Nica Borradaile
Assistant Professor
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PH.D. Biochemistry, The University of Western Ontario |
Obesity and type 2 diabetes mellitus (T2DM) are epidemic in North America and result in multiple organ complications which are a significant burden on our health care systems. Increased blood lipids are characteristic of these metabolic diseases and can lead to excessive lipid accumulation in tissues other than adipose. Through a process termed lipotoxicity, this "ectopic" lipid accumulation results in cell dysfunction, cell death, and eventually organ dysfunction. Lipotoxicity can impair tissue and organ function in the liver, heart, blood vessels, skeletal muscle, and pancreas, and so contributes significantly to the pathophysiology of obesity and T2DM. The two most common complications of obesity and T2DM are cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). Remarkably, both the liver and heart can export bulk excess lipid as lipoproteins. Research in my lab will focus on understanding the biochemical and molecular pathways involved in liver, heart and blood vessel responses to excess lipid. Using cultured hepatocytes, cardiomyocytes and endothelial cells, and mouse models of obesity and T2DM, we will answer the following questions:
(1) Why are organs that have the ability to unload lipid through lipoprotein secretion (liver and heart) unable to prevent excess cellular lipid accumulation during obesity and T2DM?
(2) Can the optimization of lipoprotein secretion and NAD+ metabolism prevent lipotoxicity in the liver, heart and blood vessels during obesity and T2DM?
Hopefully, the answers to these questions will reveal new therapeutic approaches for managing the two most common complications of these metabolic diseases.
Borradaile NM, Pickering JG. (2009) Nicotinamide phosphoribosyltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environment. Aging Cell 8, 100 - 112. Borradaile NM, Pickering JG. (2009) NAD+, sirtuins, and cardiovascular disease.Curr Pharm Des 15, 110 -117. Borradaile NM, Han X, Gross R, Harp J, Gale SE, Ory DS, Schaffer JE. (2006) Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. J Lipid Res 47, 2726 - 2737. Borradaile NM, Buhman KK, Listenberger LL, Magee CJ, Morimoto ETA, Ory DS, Schaffer JE. (2006) A critical role for eukaryotic elongation factor (eEF) 1A-1 in lipotoxic cell death. Mol Biol Cell 17, 770 - 778. Borradaile NM, Schaffer JE. (2005) Lipotoxicity in the heart. Curr Hypertens Rep 7, 412 - 417. Borradaile NM, de Dreu LE, Huff MW. (2003) Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid, naringenin, involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. Diabetes 52, 2554 - 2561.
