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 Professor(University of Toronto) AHFMR Senior Scholar Phone: 780-492-2963 Research Interests Regulation of cellular triacylglycerol and cholesterol metabolism Triacylglycerol (TG), commonly referred to as fat, is the most concentrated form of energy storage available to mammals. Excessive TG storage is manifested as obesity, which is a major health problem in the Western world. Obesity currently affects more than 20% of adults in North America and it is a risk factor for hypertension, diabetes and cardiovascular disease. TG is secreted by the liver into circulation in very-low density lipoprotein (VLDL) particles. VLDL is converted in blood to low-density lipoprotein (LDL) – a carrier of “bad” cholesterol. Elevated plasma LDL cholesterol levels are directly correlated with the risk of atherosclerosis. Therefore, there is a substantial pharmacological interest in the enzymes that control TG metabolism in tissues. I. Triacylglycerol Hydrolase (TGH): Hypothesis: TGH is involved in the mobilization of intracellular TG stores in the liver and adipose tissue and inhibition of the enzyme will result in decreased plasma lipid levels. Project involves: cell biology (localization and targeting, lipid droplet formation and turnover), biochemistry (active site, lipid binding, structure), physiology (generation and analysis of TGH transgenic and knock out mice). II. Carboxylesterase Es-x: Hypothesis: Es-x participates in lipid absorption and storage. Project involves: studies on the role of the enzyme in lipid metabolism in the intestine as well as in the liver utilizing cell biology and molecular biology approaches iand Es-x knockout mice. III. Arylacetamide deacetylase (AADA) and intracellular hepatic lipase (HL): Hypothesis: AADA and HL participate in hepatic lipid metabolism. Project involves: cell biology of retention of AADA in the endoplasmic reticulum; studies on the role of the enzyme in lipid metabolism in hepatocytes transfected with AADA cDNA, and in AADA transgenic and knock out mice. Assessment of AADA and HL as potential Gene therapy targets. Selected Publications V. Lo, B. Erickson, M. Thomason-Hughes, K.W.S. Ko, V.W. Dolinsky, R. Nelson and R. Lehner. Arylacetamide deacetylase attenuates fatty acid-induced triacylglycerol accumulation in rat hepatoma cells. J. Lipid Res. (in press) K.W.S. Ko, B. Erickson and R. Lehner (2009) Es-x/Ces1 prevents triacylglycerol accumulation in McArdle RH7777 cells. Biochim. Biophys. Acta - MCBL 1791, 1133-1143 B. Manmontri, M. Sariahmetoglu, J. Donkor, M. Bou Khalil, M. Sundaram, Z. Yao, K. Reue, R. Lehner and D.N. Brindley (2008) Glucocorticoids and cAMP selectively increase hepatic lipin-1 expression and insulin acts antagonistically. J. Lipid Res. 49, 1056-1067 C. Minahk, K.W. Kim, R. Nelson, B. Trigatti, R. Lehner and D.E. Vance (2008) Conversion of low density lipoprotein-associated phosphatidylcholine to triacylglycerol by primary hepatocytes. J. Biol. Chem. 283, 6449-6458 E. Wei, M. Alam, F. Sun, L.B. Agellon, D.E. Vance and R. Lehner (2007) ApoB and triacylglycerol secretion in human triacylglycerol hydrolase transgenic mice. J. Lipid Res. 48, 2597-2606 H. Wang, D. Gilham and R. Lehner (2007) Proteomic and lipid characterization of apolipoproteinB-free lipid droplets from the lumen of the endoplasmic reticulum: Implications for very-low density lipoprotein assembly. J. Biol. Chem. 282, 33218-33226 E. Wei, W. Gao and R. Lehner (2007) Attenuation of adipocyte triacylglycerol hydrolase activity decreases basal fatty acid efflux. J. Biol. Chem. 282, 8027-8035 M. Alam, D. Gilham, D.E. Vance and R. Lehner (2006) Mutation of F417 but not of L418 or L420 in the lipid binding domain decreases activity of triacylglycerol hydrolase. J. Lipid Res. 47, 375-383 D. Gilham, K.R. Perreault, C.F.B. Holmes, D.N. Brindley, D.E. Vance and R. Lehner (2005) Insulin, glucagon and fatty acid treatment of hepatocytes does not result in phosphorylation or changes in activity of triacylglycerol hydrolase. Biochim. Biophys. Acta - MCBL 1736, 189-199 D. Gilham and R. Lehner (2005) Techniques to measure lipase and esterase activity in vitro. Methods 36, 139-147 E. Wei, R. Lehner and D.E. Vance (2005) CCAAT/enhancer binding-protein alpha activates transcription of triacylglycerol hydrolase in 3T3-L1 adipocytes. Biochem. J. 388, 959-966 D. Gilham, M. Alam, D.E. Vance and R. Lehner (2005) Triacylglycerol hydrolase is localized to the ER by an unusual retention sequence where it associates with nascent VLDL without utilizing the component lipids as substrates. Mol. Biol. Cell 16, 984-996. K. Tedrick, T.C. Trischuk, R. Lehner and G. Eitzen (2004) Enhanced membrane fusion in sterol-enriched vacuoles bypasses the Vrp1p requirement. Mol. Biol. Cell 15, 4609-4621 (AHSF) K. G. Soni, R. Lehner, P. Metalnikov, P. O'Donnell, M. Semache, W. Gao, K. Ashman, A. V. Pshezhetsky and G. A Mitchell (2004) Carboxylesterase 3 (EC 3.1.1.1) is a major adipocyte lipase. J. Biol. Chem. 279, 40683-40689 D. Gilham and R. Lehner (2004) Physiological role of triacylglycerol hydrolase. Rev. Endocr. Metab. Disord. 5, 303-309 V.W. Dolinsky, D. Gilham, M. Alam, D.E. Vance and R. Lehner (2004) Triacylglycerol hydrolase: Role in intracellular lipid metabolism. Cell. Mol. Life Sci. 61, 1633-1651 D. Sahoo, T.C. Trischuk, V.A.B. Drover, S. Ho, T. Chan, G. Chimini, L.B. Agellon, R. Agnihotri, G.A. Francis and R. Lehner. (2004) ABCA1-dependent lipid efflux to apolipoprotein A-I mediates HDL particle formation and decreases VLDL secretion from primary rat and mouse hepatocytes. J. Lipid Res. 45, 1122-1131 M. Rasouli, T.C. Trischuk and R. Lehner (2004) Calmodulin antagonist W-7 inhibits de novo synthesis of cholesterol and suppresses secretion of de novo synthesized and preformed lipids from cultured hepatocytes. Biochim. Biophys. Acta 1682, 92-101 V.W. Dolinsky, D.N. Douglas, R. Lehner and D.E. Vance (2004) Regulation of enzymes of hepatic microsomal triacylglycerol lipolysis and re-esterification by the glucocorticoid, dexamethasone. Biochem. J. 378, 967-974 Current Research Staff
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