Epoxyeicosatrienoic acid agonist regulates human mesenchymal stem cell-derived adipocytes through activation of HO-1-pAKT signaling and a decrease in PPARγ.
Human mesenchymal stem cells (MSCs) expressed substantial levels of CYP2J2, a major CYP450 involved in epoxyeicosatrienoic acid (EET) formation. MSCs synthesized significant levels of EETs (65.8 ± 5.8 pg/mg protein) and dihydroxyeicosatrienoic acids (DHETs) (15.83 ± 1.62 pg/mg protein), suggesting the presence of soluble epoxide hydrolase (sEH). The addition of an sEH inhibitor to MSC culture decreased adipogenesis. EETs decreased MSC-derived adipocytes in a concentration-dependent manner, 8,9- and 14,15-EET having the maximum reductive effect on adipogenesis. We examined the effect of 12-(3-hexylureido)dodec-8(Z)-enoic acid, an EET agonist, on MSC-derived adipocytes and demonstrated an increased number of healthy small adipocytes, attenuated fatty acid synthase (FAS) levels (P < 0.01), and reduced PPARγ, C/EBPα, FAS, and lipid accumulation (P < 0.05). These effects were accompanied by increased levels of heme oxygenase (HO)-1 and adiponectin (P < 0.05), and increased glucose uptake (P < 0.05). Inhibition of HO activity or AKT by tin mesoporphyrin (SnMP) and LY2940002, respectively, reversed EET-induced inhibition of adipogenesis, suggesting that activation of the HO-1-adiponectin axis underlies EET effect in MSCs. These findings indicate that EETs decrease MSC-derived adipocyte stem cell differentiation by upregulation of HO-1-adiponectin-AKT signaling and play essential roles in the regulation of adipocyte differentiation by inhibiting PPARγ, C/EBPα, and FAS and in stem cell development. These novel observations highlight the seminal role of arachidonic acid metabolism in MSCs and suggest that an EET agonist may have potential therapeutic use in the treatment of dyslipidemia, diabetes, and the metabolic syndrome.
Kim
Dong Hyun
DH
Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio 43614, USA.
Vanella
Luca
L
Inoue
Kazuyoshi
K
Burgess
Angela
A
Gotlinger
Katherine
K
Manthati
Vijaya Lingam
VL
Koduru
Sreenivasulu Reddy
SR
Zeldin
Darryl C
DC
Falck
John R
JR
Schwartzman
Michal L
ML
Abraham
Nader G
NG
D015126:8,11,14-Eicosatrienoic Acid / Q000819:agonists / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects*; D052242:Adiponectin / Q000032:analysis; D016718:Arachidonic Acid / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D064429:Fatty Acid Synthases / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005947:Glucose / Q000032:analysis; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000819:agonists / Q000494:pharmacology; D008055:Lipids / Q000032:analysis; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008665:Metalloporphyrins / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
C558427:12-(3-hexylureido)dodec-8(Z)-enoic acid; D052242:Adiponectin; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C000717350:CYP2J2 protein, human; D002867:Chromones; D005229:Fatty Acids, Monounsaturated; D006893:Hydroxyeicosatetraenoic Acids; D008055:Lipids; D008665:Metalloporphyrins; D009025:Morpholines; D047495:PPAR gamma; C055421:tin mesoporphyrin; D016718:Arachidonic Acid; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D064429:Fatty Acid Synthases; D051057:Proto-Oncogene Proteins c-akt; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; D005947:Glucose
Blood Rev. 1991 Mar;5(1):19-28
2032026
Cardiovasc Drug Rev. 2006 Summer;24(2):169-88
16961727
J Cell Biochem. 2010 Apr 1;109(5):1033-44
20108250
Curr Opin Pharmacol. 2010 Apr;10(2):111-5
20060780
J Clin Invest. 2003 Dec;112(12):1785-8
14679172
Circ Res. 2008 Jan 4;102(1):59-67
17975109
J Cell Biochem. 2007 Mar 1;100(4):815-23
17131376
Circ Res. 2002 Jan 11;90(1):5-7
11786509
Biochem Biophys Res Commun. 2004 Jan 30;314(1):197-207
14715266
J Lipid Res. 2009 Jul;50(7):1293-304
19224872
Am J Physiol Heart Circ Physiol. 2006 Oct;291(4):H1999-2002
16798831
Am J Physiol Renal Physiol. 2007 Jan;292(1):F148-57
16940561
Biochem Biophys Res Commun. 2005 May 27;331(1):347-50
15845398
Blood. 1991 Sep 15;78(6):1461-6
1909194
Am J Physiol Cell Physiol. 2007 Mar;292(3):C996-1012
16987999
J Autoimmun. 2008 May;30(3):128-35
18243659
Science. 2000 Aug 11;289(5481):950-3
10937998
Am J Physiol Renal Physiol. 2005 Sep;289(3):F496-503
16093425
Hypertension. 2009 Mar;53(3):508-15
19171794
Biochem J. 1993 Mar 1;290 ( Pt 2):297-308
8452515
Biochim Biophys Acta. 2009 Mar;1791(3):212-9
19159696
Diabetes. 2002 Jul;51(7):2199-206
12086950
Hypertension. 2007 Mar;49(3):590-6
17200437
J Mol Cell Cardiol. 2009 Jun;46(6):978-88
19336274
Circ Res. 2004 Sep 3;95(5):506-14
15256482
Stem Cells. 2009 Feb;27(2):399-407
19038792
Stem Cells. 2010 Mar 31;28(3):555-63
20073042
Bone. 2010 Jan;46(1):236-43
19853072
Clin Sci (Lond). 2010 Feb;118(4):291-301
19728860
J Bone Miner Metab. 2010 May;28(3):276-88
19924377
Mol Cell Biol. 2004 Sep;24(17):7567-77
15314166
J Lipid Res. 2008 Aug;49(8):1658-69
18426778
Prostaglandins Other Lipid Mediat. 2007 Jan;82(1-4):155-61
17164143
Diabetes. 2008 Jun;57(6):1526-35
18375438
J Pharmacol Exp Ther. 2009 Dec;331(3):906-16
19717790
J Endocrinol Invest. 2010 Feb;33(2):96-102
19636223
J Clin Pathol. 2007 Aug;60(8):956-8
17293389
Am J Physiol. 1995 Oct;269(4 Pt 1):C831-40
7485450
J Pharmacol Exp Ther. 2008 Jun;325(3):833-40
18334666
Stem Cells. 2008 Feb;26(2):381-6
17975228
J Physiol. 2009 Sep 1;587(Pt 17):4319-27
19596898
Nature. 2006 Apr 13;440(7086):944-8
16612386
Stem Cells. 2010 Mar 31;28(3):585-96
19967788
J Med Chem. 2009 Aug 27;52(16):5069-75
19653681
J Biol Chem. 1991 Oct 5;266(28):18550-4
1917977
Diabetes. 2003 Jul;52(7):1655-63
12829629
Circ J. 2009 Jan;73(1):13-8
19043226
J Pharmacol Exp Ther. 2004 Feb;308(2):636-43
14600247
Antioxid Redox Signal. 2007 Dec;9(12):2065-74
17883332
J Biol Chem. 2006 Jun 9;281(23):15687-93
16595661
J Biol Chem. 2001 Sep 28;276(39):36059-62
11451964
Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H517-31
16617127