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The 53rd ICBL Young Investigator Awards

The final session of the ICBL meeting was capped off with the presentations of the Herbert Tabor Young Investigator
Award, which was awarded to Susanne E. Horvath (Austria), the ASBMB Award to Petra Kienesberger (Canada) and the Cell Metabolism Awards to Andrea Dichlberger (Finland) and Maggie S. Strable (USA).

Presenting the awards was George M. Carman (Associate Editor, Journal of Biological Chemistry). The titles and abstracts of the four Young Investigator award winner presentations are shown below.

George M. Carman, ICBL Corresponding Member

JBC/Herbert Tabor Young Investigator Award: Susanne E. Horvath (Austria)

Characterization of phosphatidylserine decarboxylase 1 from yeast

Susanne E. Horvath1, Thomas Becker2, Nikolaus Pfanner2, and Günther Daum1

1 Institute of Biochemistry, Graz University of Technology, Graz, Austria
2 Institute of Biochemistry and Molecular Biology, ZBMZ, University Freiburg, Freiburg im Breisgau, Baden-Württemberg, Germany

The majority of phosphatidylethanolamine (PE), one of the prominent phospholipids from yeast membranes, is synthesized by phosphatidylserine decarboxylase 1 (Psd1), an enzyme localized to mitochondria. Like most mitochondrial proteins, Psd1 is synthesized on free ribosomes and imported into mitochondria where processing/protein maturation occurs. Psd1 in the precursor form contains a mitochondrial targeting sequence, an internal sorting sequence, and an α- and a β-subunit which are linked by an LGST cleavage site. Cleavage at this site leads to the mature and active form of the enzyme which contains a pyruvoyl group at the N terminus of the α-subunit. In this study we investigated the effect of mitochondrial processing peptidases on protein maturation and the topology of Psd1, in particular localization of α- and β-subunits within mitochondrial compartments. We report that two matrix-located processing peptidases, MPP and Oct1, sequentially remove N-terminal signal peptides from the Psd1 precursor. Cleavage of α- and β-subunit was prevented by replacing serine with alanine at the highly conserved LGST motif. This processing step does not depend on a membrane potential but is restricted to mitochondria. Localization experiments, including proteinase protection assays and carbonate treatment of mitochondria, showed that the β-subunit forms the membrane anchor for the intermembrane space-localized α-subunit of Psd1 and attaches the whole protein to the inner mitochondrial membrane. Deletion of the predicted membrane anchor within the β-subunit results in mislocalization and reduced activity of the enzyme, but does not affect separation of the nonidentical Psd1 subunits. This finding suggests that correct localization of Psd1 is required for proper enzymatic activity and supply of the substrate to its site of conversion.

ASBMB Award: Petra Kienesberger (Canada)

Obesity-induced Myocardial Steatosis and Cardiomyopathy Are Attenuated in Mice with Cardiomyocyte-specific ATGL Overexpression

Petra Kienesberger1, Thomas Pulinilkunnil1, Jeevan Nagendran1, Emma Heydari1, Rammy Khadour1, Martin Young2, Guenter Haemmerle3, Rudolf Zechner3, and Jason Dyck1

1 University of Alberta, Edmonton, AB, Canada
2 University of Alabama at Birmingham, Birmingham, AL
3 University of Graz, Graz, Austria

Lipotoxic remodeling of the heart during obesity is associated with augmented myocardial triacylglycerol (TAG) deposition and diminished contractile function. However, it is unclear whether myocardial TAG accumulation contributes to cardiac dysfunction. To examine the role of adipose triglyceride lipase (ATGL), which regulates cardiomyocyte TAG accumulation, in cardiac metabolism and function during obesity, we fed wildtype (WT) and cardiomyocyte-specific ATGL-overexpressing (MHC- ATGL) mice chow or high fat-high sucrose (HFHS; 45 kcal% from fat) diet for 15 weeks. HFHS-fed WT and MHCATGL mice exhibited a comparable increase in body weight and developed similar glucose intolerance and systemic insulin resistance. Whereas HFHS feeding led to a 50% increase in cardiac TAG content in WT mice, despite increased myocardial ATGL protein expression, MHC-ATGL mice were protected from HFHS diet-induced cardiac steatosis. Importantly, systolic and diastolic functions were decreased in hearts from HFHSfed WT, but not MHC-ATGL mice. To determine the effect of HFHS feeding on oxidative substrate metabolism, hearts were perfused ex vivo in the working mode. As reported previously, MHC-ATGL hearts showed decreased palmitate oxidation and increased glucose oxidation rates compared with the WT on chow diet. HFHS diet feeding led to an increased reliance on palmitate oxidation in both WT and MHC-ATGL hearts. However, HFHS-fed MHC-ATGL mice still exhibited reduced myocardial palmitate oxidation rates compared with the  HFHS-fed WT mice, which was associated with decreased expression of the fatty acid utilization proteins, CD36, ACSL1, and UCP3. Collectively, these findings suggest that upregulation of cardiac ATGL during HFHS diet-induced obesity is an adaptive albeit insufficient response to compensate for the increased accumulation of myocardial TAG and that overexpression of ATGL prevents excessive TAG accumulation and cardiomyopathy associated with diet-induced obesity.

