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

Dong Hyun Kim, Luca Vanella, Kazuyoshi Inoue, Angela Burgess, Katherine Gotlinger, Vijaya Lingam Manthati, Sreenivasulu Reddy Koduru, Darryl C. Zeldin, J R Falck, Michal L. Schwartzman, Nader G. Abraham

Research output: Contribution to journalArticle

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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±5.8pg/mg protein) and dihydroxyeicosatrienoic acids (DHETs) (15.83±1.62pg/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.

Original languageEnglish (US)
Pages (from-to)1863-1873
Number of pages11
JournalStem Cells and Development
Volume19
Issue number12
DOIs
StatePublished - Dec 1 2010

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Peroxisome Proliferator-Activated Receptors
Heme Oxygenase-1
Mesenchymal Stromal Cells
Adipocytes
Acids
Fatty Acid Synthases
Adipogenesis
Adiponectin
Epoxide Hydrolases
Stem Cells
Heme Oxygenase (Decyclizing)
Therapeutic Uses
Dyslipidemias
Arachidonic Acid
Cell Differentiation
Proteins
Up-Regulation
Cell Culture Techniques
Lipids
Glucose

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Hematology

Cite this

Epoxyeicosatrienoic acid agonist regulates human mesenchymal stem cell-derived adipocytes through activation of HO-1-pAKT signaling and a decrease in PPARγ. / Kim, Dong Hyun; Vanella, Luca; Inoue, Kazuyoshi; Burgess, Angela; Gotlinger, Katherine; Manthati, Vijaya Lingam; Koduru, Sreenivasulu Reddy; Zeldin, Darryl C.; Falck, J R; Schwartzman, Michal L.; Abraham, Nader G.

In: Stem Cells and Development, Vol. 19, No. 12, 01.12.2010, p. 1863-1873.

Research output: Contribution to journalArticle

Kim, DH, Vanella, L, Inoue, K, Burgess, A, Gotlinger, K, Manthati, VL, Koduru, SR, Zeldin, DC, Falck, JR, Schwartzman, ML & Abraham, NG 2010, 'Epoxyeicosatrienoic acid agonist regulates human mesenchymal stem cell-derived adipocytes through activation of HO-1-pAKT signaling and a decrease in PPARγ', Stem Cells and Development, vol. 19, no. 12, pp. 1863-1873. https://doi.org/10.1089/scd.2010.0098
Kim, Dong Hyun ; Vanella, Luca ; Inoue, Kazuyoshi ; Burgess, Angela ; Gotlinger, Katherine ; Manthati, Vijaya Lingam ; Koduru, Sreenivasulu Reddy ; Zeldin, Darryl C. ; Falck, J R ; Schwartzman, Michal L. ; Abraham, Nader G. / Epoxyeicosatrienoic acid agonist regulates human mesenchymal stem cell-derived adipocytes through activation of HO-1-pAKT signaling and a decrease in PPARγ. In: Stem Cells and Development. 2010 ; Vol. 19, No. 12. pp. 1863-1873.
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