Oleic acid-induced ADRP expression requires both AP-1 and PPAR response elements, and is reduced by Pycnogenol through mRNA degradation in NMuLi liver cells

Bin Fan, Shoichiro Ikuyama, Jian Qiu Gu, Ping Wei, Jun Ichi Oyama, Toyoshi Inoguchi, Junji Nishimura

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30 Citations (Scopus)

Abstract

Fatty acids stimulate lipid accumulation in parallel with increased expression of adipose differentiation-related protein (ADRP) in liver cells. Although it is generally considered that the fatty acid effect on ADRP expression is mediated by peroxisome proliferator-activated receptors (PPARs), we identified here an additional molecular mechanism using the NMuLi mouse liver nonparenchymal cell line, which expresses PPARγ and δ but not α. Oleic acid (OA) and specific ligands for PPARγ and -δ stimulated ADRP expression as well as the -2,090-bp ADRP promoter activity which encompasses the PPAR response element (PPRE) adjacent to an Ets/activator protein (AP)-1 site. When the AP-1 site was mutated, OA failed to stimulate the activity despite the presence of the PPRE, whereas ligands for PPARγ and -δ did stimulate it and so did a PPARα ligand under the coexpression of PPARα. DNA binding of AP-1 was stimulated by OA but not by PPAR ligands. Because we previously demonstrated that Pycnogenol (PYC), a French maritime pine bark extract, suppressed ADRP expression in macrophages partly by suppression of AP-1 activity, we tested the effect of PYC on NMuLi cells. PYC reduced the OA-induced ADRP expression along with suppression of lipid droplet formation. However, PYC neither suppressed the OA-stimulated ADRP promoter activity nor DNA binding of AP-1 but, instead, reduced the ADRP mRNA half-life. All these results indicate that the effect of OA on ADRP expression requires AP-1 as well as PPRE, and PYC suppresses the ADRP expression in part by facilitating mRNA degradation. PYC, a widely used dietary supplement, could be beneficial for the prevention of excessive lipid accumulation such as hepatic steatosis.

Original languageEnglish
Pages (from-to)E112-E123
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume297
Issue number1
DOIs
Publication statusPublished - Jul 1 2009

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All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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