Adenosine Triphosphate Binding Cassette (ABC) Transporters Are Expressed and Regulated During Terminal Keratinocyte Differentiation: A Potential Role for ABCA7 in Epidermal Lipid Reorganization

Abstract

Central aspects of the cellular lipid trafficking mechanisms that occur during keratinocyte differentiation are still not well understood. In the past years, evidence has accumulated to suggest that members of the superfamily of adenosine triphosphate binding cassette (ABC) transporters are critically involved in the transmembrane transport of cellular lipids. To test the hypothesis that ABC molecules are potentially involved in the epidermal transport of sphingolipids, glycerophospholipids, cholesterol, and fatty acids, we performed mRNA expression profiling of all currently known ABC molecules during in vitro differentiation of human keratinocytes and HaCaT cells. We identified six ABC molecules that displayed significant regulation during differentiation of these cells. The recently cloned transporter ABCA7 was highly expressed in keratinocytes and HaCaT cells and upregulated during differentiation. Overexpression of ABCA7 in HeLa cells resulted in increased expression of intracellular and cell surface ceramide and elevated intracellular phosphatidylserine levels. Given the observation that during terminal keratinocyte differentiation intracellular and surface ceramide levels are increased, our results render ABCA7 a candidate regulator of ceramide transport in this process. In addition to ABCA7, the cholesterol transporters ABCB1 and ABCG1 and the glutathione/glucuronide sulfate transporters ABCC1, ABCC3, and ABCC4, were strongly upregulated during keratinocyte and HaCaT cell differentiation. These findings support the notion that ABCB1 and ABCG1 are potentially implicated in cholesterol transport, whereas ABCC1, ABCC3, and ABCC4 are candidate regulators of the translocation of sulfated lipids during stratum corneum keratinization. Our results suggest specific biologic functions for members of the ABC transporter family in epidermal lipid reorganization during terminal keratinocyte differentiation.

Regulation of ABCA1 expression in human keratinocytes and murine epidermis

“…When these cells were differentiated by increasing the calcium content of the medium, there was no change in ABCA1 mRNA levels, indicating that the expression of ABCA1 in CHKs is not regulated by changes in differentiation alone. These results confirm previous studies by Schmitz's group (39) demonstrating that ABCA1 is expressed in CHKs but does not change with differentiation.…”

Nitric Oxide Storage and Transport in Cells Are Mediated by Glutathione S-Transferase P1-1 and Multidrug Resistance Protein 1 via Dinitrosyl Iron Complexes

“…In summary, the results in Fig. 3, A-D 59 Fe Efflux-To examine NO-mediated 59 Fe release from cells expressing endogenous GST P1-1, HaCaT cells were used, which express high levels of GST P1-1 (25) and MRP1 (26). We transiently transfected siRNA specific for GSTP1 relative to a scrambled siRNA control to assess the effect of decreased expression of this protein on GSNO-mediated 59 Fe release (Fig.…”

The Role of ATP Binding Cassette Transporters in Tissue Defense and Organ Regeneration

“…In human liver disease, expression levels of MRP1 and MRP3 were markedly increased, which was also seen in a comparable model conducted in rats (Ros et al, 2003a,b). Furthermore, in human keratinocytes, the differentiation of epidermal cells is characterized by the RNA up-regulation of several ABC transporters, such as MRP1, MRP3, MRP4, ABCG1, and especially ABCA7 (Kielar et al, 2003). It was suggested that ABCB1 and ABCG1 mediate the transport of phospholipids and the translocation of cholesterol.…”