Induction of Adipose Differentiation Related Protein and Neutral Lipid Droplet Accumulation in Keratinocytes by Skin Irritants

Corsini, E.; Viviani, Bárbara; Zancanella, Omar; Lucchi, Laura; Visioli, Francesco; Serrero, Ginette; Bartesaghi, Stefano; Galli, C. L.; Marinovich, Marina

doi:10.1046/j.1523-1747.2003.12371.x

Cited by 26 publications

(20 citation statements)

References 37 publications

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“…Although it has been shown that several pathological or pharmacological stimuli enhance ADRP expression, the precise molecular mechanism regulating the expression is not fully elucidated. In previous studies, we and others demonstrated that an inflammatory signal, such as PMA or LPS, stimulates ADRP expression in macrophages (14,23,62), hepatocytes (46), and keratinocytes (15). We identified the Ets/AP-1 composite element in the mouse ADRP promoter and proved that it mediates, in part, the action of PMA or LPS, which enhances ADRP expression in RAW264.7 cells (23,62).…”

Section: Discussionmentioning

confidence: 60%

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

Fan¹,

Ikuyama²,

Gu³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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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...

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Section: Discussionmentioning

confidence: 60%

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

Fan¹,

Ikuyama²,

Gu³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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“…keratinocytes exposed to irritants (Corsini et al, 2003). Since studies by other investigators have shown that activation of PPAR-b/d stimulates adipocyte differentiation (Bastie et al, 2000), we assessed if treatment of keratinocytes with PPAR-b/d activator was inducing an adipocyte phenotype in keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

“…ADRP is associated with intracellular lipid droplets (Brasaemle et al, 1997;Frolov et al, 2000;Corsini et al, 2003;Schmuth, 2003) and reportedly facilitates fatty acid binding and uptake in COS-7 cells (Gao et al, 2000), as well as the transfer of triacylglycerol from lipofibroblasts to surfactant producing epithelial cells in the lung (Schultz et al, 2002). FIAF was previously reported to be increased in liver and white adipose tissue during fasting but the function of this protein is unknown.…”

Section: Figurementioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor (PPAR)-β/δ Stimulates Differentiation and Lipid Accumulation in Keratinocytes

Schmuth

Haqq

Cairns

et al. 2004

Journal of Investigative Dermatology

219

214

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Peroxisome proliferator-activated receptor (PPAR) are nuclear hormone receptors that are activated by endogenous lipid metabolites. Previous studies have demonstrated that PPAR-alpha activation stimulates keratinocyte differentiation in vitro and in vivo, is anti-inflammatory, and improves barrier homeostasis. Recent studies have shown that PPAR-beta/delta activation induces keratinocyte differentiation in vitro. This study demonstrated that topical treatment of mice with a selective PPAR-beta/delta agonist (GW1514) in vivo had pro-differentiating effects, was anti-inflammatory, improved barrier homeostasis, and stimulated differentiation in a disease model of epidermal hyperproliferation [corrected]. In contrast to PPAR-alpha activation, PPAR-beta/deltain vivo did not display anti-proliferative or pro-apoptotic effects. The pro-differentiating effects persisted in mice lacking PPAR-alpha, but were decreased in mice deficient in retinoid X receptor-alpha, the major heterodimerization partner of PPAR. Furthermore, in vitro PPAR-beta/delta activation, aside from stimulating differentiation-related genes, additionally induced adipose differentiation-related protein (ADRP) and fasting induced adipose factor (FIAF) mRNA in cultures keratinocytes, which was paralleled by increased oil red O staining indicative of lipid accumulation, the bulk of which were triglycerides (TG). Comparison of differentially expressed genes between PPAR-beta/delta and PPAR-alpha activation revealed distinct profiles. Together, these studies indicate that PPAR-beta/delta activation stimulates keratinocyte differentiation, is anti-inflammatory, improves barrier homeostasis, and stimulates TG accumulation in keratinocytes.

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“…Adfp expression is induced during differentiation of adipocytes and other specialized cells such as keratinocytes and trophoblasts (1,55), upon lipid loading, or under pathological conditions in other tissues and cells (5,11,13,22,54,60,66). Adfp expression is upregulated in 1246 cells by long-chain but not short-chain FAs (17).…”

mentioning

confidence: 99%

Protection against Fatty Liver but Normal Adipogenesis in Mice Lacking Adipose Differentiation-Related Protein

Chang

Li²,

Paul

et al. 2006

Molecular and Cellular Biology

289

298

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Adipose differentiation-related protein (ADFP; also known as ADRP or adipophilin), is a lipid droplet (LD) protein found in most cells and tissues. ADFP expression is strongly induced in cells with increased lipid load. We have inactivated the Adfp gene in mice to better understand its role in lipid accumulation. The Adfpdeficient mice have unaltered adipose differentiation or lipolysis in vitro or in vivo. Importantly, they display a 60% reduction in hepatic triglyceride (TG) and are resistant to diet-induced fatty liver. To determine the mechanism for the reduced hepatic TG content, we measured hepatic lipogenesis, very-low-density lipoprotein (VLDL) secretion, and lipid uptake and utilization, all of which parameters were shown to be similar between mutant and wild-type mice. The finding of similar VLDL output in the presence of a reduction in total TG in the Adfp-deficient liver is explained by the retention of TG in the microsomes where VLDL is assembled. Given that lipid droplets are thought to form from the outer leaflet of the microsomal membrane, the reduction of TG in the cytosol with concomitant accumulation of TG in the microsome of Adfp ؊/؊ cells suggests that ADFP may facilitate the formation of new LDs. In the absence of ADFP, impairment of LD formation is associated with the accumulation of microsomal TG but a reduction in TG in other subcellular compartments.Adipose differentiation-related protein (ADFP) was first isolated by differential hybridization screening of 1246 cells during their differentiation to adipocytes (29). Its mRNA is induced 100 fold during the process. Using 3T3L1 cells, Brasaemle et al. (3) showed that Adfp gene expression is induced early, at day 1 of adipocyte differentiation, and that mRNA levels are maintained throughout differentiation. In contrast, ADFP protein levels, initially upregulated, gradually go down after day 4 (3), suggesting that these levels are subject to significant translational or posttranslational regulation. At the same time, upregulation of perilipin (PLIN), another lipid droplet (LD) protein, is observed at day 4 of differentiation; it has been postulated that perilipin and ADFP might compete for LD localization during the differentiation of 3T3L1 cells (3, 36). ADFP protein is localized to the surface of the LD, though it also has been detected in the LD core by freeze fracture electron microscopy (49, 50).ADFP shares sequence homology with other LD proteins including perilipin and Tip47, collectively known as PAT domain-containing proteins (36, 43), as well as with another LD protein, S3-12 (53). S3-12 shares a 11-amino-acid repeat motif with ADFP, in addition to another region of homology to both ADFP and Tip47 at its carboxyl terminus (6,24,36). With the exception of perilipin, which is expressed only in fat and steroidogenic tissues, the other LD proteins are detected in a variety of cells and tissues (22). Perilipin is phosphorylated by protein kinase A during lipolysis, resulting in an altered conformation to allow hormone-sensitive lipase ...

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Induction of Adipose Differentiation Related Protein and Neutral Lipid Droplet Accumulation in Keratinocytes by Skin Irritants

Cited by 26 publications

References 37 publications

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

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

Peroxisome Proliferator-Activated Receptor (PPAR)-β/δ Stimulates Differentiation and Lipid Accumulation in Keratinocytes

Protection against Fatty Liver but Normal Adipogenesis in Mice Lacking Adipose Differentiation-Related Protein

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