of research available could make a considerable contribution towards identifying people with pathological obesity early. New approaches are also being developed to the long-term treatment and prevention of type 2 diabetes and fatty liver, both of which are common consequences of pathological obesity.

CELL: Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man.
Alexander Jais, Elisa Einwallner, Omar Sharif, Klaus Gossens, Tess Tsai-Hsiu Lu, Selma M. Soyal, David Medgyesi, Daniel Neureiter, Jamile Paier-Pourani, Kevin Dalgaard, J. Catharina Duvigneau, Josefine Lindroos Christensen, Thea-Christin Zapf, Sabine Amann, Simona Saluzzo, Florian Jantscher, Patricia Stiedl, Jelena Todoric, Rui Martins, Hannes Oberkofler, Simone Müller, Cornelia Hauser-Kronberger, Lukas Kenner, Emilio Casanova, Hedwig Sutterlüty-Fall, Martin Bilban, Karl Miller, Andrey V. Kozlov, Franz Krempler, Sylvia Knapp, Carey N. Lumeng, Wolfgang Patsch, Oswald Wagner, J. Andrew Pospisilik, and Harald Esterbauer. 1Co-Erstautoren. Cell 158, 25-40, July 3, 2014. DOI:

A Conversation with Harald Esterbauer - Audio Interview.