Dennis Vance, PhD

Office:    320 Heritage Medical Research Centre
Mail:      University of Alberta, Edmonton AB T6G 2S2
Phone:   780-492-8286


Current Position


Dennis Vance, PhD, FRSC, Distinguished University Professor, Department of Biochemistry and Group on the Molecular and Cell Biology of Lipids, Mazankowski Alberta Heart Institute, Alberta Diabetes Institute, University of Alberta



Research Areas


Molecular and cell biology of phospholipid biosynthesis and function.   



Current Research Activities


We investigate the regulation of phosphatidylcholine (PC) biosynthesis in mammalian cells and the function of PC synthesis in liver failure, muscular dystrophy, axonal elongation and lipoprotein metabolism related to atherosclerosis, 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) (Vance and Vance, 2005). PEMT is a small protein (20 kDa) that spans the ER membrane 4 times with the catalytic site facing the cytosol (Shields et al. 2003).  We, in collaboration with Lou Agellon, 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 have also made the unexpected finding that livers from male Pemt -/- mice have a defect in the secretion of apo B100-containing very low density lipoproteins (Noga et al. 2002).  Moreover, studies with Pemt -/- mice have allowed us to demonstrate that the PEMT reaction in liver is a major source of plasma homocysteine, an independent risk factor for cardiovascular disease (Noga et al. 2003).  Consistent with these studies, we have shown that a lack of PEMT will greatly decrease the development of atherosclerosis in mice (Zhao et al. 2009).  Pemt -/- mice have a striking protection against diet induced obesity and insulin resistance. Future research is directed towards understanding the role of PEMT in the development of liver disease in mice and humans and the role of PEMT in obesity and diabetes. We are also studying the transcriptional regulation of PEMT expression.


The CTP:phosphocholine cytidylyltransferase alpha (CTalpha) gene encodes the rate-limiting and regulated enzyme in the CDP-choline pathway for PC biosynthesis. We are interested in metabolic interrelationships between CT and PEMT.  We have found that mice that lack CTalpha specifically in the liver have defects in the secretion of very low-density lipoproteins and in high-density lipoprotein metabolism (Jacobs et al. 2004, 2008). The CTalpha mice also have a 2-fold increase in PEMT activity that causes enhanced secretion of homocysteine (Jacobs et al. 2005). More recently, we have found that ABCA1 expression and cholesterol efflux for HDL formation are attenuated in the liver-specific CTalpha KO mice (Jacobs et al., 2008). Interestingly, the lack of hepatic CTalpha, unlike the lack of PEMT, does not protect mice against diet induced obesity or insulin resistance.


We have initiated research on 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) The quantitative significance of delivery of lipoprotein-PC to liver is under investigation.


In collaboration with a group at Jackson labs, we have discovered that one form of hindlimb muscular dystrophy in mice is due to a lack of choline kinase beta (Sher et al., 2006). We have been able to show that this is due to the lack of choline kinase beta in the hindlimbs (Wu et al. 2009). The forelimbs of these mice have relatively more choline kinase alpha than hindlimbs and that provides sufficient choline kinase activity to prevent the development of muscular dystrophy in forelimbs of choline kinase beta knockout mice (Wu et al. 2010). The choline kinase beta knockout mice have a neonatal bone deformity in the forelimbs and we are currently investigating the mechanism by which this occurs.


We have a long-term collaboration with R. Campenot (Cell Biology) and J. Vance (Medicine) on lipid synthesis and transport in neurons. Current work is focused on cholesterol transport in the murine model for Niemann-Pick C disease (Karten et al. 2003) and the relationship between astrocyte-derived lipoproteins and neuronal growth and survival  (Hayashi et al. 2004, 2007). We are also studying the role of CTbeta expression in neurons (Carter et al. 2003; Carter, Demizieux et al. 2008).