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

Abstract

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 PPAR␥ and ␦ but not ␣. Oleic acid (OA) and specific ligands for PPAR␥ and -␦ stimulated ADRP expression as well as the Ϫ2,090-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 PPAR␥ and -␦ did stimulate it and so did a PPAR␣ ligand under the coexpression of PPAR␣. 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 OAinduced 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. lipid droplet; hepatic steatosis; adipose differentiation-related protein; activator protein-1; peroxisome proliferator-activated receptor CYTOSOLIC LIPID DROPLETS are physiologically important because they have specific function in various cell types or tissues, for example, as an energy reservoir in adipocytes, sites of storage and biosynthesis of eicosanoids in leukocytes, and sites of production of pulmonary surfactants in pneumocytes (44). It has been demonstrated that excessive lipid accumulation, not only in an adipose tissue but also in various nonadipose tissues, is closely related to a variety of pathological conditions, including insulin resistance, type 2 diabetes mellitus, cardiovascular diseases, and fatty liver or nonalcoholic steatohepatitis (2, 59), all of which are emerging as important clinical ands socioeconomical worldwide problems. Mechanisms of intracellular lipid droplet formation have, therefore, increasingly attracted clinical and scientific interests.A variety of proteins are associated with intracellular lipid droplets (10). Among them, PAT family proteins, which comprise perilipin, adipose differentiation-related protein (ADRP), TIP47, S3-12 and OXPAT/MLDP, are implicated in the formation, stabilization, and metabolism of lipid droplets (8, 37). ADRP was first identified in the early stages of adipocyte differentiation (33). Later studies revealed that ADRP does not directly induce adipogenesis but instead facilitates uptake of fatty ac...

Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia

“…Fatty acids can bind peroxisome proliferator activated receptors (PPAR) α-and -γ and thereby regulate gene expression [52]. A PPAR response element (PPRE) is located in the promoter region of perilipin-2 [53] and regulates perilipin-2 expression in OA-treated cells [54]. OA was also shown to affect the post-translational regulation of perilipin-2 (ADRP).…”

Pine Bark Extracts: Nutraceutical, Pharmacological, and Toxicological Evaluation

“…Fan et al (2009) demonstrated that PYC achieved these effects by enhancing ADRP mRNA degradation. The intracellular lipid accumulation suppressing activity of PYC indicates a potential use in treating fatty liver disease (Fan et al, 2009).…”

“…These findings strongly implicate ADRP as a promising target for preventing excessive lipid accumulation, which can induce the production of oleic acid if intracellular. PYC has been shown to reduce oleic acid-induced ADRP expression and suppress the formation of lipid droplets (Fan et al, 2009). Fan et al (2009) demonstrated that PYC achieved these effects by enhancing ADRP mRNA degradation.…”

“…PYC has been shown to reduce oleic acid-induced ADRP expression and suppress the formation of lipid droplets (Fan et al, 2009). Fan et al (2009) demonstrated that PYC achieved these effects by enhancing ADRP mRNA degradation. The intracellular lipid accumulation suppressing activity of PYC indicates a potential use in treating fatty liver disease (Fan et al, 2009).…”

Regulation of fat specific protein 27 by isoproterenol and TNF-α to control lipolysis in murine adipocytes

“…The detailed molecular mechanisms whereby TNF-␣ downregulates FSP27 mRNA and protein levels is an important topic for future investigations. let protein ADRP via the transcription factor AP1 and the PPAR response element ( 53 ). The increase in FSP27 after oleic acid treatment may involve similar mechanisms because the FSP27 promoter also has a PPAR response element.…”