title: DHA and EPA reverse cystic fibrosis-related FA abnormalities by suppressing FA desaturase expression and activity.
abstract: Patients and models of cystic fibrosis (CF) exhibit consistent abnormalities of polyunsaturated fatty acid composition, including decreased linoleate (LA) and docosahexaenoate (DHA) and variably increased arachidonate (AA), related in part to increased expression and activity of fatty acid desaturases. These abnormalities and the consequent CF-related pathologic manifestations can be reversed in CF mouse models by dietary supplementation with DHA. However, the mechanism is unknown. This study investigates this mechanism by measuring the effect of exogenous DHA and eicosapentaenoate (EPA) supplementation on fatty acid composition and metabolism, as well as on metabolic enzyme expression, in a cell culture model of CF. We found that both DHA and EPA suppress the expression and activity of Δ5- and Δ6-desaturases, leading to decreased flux through the n-3 and n-6 PUFA metabolic pathways and decreased production of AA. The findings also uncover other metabolic abnormalities, including increased fatty acid uptake and markedly increased retroconversion of DHA to EPA, in CF cells. These results indicate that the fatty acid abnormalities of CF are related to intrinsic alterations of PUFA metabolism and that they may be reversed by supplementation with DHA and EPA.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Sarah W
authors.initials: SW
authors.lastname: Njoroge
authors.forename: Michael
authors.initials: M
authors.lastname: Laposata
authors.forename: Waddah
authors.initials: W
authors.lastname: Katrangi
authors.forename: Adam C
authors.initials: AC
authors.lastname: Seegmiller
mesh_terms: D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000178:diet therapy / Q000378:metabolism* / Q000473:pathology; D000090943:Delta-5 Fatty Acid Desaturase; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000378:metabolism / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D015525:Fatty Acids, Omega-3 / Q000378:metabolism; D043371:Fatty Acids, Omega-6 / Q000378:metabolism; D006801:Humans; D050602:Linoleoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D005227:Fatty Acids; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D044943:Fatty Acid Desaturases; D050602:Linoleoyl-CoA Desaturase
references.citation: J Lipid Res. 2011 May;52(5):1011-22
references.pmid: 21335323
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2003 Feb;68(2):145-50
references.pmid: 12538078
references.citation: DNA Cell Biol. 1997 Jun;16(6):749-59
references.pmid: 9212168
references.citation: J Pediatr Gastroenterol Nutr. 2006 Mar;42(3):275-81
references.pmid: 16540796
references.citation: J Pediatr Gastroenterol Nutr. 2008 Nov;47(5):635-44
references.pmid: 18955866
references.citation: Am J Clin Nutr. 2011 May;93(5):950-62
references.pmid: 21367944
references.citation: Ann Nutr Metab. 2007;51(6):541-9
references.pmid: 18227622
references.citation: Prostaglandins Leukot Essent Fatty Acids. 1996 Dec;55(6):419-25
references.pmid: 9014220
references.citation: J Pediatr. 2001 Nov;139(5):650-5
references.pmid: 11713441
references.citation: Clin Exp Immunol. 1994 Oct;98(1):12-6
references.pmid: 7923869
references.citation: Chem Phys Lipids. 2008 May;153(1):3-13
references.pmid: 18343222
references.citation: J Cyst Fibros. 2006 May;5(2):77-84
references.pmid: 16507353
references.citation: Pediatr Pulmonol. 1994 Oct;18(4):211-7
references.pmid: 7838619
references.citation: Proc Natl Acad Sci U S A. 1986 Dec;83(23):9202-6
references.pmid: 3097647
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Nov;299(5):L599-606
references.pmid: 20656894