Cell metabolism award: Andrea Dichlberger (Finland)

Acyl-CoA Synthetases as Regulators of Arachidonic Acid Availability for Eicosanoid Metabolism in Human Mast Cells

Andrea Dichlberger1, Stefanie Schlager1, Reijo Käkelä2, Wolfgang J. Schneider3, and Petri T. Kovanen1

1 Wihuri Research Institute, Helsinki, Finland
2 University of Helsinki, Institute of Biotechnology, Helsinki, Finland
3 Department of Medical Biochemistry, Medical University of Vienna, Vienna, Austria

Mast cells (MCs) are potent effector cells of innate immunity and are involved in various inflammatory diseases such as atherosclerosis. Activation of MCs triggers the release of potent biologically active lipid mediators deriving from arachidonic acid (AA). Importantly, human MCs have been shown to contain large amounts of AA in triglycerides (TGs) stored in cytoplasmic lipid bodies (LBs), which implies great potential for eicosanoid biosynthesis in this cellular compartment. Thus, our study aims at elucidating the role of MC lipid bodies with particular emphasis on their large TG pool as a distinct source of AA for the generation of biologically active lipid mediators. Cultured human MCs generated from peripheral blood-derived CD34+ progenitors contain TG-rich cytoplasmic LBs. In contrast to saturated fatty acids (FAs), unsaturated FAs, such as AA and docosahexaenoic acid (DHA), are able to induce the formation of LBs in MCs, and AA is incorporated preferentially into the large TG pool of LBs. Triacsin C, a potent inhibitor of long chain acyl-CoA synthetases and de novo TG synthesis, efficiently blocks the AA-enhanced LB generation, thus leading to a depletion of LBs in these cells. The analysis of mRNA expression of ACSL family members revealed a significant increase of ACSL3 and ACSL4 transcripts during the initial phase of AA-enhanced LB formation. MC activation by antigen-induced IgE receptormediated cross-linking triggers a rapid release of large amounts of PGD2, which is totally blocked in triacsin C-treated MCs. Moreover, siRNA-mediated gene silencing of ACSL3 and ACSL4 leads to a significantly reduced release of PGD2 from activated MCs. Thus, ACSL3 and ACSL4 seem to play an important role in the genesis of AA-containing TGs during LB formation. Besides their implication in TG synthesis and LB generation, ACSL3 and/or ACSL4 might exert additional function(s) regarding the metabolism of eicosanoids in human mast cells.

Cell metabolism award: Maggie S. Strable (USA)

Differential Metabolic Effects of Hepatic Monounsaturated Fatty Acids

Maggie S. Strable and James M. Ntambi

University of Wisconsin, Madison, WI

Stearoyl-CoA desaturase (SCD) catalyzes the de novo synthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids. Past work demonstrated that SCD1 deficiency impairs hepatic lipogenesis and protects against diet-induced obesity. Our objectives were to determine whether hepatic MUFA synthesis is sufficient to restore the impaired lipogenic program in SCD1 global knock-out mice (GKO) and to determine whether the major MUFA products of the SCD1-catalyzed reaction exert differential metabolic effects. To address our objectives, we produced liver-specific transgenic mice expressing either human SCD5, which preferentially synthesizes oleate (18:1n-9), or mouse SCD3, which preferentially synthesizes palmitoleate (16:1n-7), and introduced these transgenes into SCD1 GKO mice. The mice were fed a lipogenic high sucrose/very low fat diet for 10 days. Hepatic oleate synthesis induced hepatic lipogenic gene expression more than palmitoleate did whereas palmitoleate synthesis significantly induced hepatic mitochondrial fatty acid oxidation gene expression. Hepatic MUFA synthesis reduced hepatic PGC-1α expression. Additionally, oleate synthesis restored body weight and liver triglycerides to wild-type levels whereas palmitoleate synthesis did not significantly change these phenotypes. Hepatic oleate also increased plasma glucose levels to a greater extent than hepatic palmitoleate. Fatty acid composition of extrahepatic tissues was influenced by hepatic MUFA synthesis, whereas oleate was increased in SCD5Tg, and palmitoleate was increased in SCD3Tg epididymal white adipose tissue. Overall, this work suggests that hepatic MUFAs are involved in regulation of de novo lipogenesis, fatty acid oxidation, and gluconeogenesis and that oleate and palmitoleate exert differential effects on these pathways.

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