Epoxyeicosatrienoic acid agonist regulates human mesenchymal stem cell-derived adipocytes through activation of HO-1-pAKT signaling and a decrease in PPARγ.

Abstract

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.

• Authors: Dong Hyun Kim, Luca Vanella, Kazuyoshi Inoue, Angela Burgess, Katherine Gotlinger, Vijaya Lingam Manthati, Sreenivasulu Reddy Koduru, Darryl C Zeldin, John R Falck, Michal L Schwartzman, Nader G Abraham
• Journal: Stem cells and development (Stem Cells Dev) Vol. 19 Issue 12 Pg. 1863-73 (Dec 2010) ISSN: 1557-8534 [Electronic] United States
• PMID: 20412023 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• 12-(3-hexylureido)dodec-8(Z)-enoic acid
• Adiponectin
• CCAAT-Enhancer-Binding Proteins
• CEBPA protein, human
• CYP2J2 protein, human
• Chromones
• Fatty Acids, Monounsaturated
• Hydroxyeicosatetraenoic Acids
• Lipids
• Metalloporphyrins
• Morpholines
• PPAR gamma
• tin mesoporphyrin
• Arachidonic Acid
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• 5-hydroxy-6,8,11,14-eicosatetraenoic acid
• Cytochrome P-450 Enzyme System
• Cytochrome P-450 CYP2J2
• HMOX1 protein, human
• Heme Oxygenase-1
• Fatty Acid Synthases
• Proto-Oncogene Proteins c-akt
• Epoxide Hydrolases
• 8,11,14-Eicosatrienoic Acid
• Glucose

Topics

• 8,11,14-Eicosatrienoic Acid (agonists, analogs & derivatives, metabolism, pharmacology)
• Adipocytes (cytology, metabolism)
• Adipogenesis (drug effects)
• Adiponectin (analysis)
• Arachidonic Acid (metabolism)
• CCAAT-Enhancer-Binding Proteins (metabolism)
• Chromones (pharmacology)
• Cytochrome P-450 CYP2J2
• Cytochrome P-450 Enzyme System (genetics, metabolism)
• Epoxide Hydrolases (antagonists & inhibitors)
• Fatty Acid Synthases (metabolism)
• Fatty Acids, Monounsaturated (pharmacology)
• Glucose (analysis)
• Heme Oxygenase-1 (antagonists & inhibitors, metabolism)
• Humans
• Hydroxyeicosatetraenoic Acids (agonists, pharmacology)
• Lipids (analysis)
• Mesenchymal Stem Cells (cytology)
• Metalloporphyrins (pharmacology)
• Morpholines (pharmacology)
• PPAR gamma (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction