The Path to a Fatty Heart

Byron's Comments:

Weight gain causes your heart to switch from fatty acid burning to sugar burning, with the consequence of fatty build up in the structure of the heart.

Study Title:

Activation of a HIF1α-PPARγ Axis Underlies the Integration of Glycolytic and Lipid Anabolic Pathways in Pathologic Cardiac Hypertrophy.

Study Abstract:

Development of cardiac hypertrophy and progression to heart failure entails profound changes in myocardial metabolism, characterized by a switch from fatty acid utilization to glycolysis and lipid accumulation. We report that hypoxia-inducible factor (HIF)1 and PPAR, key mediators of glycolysis andlipid anabolism, respectively, are jointly upregulated in hypertrophic cardiomyopathy and cooperate to mediate key changes in cardiac metabolism. In response to pathologic stress, HIF1 activates glycolytic genes and PPAR, whose product, in turn, activates fatty acid uptake and glycerolipid biosynthesis genes. These changes result in increased glycolytic flux and glucose-to-lipid conversion via the glycerol-3-phosphate pathway, apoptosis, and contractile dysfunction. Ventricular deletion of Hif1 in mice prevents hypertrophy-induced PPAR activation, the consequent metabolic reprogramming, and contractile dysfunction. We propose a model in which activation of the HIF1-PPAR axis by pathologic stress underlies key changes in cell metabolism that are characteristic of and contribute to common forms of heart disease.

From press release:

Heart failure is one of the world’s most frequent causes of death - caused by conditions such as diabetes and obesity. With people who are overweight, the heart has to do more work in order to pump the blood through the circulatory system and this causes an increase in blood pressure. The heart itself becomes enlarged as the myocardial muscle cells increase in mass.

To enable the heart to grow there also has to be an increased supply of energy and oxygen. However, the myocardial muscle cells suffer from a lack of oxygen and energy until such time as there are enough blood vessels to support the tissue.
This is the critical moment in which the cells convert their metabolism. A healthy heart burns fat. But the abnormally enlarged heart cells burn sugar in the form of glucose because this form of energy is quickly available. The protein HIF1-alpha is responsible for this conversion to sugar combustion. This has been demonstrated in research work done by Jaya Krishnan from the group of Wilhelm Krek, Professor of Cell Biology at ETH Zurich.

Cells undergo fatty change and die off

However, HIF1-alpha does not merely result in modified metabolism, it also activates other genes. One of the genes regulated by HIF1-alpha is known as PPARgamma. It causes the cardiac cells to produce and store fat. This results in the cells becoming fatty and dying off. Myocardial contraction is disrupted and this can lead to fatal heart failure. With HIF1-alpha, the researchers have identified a protein which has an effect that is not only of significance in connection with heart failure. This protein is in fact the most important catalyst that causes cells to convert glucose into fat.

Healthy heart despite high blood pressure

The researchers working around Krek have discovered an amazing fact - mice lacking the corresponding gene, and by which HIF1-alpha is therefore ineffective, do not suffer from heart disease. And this does not change even if the mice have high blood pressure. Their hearts also do not enlarge under such conditions of pathologic stress unlike the hearts of normal mice. They burn fat instead of sugar and function like healthy hearts.
At the same time, the research team has been able to provide an explanation for a phenomenon that is especially important to diabetics: some diabetics are given PPARgamma-promoting medicine to help muscles and other organs better respond to insulin. Clinical studies have shown that these patients have a higher risk of dying from heart failure. This research by Krishnan and Krek has shown why these drugs may be risky.

Dream pill in the distant future

In order to combat heart failure, a substance has to be found that binds itself to the protein HIF1-alpha in order to block it. It might be hard to locate a satisfactory antagonist to HIF1-alpha because the protein has no enzymatic docking site. Nevertheless, research is under way to develop a suitable molecule although Professor Wilhelm Krek does not think this will be quickly achieved. He is, however, convinced that with an effective remedy, the burden associated with this disease of civilization can be reduced.

Study Information:

Jaya Krishnan, Marianne Suter, Renata Windak, Tatiana Krebs, Allison Felley, Christophe Montessuit, Malgorzata Tokarska-Schlattner, Ellen Aasum, Anna Bogdanova, Evelyne Perriard, Jean-Claude Perriard, Terje Larsen, Thierry Pedrazzini, Wilhelm Krek Activation of a HIF1α-PPARγ Axis Underlies the Integration of Glycolytic and Lipid Anabolic Pathways in Pathologic Cardiac Hypertrophy. Cell Metabolism 2009 May 
Institute of Cell Biology and Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, 8093 Zurich, Switzerland.

Full Study:

http://download.cell.com/cell-metabolism/pdf/PIIS1550413109001399.pdf?intermediate=true


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