The long-term objective of these studies is to define how (n-3) fatty acids mediate physiological processes regulated by prostaglandins and leukotrienes. Rats will be fed three levels of fish oil and pure 20:5(n-3) and 22:6(n-3) as sources of (n-3) fatty acids. The fatty acid composition of individual phospholipids from blood granulocytes, platelets, liver, heart, kidney and pancreas will be measured to define if various levels of (n-3) acids modify the membrane fatty acid composition of circulating cells differently from tissues which also make autocoids. Platelets and granulocytes from the different groups will be stimulated with agonists to titrate whether fatty acid compositional changes correlate with altered autocoid synthesis and lipolytic activity. Metabolites will be separated by high performance liquid chromatography and the relase and metabolism of specific acids will be quantitated by mass spectrometry using deuterated fatty acids as internal standards. These acids will be prepared by total synthesis. Enzymatic studies with intact human platelets and platelet homogenates, using selective inhibitors and activators, will define if platelets contain a second lipoxygenase which is rather specific for long chain (n-3) acids. Related studies will determine whether human granulocytes metabolize 20:5(n-3) into leukotrienes other than those containing their hydroxyl groups at carbons 5 and 12 and whether 22:6(n-3) is metabolized by the w8 lipoxygenase. The metabolites produced when 22:5(n-3) and 22:6(n-3) are incubated with platelets will be isolated and added to neutrophils to ascertain if they are further metabolized or alternatively modulate arachidonic acid metabolism from ionophore A23187 stimulated cells. Kidney and lung microsomes will be incubated with radioactive (n-3) acids to define if these acids are metabolized by these tissues. The rationale for these studies being that dietary (n-3) acids probably will result in an increase in their levels of tissues which also synthesize autocoids from arachidonic acid.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK020387-11
Application #
3226715
Study Section
Metabolism Study Section (MET)
Project Start
1977-07-01
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
11
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Sprecher, H (2000) Metabolism of highly unsaturated n-3 and n-6 fatty acids. Biochim Biophys Acta 1486:219-31
Mohammed, B S; Luthria, D L; Bakousheva, S P et al. (1997) Regulation of the biosynthesis of 4,7,10,13,16-docosapentaenoic acid. Biochem J 326 ( Pt 2):425-30
Luthria, D L; Sprecher, H (1997) Studies to determine if rat liver contains multiple chain elongating enzymes. Biochim Biophys Acta 1346:221-30
Sprecher, H (1996) New advances in fatty-acid biosynthesis. Nutrition 12:S5-7
Luthria, D L; Mohammed, B S; Sprecher, H (1996) Regulation of the biosynthesis of 4,7,10,13,16,19-docosahexaenoic acid. J Biol Chem 271:16020-5
Luthria, D L; Sprecher, H (1995) Metabolism of deuterium-labeled linoleic, 6,9,12-octadecatrienoic, 8,11,14-eicosatrienoic, and arachidonic acids in the rat. J Lipid Res 36:1897-904
Sprecher, H W; Baykousheva, S P; Luthria, D L et al. (1995) Differences in the regulation of biosynthesis of 20- versus 22-carbon polyunsaturated fatty acids. Prostaglandins Leukot Essent Fatty Acids 52:99-101
Luthria, D L; Baykousheva, S P; Sprecher, H (1995) Double bond removal from odd-numbered carbons during peroxisomal beta-oxidation of arachidonic acid requires both 2,4-dienoyl-CoA reductase and delta 3,5,delta 2,4-dienoyl-CoA isomerase. J Biol Chem 270:13771-6
Sprecher, H; Luthria, D L; Mohammed, B S et al. (1995) Reevaluation of the pathways for the biosynthesis of polyunsaturated fatty acids. J Lipid Res 36:2471-7
Mohammed, B S; Sankarappa, S; Geiger, M et al. (1995) Reevaluation of the pathway for the metabolism of 7,10,13, 16-docosatetraenoic acid to 4,7,10,13,16-docosapentaenoic acid in rat liver. Arch Biochem Biophys 317:179-84

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