The overall goal of this project is to understand how the turnover of phospholipid acyl groups is regulated in intact cells. Based on recent work carried out with rat hepatocytes, we are able to distinguish de novo synthesis from remodeling through deacylation-reacylation by following the incorporation of 18(O) from H2 18(O)-containing media into individual molecular species of phospholipids. This novel approach to quantifying lipid turnover will be supplemented with conventional radioisotope techniques utilizing [14C] glycerol.
Under Aim 1 we will examine the hypothesis that, in hepatocytes, de novo phospholipid synthesis and remodeling are quantitatively similar and closely linked to each other and to intracellular phospholipic transport and degradation, that there exist specific precursor-product relationships among phospholipid molecular species involving exchanges of acyl groups at the sn-1 and sn-2 positions of glycerol, and that alterations in the fatty acid composition of membrane phospholipids occur primarily through the de novo pathway.
Under Aim 2 we will determine whether or not oxidative stress selectively enhances turnover of polyunsaturated acyl groups in membrane phospholipids. We suspect that acyl turnover through de novo synthesis, remodeling, transport and complete deacylation is sufficiently rapid and complete to eliminate peroxidized fatty acids and to accomplish membrane """"""""repair"""""""" through recycling of the components of complex lipids rather than through selective replacement of oxidatively modified acyl groups in situ.
Under Aim 3 we will compare parameters of phospholipid acyl turnover between rat hepatocytes and mouse peritoneal macrophages. We expect to find similar relationships between de novo synthesis and remodeling of diacylglycerophospholipids and to obtain new information on the turnover of their alkylacyl and alkenylacyl analogs. Finally, we expect to obtain evidence on how stimulated acyl turnover and fatty acid liberation are superimposed on acyl turnover in testing cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM045741-03
Application #
2183357
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1993-08-01
Project End
1996-07-31
Budget Start
1995-08-01
Budget End
1996-07-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
McVey, Douglas C; Schmid, Patricia C; Schmid, Harald H O et al. (2003) Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1). J Pharmacol Exp Ther 304:713-22
Gonzalez, Sara; Schmid, Patricia C; Fernandez-Ruiz, Javier et al. (2003) Region-dependent changes in endocannabinoid transmission in the brain of morphine-dependent rats. Addict Biol 8:159-66
Schmid, Patricia C; Wold, Lester E; Krebsbach, Randy J et al. (2002) Anandamide and other N-acylethanolamines in human tumors. Lipids 37:907-12
Schmid, Harald H O; Schmid, Patricia C; Berdyshev, Evgueni V (2002) Cell signaling by endocannabinoids and their congeners: questions of selectivity and other challenges. Chem Phys Lipids 121:111-34
Schmid, H H O; Berdyshev, E V (2002) Cannabinoid receptor-inactive N-acylethanolamines and other fatty acid amides: metabolism and function. Prostaglandins Leukot Essent Fatty Acids 66:363-76
Zhang, Y; Mattjus, P; Schmid, P C et al. (2001) Involvement of the acid sphingomyelinase pathway in uva-induced apoptosis. J Biol Chem 276:11775-82
Berdyshev, E V; Schmid, P C; Krebsbach, R J et al. (2001) Activation of PAF receptors results in enhanced synthesis of 2-arachidonoylglycerol (2-AG) in immune cells. FASEB J 15:2171-8
Berdyshev, E V; Schmid, P C; Krebsbach, R J et al. (2001) Role of N-acylethanolamines in cell signaling. World Rev Nutr Diet 88:207-14
Paria, B C; Song, H; Wang, X et al. (2001) Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation. J Biol Chem 276:20523-8
Berdyshev, E V; Schmid, P C; Krebsbach, R J et al. (2001) Cannabinoid-receptor-independent cell signalling by N-acylethanolamines. Biochem J 360:67-75

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