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.
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 PPARgamma and delta but not alpha. Oleic acid (OA) and specific ligands for PPARgamma and -delta 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 PPARgamma and -delta did stimulate it and so did a PPARalpha ligand under the coexpression of PPARalpha. 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.
Fan
Bin
B
Division of Clinical Immunology, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Beppu 874-0838, Japan.
Ikuyama
Shoichiro
S
Gu
Jian-Qiu
JQ
Wei
Ping
P
Oyama
Jun-ichi
J
Inoguchi
Toyoshi
T
Nishimura
Junji
J
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D005227:Fatty Acids / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D019301:Oleic Acid / Q000494:pharmacology*; D000070780:Perilipin-2; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism / Q000502:physiology*; D010936:Plant Extracts; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D005227:Fatty Acids; D005419:Flavonoids; D008565:Membrane Proteins; D000070780:Perilipin-2; D047492:Peroxisome Proliferator-Activated Receptors; D010936:Plant Extracts; C000602983:Plin2 protein, mouse; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D019301:Oleic Acid; C024070:pycnogenols