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Fat signals: Lipid cleaving enzyme produces signaling molecule essential in lipid metabolism

Date:
August 22, 2011
Source:
Österreichisches Genomforschungsprogramm GEN-AU
Summary:
Normal lipid and energy metabolism requires complex regulation by a network of signaling processes. Researchers now show that mice that lack the fat cleaving enzyme ATGL cannot produce signaling molecules needed to regulate nuclear receptors. As a consequence, mitochondria, the power plants of the cells, fail to function properly in these animals. The findings provide a promising therapeutic strategy for patients suffering from Neutral Lipid Storage Disease (NLSD).

Obesity, diabetes, and cardiovascular diseases are daunting modern-day epidemics. In Western Europe more than 50% of the population is overweight and approximately 15 million people die from cardiovascular diseases such as heart attacks and stroke every year. These conditions are often caused by disorders of fat metabolism, resulting in a massive accumulation of fat in various tissues and of cholesterol in the walls of arteries.

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Fats are known to perform long-term storage of energy, but they also act as signaling molecules in the body. Consequently, fat is stored not only in adipose tissue, but also in smaller amounts in almost all cells of the body. Special fat cleaving enzymes, called lipases, are used to remobilize stored fat from cellular depots. One of them, Adipose Triglyceride Lipase (ATGL), is responsible for the first step in the breakdown of fat. Scientists from the University of Graz and colleagues from several countries report in the journal Nature Medicine that ATGL also produces key signaling molecules that are essential for the regulation of energy metabolism.

Normal lipid and energy metabolism requires complex regulation by a network of signaling processes. Nuclear receptor proteins are important players in this regulatory network. Binding of special signaling molecules activates nuclear receptors, which then leads to increased expression of genes responsible for energy production.

Günter Hämmerle, Rudolf Zechner and colleagues now show that mice that lack the fat cleaving enzyme ATGL cannot produce these signaling molecules needed to regulate nuclear receptors. As a consequence, mitochondria, the power plants of the cells, fail to function properly in these animals. Cellular energy production from the oxidation of fat or sugar is strongly reduced. The loss of mitochondrial activity causes massive fat accumulation in the heart and other tissues and leads to lethal heart failure within a few months after birth. Importantly, when the requirement for ATGL was bypassed in these animals by treating them with drugs that activate nuclear receptors directly, mitochondrial function improved, heart functions returned to normal and the animals survived.

These findings provide a promising therapeutic strategy for patients suffering from Neutral Lipid Storage Disease (NLSD). This disorder is caused by dysfunctional ATGL and -- similar to the symptoms shown by ATGL-deficient mice -- patients with NLSD suffer from systemic fat accumulation and severe heart dysfunction that often requires organ transplantation. Treatment with drugs activating nuclear receptors may improve heart function and prevent the lethal cardiac complications. Several of these drugs are already approved for the treatment of other diseases and can be tested for the treatment of patients with NLSD.


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The above story is based on materials provided by Österreichisches Genomforschungsprogramm GEN-AU. Note: Materials may be edited for content and length.


Journal Reference:

  1. Guenter Haemmerle, Tarek Moustafa, Gerald Woelkart, Sabrina Büttner, Albrecht Schmidt, Tineke van de Weijer, Matthijs Hesselink, Doris Jaeger, Petra C Kienesberger, Kathrin Zierler, Renate Schreiber, Thomas Eichmann, Dagmar Kolb, Petra Kotzbeck, Martina Schweiger, Manju Kumari, Sandra Eder, Gabriele Schoiswohl, Nuttaporn Wongsiriroj, Nina M Pollak, Franz P W Radner, Karina Preiss-Landl, Thomas Kolbe, Thomas Rülicke, Burkert Pieske, Michael Trauner, Achim Lass, Robert Zimmermann, Gerald Hoefler, Saverio Cinti, Erin E Kershaw, Patrick Schrauwen, Frank Madeo, Bernd Mayer, Rudolf Zechner. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1. Nature Medicine, 2011; DOI: 10.1038/nm.2439

Cite This Page:

Österreichisches Genomforschungsprogramm GEN-AU. "Fat signals: Lipid cleaving enzyme produces signaling molecule essential in lipid metabolism." ScienceDaily. ScienceDaily, 22 August 2011. <www.sciencedaily.com/releases/2011/08/110822091603.htm>.
Österreichisches Genomforschungsprogramm GEN-AU. (2011, August 22). Fat signals: Lipid cleaving enzyme produces signaling molecule essential in lipid metabolism. ScienceDaily. Retrieved December 19, 2014 from www.sciencedaily.com/releases/2011/08/110822091603.htm
Österreichisches Genomforschungsprogramm GEN-AU. "Fat signals: Lipid cleaving enzyme produces signaling molecule essential in lipid metabolism." ScienceDaily. www.sciencedaily.com/releases/2011/08/110822091603.htm (accessed December 19, 2014).

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