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The 54th ICBL Young Investigator Awards

The final session of the ICBL meeting was capped off with the presentations of the Journal of Biological Chemistry/Herbert Tabor Young Investigator Award, which was awarded to Ursula Loizides-Mangold.

Loizides, a senior scientist in Howard Riezman’s laboratory at the University of Geneva, uses mass-spectrometry-based lipidomics to dissect the role of lipids in cell function and the effects of nutrition on whole body metabolism.

Working with Bernard Thorens’ group at the University of Lausanne, Loizides studied the L-peroxisomal bifunctional enzyme, or L-PBE, which has been associated with steatohepatitis, insulin resistance and diabetes.

They found that L-PBE is required to prevent dietary toxicity of medium-chain fatty acids, such as the ones found in coconut oil. These fatty acids induce production of dicarboxylic fatty acids, which accumulate due to L-PBE deficiency resulting in liver failure, inflammation and fibrosis.

These results highlight DCAs’ potential toxicity and suggest that specific metabolic pathways can be activated by different nutrients to adapt the organism to the available resources.

During Loizides’ postdoctoral studies, she worked on the regulation of polyamine biosynthesis. She said she was
inspired by Herbert and Celia Tabor’s work on polyamine metabolism and that it is a very special honor for her to receive the Tabor award. Presenting the award was George M. Carman (Associate Editor, Journal of Biological Chemistry). The title and abstract of the Young Investigator award winner presentations is shown below.

George M. Carman, ICBL Corresponding Member

The peroxisomal enzyme L-PBE is required to prevent the dietary toxicity of medium chain fatty acids

Ursula Loizides-Mangold1, Jun Ding2, Gianpaolo Rando2, Janardan K. Reddy3, Walter Wahli2, Howard Riezman1, Bernard Thorens2

1 Department of Biochemistry, NCCR Chemical Biology, University of Geneva, CH-1211 Geneva, Switzerland
2 Center for Integrative Genomics, University of Lausanne, Lausanne, CH-1015 Switzerland
3 Department of Pathology, Northwestern University, Chicago, IL 60611, USA

Fatty acids are oxidized in either mitochondria or peroxisomes. L-PBE is the second enzyme of the inducible peroxisomal β-oxidation system with unclear substrate specificity. The aim of this study was to identify the specific role of L-PBE in the adaptation to a high fat diet that is rich in medium chain fatty acids. Here we show that L-pbe-/- mice fed a coconut oil based high fat diet die from fulminant liver failure, with massive hepatic inflammation and fibrosis. Lipid profiling of L-pbe-/- mice revealed elevated sphingolipid levels and high levels of medium-chain dicarboxylic fatty acids (DCAs). Inhibition of ceramide biosynthesis modestly prolonged mice lifespan whereas inhibition of dicarboxylic fatty acid production completely protected L-pbe-/- mice against liver failure caused by a medium chain rich diet. Here we show, that the accumulation of DCAs is due to the activation of the liver ω-oxidation system. The medium chain rich diet strongly induced the ω-oxidation genes Cyp4a10 and Cyp4a14 in a PPARα and PPARγ dependent manner. Taken together, these results show a major role for L-PBE in the degradation of DCAs and demonstrate that an imbalanced production of DCAs has severe metabolic consequences.

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