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Dennis Vance

 

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Distinguished University Professor
Ph.D., University of Pittsburgh
 
Department of Biochemistry
Faculty of Medicine & Dentistry
University of Alberta
320 Heritage Medical Research Center
Edmonton, Alberta, Canada  T6G 2S2
 
Tel: 780.492.8286
Lab Tel: 780.492.7310
Fax:  780.492.3383
 
Research:

 

We investigate the regulation of phosphatidylcholine (PC) biosynthesis in mammalian cells and the function of PC synthesis in liver failure, obesity, and diabetes.
All mammalian cells make PC via the CDP-choline pathway. In addition, the liver makes PC via the methylation of phosphatidylethanolamine (PE) catalyzed by PE methyltransferase (PEMT). We disrupted in mice the gene (Pemt) that encodes PEMT (Walkey et al. 1997). Pemt -/- mice showed no obvious phenotype when maintained on a diet supplemented with choline. However, when fed a choline-deficient diet for 3 days, severe liver failure occurred (Walkey et al. 1998). We concluded that PEMT survived in evolution as a liver specific enzyme to provide choline and PC when the dietary source was insufficient. We have used this and another mouse model to demonstrate that choline is an essential nutrient and that the molar ratio of PC to PE is a key regulator of membrane integrity in mouse liver (Li et al. 2005, 2006). We also demonstrated that livers from male Pemt -/- mice have a defect in the secretion of apo B100-containing very low density lipoproteins (Noga et al. 2002). Consistent with these studies, we have shown that a lack of PEMT will greatly decrease the development of atherosclerosis and lipotoxic cardiac dysfunction in mice (Zhao et al. 2009; Cole et al., Circ. Res. 2011). Pemt -/- mice have a striking protection against diet induced obesity and insulin resistance (Jacobs et al., 2010; Wu et al., 2013; van der Veen et al., 2014). We are now deeply involved in determination of the mechanism by which the lack of PEMT results in a lean, insulin sensitive phenotype. Secondly, we are pursuing ideas to find an inhibitor of PEMT that might be a therapy for obesity and type 2 diabetes.
 
We also investigated the fate of PC on HDL and LDL when taken up by the liver in mice. In contrast to cholesteryl esters, LDL-PC is not degraded in the lysosomes. Unexpectedly, approximately 50% of LDL-PC is converted to triacylglycerol via reactions catalyzed by phospholipase C and DGAT2 (diacylglycerol acyltransferase 2) (Minahk et al. 2008). The fate of HDL-PC in liver is very similar to the PC derived from LDL (Robichaud et al. 2008, 2009). We have now shown that as much PC is delivered to the liver from lipoproteins as made de novo in liver (van der Veen et al., 2012) and much of this PC is converted to triacylglycerol. The role that PC plays in the formation of fatty liver (steatosis) remains to be investigated. Recent studies have shown that the hepatic branch of the vagus nerve is required for the development of steatosis/steatohepatitis in Pemt -/- mice fed a high fat diet Gao et al., 2015).
 
 
Lab Members:

 

Suzanne Lingrell, Technologist
Randal Nelson, Technologist
Jelske van der Veen, Research Associate
Sereana Wan, Graduate Student.
  
Selected Publications:
 
Li Z, Agellon LB, Allen TM, Umeda M, Jewell L, Mason A and Vance DE. (2006) The Ratio of Phosphatidylcholine to Phosphatidylethanolamine Influences Membrane Integrity and Steatohepatitis. Cell Metabolism 3:321-331
 
Zhao Y, Su B, Jacobs RL, Kennedy B, Francis GA, Waddington E, Brosnan JT, Vance JE and Vance DE. (2009) Lack of Phosphatidylethanolamine N-Methyltransferase Alters Plasma VLDL Phospholipids and Attenuates Atherosclerosis in Mice. Arteriosclerosis Thromb. Vasc. Biol. 29:1349-1355.
 
Jacobs RL, Zhao Y, Koonen DPY, Sletten T, Su B, Lingrell S, Cao G, Peake DA, Kuo M-S, Proctor SD, Kennedy BP, Dyck JRB and Vance DE. (2010) Impaired de Novo Choline Synthesis Explains Why Phosphatidylethanolamine N-Methyltransferase-deficient Mice are Protected from Diet-Induced Obesity. J. Biol. Chem. 285:22403-22413
 
Cole LK, Dolinsky VW, Dyck JRB and Vance DE. (2011) Impaired Phosphatidylcholine Biosynthesis Reduces Athersclerosis and Prevents Lipotoxic Cardiac Dysfunction in ApoE-/- Mice. Circ. Res. 108:686-694
 
van der Veen JN, Lingrell S and Vance DE. (2012) The Membrane  Lipid Phosphatidylcholine Is an Unexpected Source of Triacylglycerol in the Liver. J. Biol. Chem. 287:23418-23426
 
van der Veen, J.N., Lingrell, S., da Silva, R. P., Jacobs, R.L. and Vance, D.E.(2014) Concentration of Phosphatidylethanolamine in Mitochondria Can Modulate ATP Production and Glucose Metabolism in Mice. Diabetes 63, 2620-2630.