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2010 Sep;83(3):121-9
references.pmid: 20673710
references.citation: FEBS Lett. 2003 May 8;542(1-3):100-4
references.pmid: 12729906
references.citation: J Pediatr Gastroenterol Nutr. 2008 Oct;47(4):406-16
references.pmid: 18852632
references.citation: Clin Nutr. 2006 Jun;25(3):418-27
references.pmid: 16325968
references.citation: Arch Bronconeumol. 2010 Feb;46(2):70-7
references.pmid: 20045240
references.citation: JPEN J Parenter Enteral Nutr. 2003 Jan-Feb;27(1):52-7
references.pmid: 12549599
references.citation: J Nutr. 2009 Dec;139(12):2358-64
references.pmid: 19828687
references.citation: Annu Rev Nutr. 2008;28:55-72
references.pmid: 18498235
references.citation: Am J Respir Cell Mol Biol. 2009 Jul;41(1):100-6
references.pmid: 19059886
references.citation: J Biol Chem. 1957 May;226(1):497-509
references.pmid: 13428781
references.citation: Prog Lipid Res. 2006 May;45(3):237-49
references.pmid: 16564093
references.citation: Am J Respir Cell Mol Biol. 1997 Oct;17(4):481-90
references.pmid: 9376123
references.citation: J Appl Physiol (1985). 2002 May;92(5):2169-76
references.pmid: 11960971
references.citation: Lipids. 2011 Aug;46(8):669-77
references.pmid: 21544602
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2007 Nov-Dec;77(5-6):309-18
references.pmid: 18036797
references.citation: Br J Clin Pharmacol. 1990 Dec;30(6):861-9
references.pmid: 1963072
references.citation: J Lipid Res. 2008 Aug;49(8):1692-700
references.pmid: 18441018
references.citation: Lancet. 2009 May 30;373(9678):1891-904
references.pmid: 19403164
references.citation: J Lipid Res. 2008 Sep;49(9):1946-54
references.pmid: 18480495
references.citation: Br J Nutr. 2006 Aug;96(2):343-9
references.pmid: 16923229
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13995-4000
references.pmid: 10570187
references.citation: Physiol Rev. 2010 Jan;90(1):367-417
references.pmid: 20086080
references.citation: Biochim Biophys Acta. 1991 Jan 4;1081(1):85-91
references.pmid: 1825021
references.citation: Neurogastroenterol Motil. 2010 Mar;22(3):341-e87
references.pmid: 19814773
references.citation: Biochem Soc Trans. 2002 Nov;30(Pt 6):1076-9
references.pmid: 12440976
references.citation: Metabolism. 2006 Sep;55(9):1192-200
references.pmid: 16919538
references.citation: J Nutr. 2000 Dec;130(12):2870-5
references.pmid: 11110839
references.citation: PLoS One. 2010 May 05;5(5):e10446
references.pmid: 20463919
references.citation: Lipids. 1997 Mar;32(3):341-5
references.pmid: 9076673
references.citation: Respir Res. 2006 Jul 30;7:104
references.pmid: 16875506
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2008 Feb;78(2):109-15
references.pmid: 18276127
references.citation: Am J Clin Nutr. 2004 May;79(5):765-73
references.pmid: 15113713
references.citation: Mol Reprod Dev. 1995 Nov;42(3):334-46
references.pmid: 8579848
references.citation: J Nutr. 2005 Nov;135(11):2503-6
references.pmid: 16251601
references.citation: Am J Clin Nutr. 1996 Oct;64(4):577-86
references.pmid: 8839503
references.citation: Am Rev Respir Dis. 1993 Oct;148(4 Pt 1):896-901
references.pmid: 8214945
references.citation: Am J Respir Cell Mol Biol. 2000 Sep;23(3):304-12
references.pmid: 10970820
references.citation: Nutrition. 2006 Jan;22(1):36-46
references.pmid: 16226012
references.citation: Biochim Biophys Acta. 1993 Jun 19;1181(3):233-9
references.pmid: 7686400
references.citation: Respir Res. 2009 Apr 03;10:26
references.pmid: 19344509
references.citation: Science. 1989 Sep 8;245(4922):1073-80
references.pmid: 2570460
references.citation: Am J Gastroenterol. 1989 Nov;84(11):1408-12
references.pmid: 2816873
references.citation: Biochim Biophys Acta. 2011 Jul-Aug;1811(7-8):431-40
references.pmid: 21605700