ATP-binding cassette (ABC) transporter, family 12 (ABCA12), a member of the ABC superfamily, facilitates the delivery of lipids to lamellar bodies (LB) in keratinocytes, which is critical for permeability barrier function. Recently, gene mutations of ABCA12 were found to underlie Harlequin ichthyosis and lamellar ichthyosis, two devastating skin disorders. Previously we and others have demonstrated that peroxisome proliferators-activated receptors (PPARs) and liver X receptor (LXR) activation improved epidermal permeability barrier homeostasis by stimulating keratinocyte differentiation, lipid synthesis, and increasing LB formation/secretion. Here we report that both PPAR-gamma and -beta/delta activators markedly stimulate ABCA12 mRNA expression in cultured human keratinocyte (CHK) in a dose- and time-dependent manner. Increased ABCA12 mRNA levels are accompanied by an increase in ABCA12 protein, suggesting biological importance of this upregulation. LXR activators also increase ABCA12 mRNA levels in CHK, but to a lesser extent. In contrast, activators of PPAR-alpha, RAR, RXR, or vitamin D receptor did not alter ABCA12 expression. Two major ABCA12 alternative transcripts and their corresponding proteins are also expressed and upregulated by PPAR or LXR activator in both undifferentiated and differentiated CHK. Together, our data demonstrate that PPAR and LXR activators increase ABCA12 expression, providing an additional mechanism by which PPAR and LXR activators promote epidermal permeability barrier homeostasis.