Induction of SREBP-1c mRNA by Differentiation and LXR Ligand in Human Keratinocytes

The epidermis is an active site of lipid metabolism, and the synthesis of fatty acids and cholesterol is required for cutaneous homeostasis. Liver X receptor-α (LXRα) and LXRβ are nuclear receptors that are activated by oxysterols and regulate cholesterol and fatty acid metabolism. LXRs, predominantly LXRβ, have been shown to be involved in keratinocyte differentiation and epidermal permeability barrier function. Although LXR regulates hepatic lipogenesis by inducing sterol-regulatory element-binding protein-1c (SREBP-1c), SREBP-1c induction by LXR in the epidermis has not been studied. In this study, we report that SREBP-1c mRNA increased during differentiation of human keratinocyte HaCaT cells and that LXR agonist effectively induced expression of LXR target genes, including SREBP-1c and ATP-binding cassette transporter A1, in differentiated HaCaT cells. Differentiation-associated and LXR-enhanced expression of SREBP-1c was also observed in malignant human keratinocyte A431 cells and primary human keratinocytes. A synthetic LXR antagonist inhibited confluency-dependent expression of SREBP-1c. Thus, SREBP-1c expression increases during keratinocyte differentiation, and LXR activation enhances its expression.