Abstract
Sirtuin3 (Sirt3) is the major deacetylase in mitochondria. It has been determined that SIRT3 null mice have deficiencies in ATP production and demonstrate a susceptibility to develop metabolic syndrome. Polychlorinated biphenyls (PCBs) are organic pollutants that accumulate in adipose tissue, and have been shown to disturb metabolism. They have been suggested to contribute to metabolic disease states such as diabetes and obesity. Our goal is to examine the effects of 4-hydroxy-3,3’-dichlorobiphenyl (4OH-PCB11), a major PCB 11 metabolite, on fatty acid and glucose metabolism using embryonic fibroblasts (MEF) isolated from SIRT3 wild type and SIRT3 null mice. RT² Profiler™ PCR Array for fatty acid metabolism exhibited a dose dependent up-regulation of Acot12, Acsbg2, Acsm2, Fabp1, Oxct2a, Gk2, Hmgs2, LpI, SLC27A5 and Acsl1 genes in Sirt3 –/– MEFs compared to Sirt3 +/+ MEFs following 24 h treatment with 0.1, 1, and 3 μM 4OH-PCB11. PCR Array for glucose metabolism also demonstrated up-regulation of G6pc, Pdk4, and Prps1L1 in both Sirt3 –/– and Sirt3 +/+ MEFs upon 3 μM 4OH-PCB11 exposure, however fold increases in the expression of these genes were more pronounced in the knockout background. On the other hand, the expression of Pygl gene was down-regulated in both Sirt3 –/– and Sirt3 +/+ MEFs at comparable levels. Our future studies will investigate the enzymatic activities of proteins encoded by these genes as well as utilize a proteomics approach to determine if they are specific Sirt3 targets during PCB induced cellular stress. Supported by NIGMS P20- GM109005, NIEHS R15 ES022781, and P42 ES013661.
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