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

Abstract

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.

Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells

“…Recent literatures suggest that PPAR-b activation induces the terminal differentiation of keratinocytes, coupled with the inhibition of cell proliferation (Schmuth et al, 2004;Kim et al, 2006;Burdick et al, 2006). These studies enable us to hypothesize that PPAR-b possibly has some role in the differentiation of colon cancer, and might affect the cell adhesion, migration and/or invasion that are associated with tumor differentiation.…”

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines

“…Anti-inflammatory activity of PPARβ/δ and/or PPARβ/δ ligands has been shown in a number of different models including immune cells, colon epithelium, macrophages, cardiomyocytes, keratinocytes, myoblasts, endothelial cells, nerve tissue and hepatocytes Graham et al 2005;Hollingshead et al 2007b;Jakobsen et al 2006;Kim et al 2006;Nagasawa et al 2006;Peters et al 2000;Polak et al 2005;Rival et al 2002;Schmuth et al 2004;Welch et al 2003;Woo et al 2006). There is also strong evidence that ligand activation of PPARβ/δ promotes terminal differentiation in intestinal epithelium, breast and colon cancer cell lines, trophoblasts and primary keratinocytes (Aung et al 2006;Burdick et al 2007;Kim et al 2006;Marin et al 2006;Nadra et al 2006;Schmuth et al 2004;Tan et al 2001;Varnat et al 2006;Westergaard et al 2001).…”

Peroxisome Proliferator‐Activated Receptors: Potential Therapeutic Targets in Lung Disease?

“…Following their identification, a rapidly increasing number of articles and reviews have been written, including those that focus on PPAR expression, function, and regulation, 2,3 as well as their role in lipid and glucose metabolism, [4][5][6][7] diabetes and obesity, [8][9][10] atherosclerosis, 4,8,11 cellular proliferation/differentiation, [12][13][14][15] neurological diseases, [16][17][18] and inflammation/immunity. 7,[19][20][21] These publications are recommended to readers who want additional information on these topics.…”

“…3,23 Activation of PPARa also appears to play a role in cellular differentiation, including promoting keratinocyte differentiation and wound-healing in skin. 14 The isoform PPARb/d is more widely expressed and appears to be important for regulating cellular differentiation, brain lipid metabolism and myelination, adipogenesis, and fertility. 3,6,14 PPARg is expressed at its highest levels in the intestine and adipose tissues.…”

“…14 The isoform PPARb/d is more widely expressed and appears to be important for regulating cellular differentiation, brain lipid metabolism and myelination, adipogenesis, and fertility. 3,6,14 PPARg is expressed at its highest levels in the intestine and adipose tissues. 7 PPARg regulates the expression of proteins involved in lipid metabolism, glucose metabolism, and differentiation of cells, including keratinocytes, adipocytes, macrophages, and epithelial cells.…”