Disturbed Epidermal Structure in Mice with Temporally Controlled Fatp4 Deficiency

Abstract

So far, little is known about the physiological role of fatty acid transport protein 4 (Fatp4, Slc27a4). Mice with a targeted disruption of the Fatp4 gene display features of a human neonatally lethal restrictive dermopathy with a hyperproliferative hyperkeratosis, a disturbed epidermal barrier, a flat dermal-epidermal junction, a reduced number of pilo-sebaceous structures, and a compact dermis, demonstrating that Fatp4 is necessary for the formation of the epidermal barrier. Because Fatp4 is widely expressed, it is unclear whether intrinsic Fatp4 deficiency in the epidermis alone can cause changes in the epidermal structure or whether the abnormalities observed are secondary to the loss of Fatp4 in other organs. To evaluate the functional role of Fatp4 in the skin, we generated a mouse line with Fatp4 deficiency inducible in the epidermis. Mice with epidermal keratinocyte-specific Fatp4 deficiency developed a hyperproliferative hyperkeratosis with a disturbed epidermal barrier. These changes resemble the histological abnormalities in the epidermis of newborn mice with total Fatp4 deficiency. We conclude that Fatp4 in epidermal keratinocytes is essential for the maintenance of a normal epidermal structure.

Keratinocyte-specific Expression of Fatty Acid Transport Protein 4 Rescues the Wrinkle-free Phenotype in Slc27a4/Fatp4 Mutant Mice

“…In contrast, Herrmann et al (6) found FATP4 expression only in the granular layer of newborn mice, when the hair follicles are beginning to develop and sebocytes are not yet differentiated. Our data are in closer agreement with those of Herrmann et al (12), as we observed FATP4 expression primarily in suprabasal keratinocytes. We have detected FATP4 in the dermis, although it is only barely detectable, and the staining is inconsistent.…”

“…We not only showed that FATP4 expression in the epidermis during development can rescue the mutation, but we further showed that FATP4 is only critical in the granular layer, and therefore it is likely to be crucial for initial barrier formation. But similar to the findings of Herrmann et al (12), we did observe areas of thickened epidermis in older Miw-Fatp4 rescued mutants by histological analysis, although the mice appeared overtly normal. This is likely because of decreased expression of the transgene in nonmuscle lineages (including skin) postnatally, which we have consistently observed in transgenic mouse studies that utilize the Miw regulatory element.…”

“…Regarding an intrinsic role for FATP4 in skin, FATP4 has been conditionally deleted in the skin of adult mice. By gross appearance the mice appear normal, but several mild histological abnormalities are present in the epidermis (12), supporting a direct role for FATP4 in the skin.…”

“…Herrmann et al (12) generated a conditional Fatp4 knockout allele and demonstrated a role for FATP4 in the mainte- nance of normal epidermal structure. In that study, mice carrying a tamoxifen-inducible keratinocyte-specific Cre and the floxed Fatp4 allele were treated topically with tamoxifen at 10 weeks for 5 days and again 2, 4, and 6 weeks later.…”

Fatty acid metabolism in adipocytes: functional analysis of fatty acid transport proteins 1 and 4

“…FATP4 null mice displayed features of a human neonatally lethal restrictive dermopathy that has been associated with a disturbed function in the epidermal barrier (18)(19)(20). FATP4 encodes an ACSL with substrate specificity to very LCFAs that may be required for the synthesis of lipids crucial in the formation of a healthy epidermis (21,22). Polymorphisms in the human FATP4 gene locus have identified this gene as a candidate for the insulin resistance syndrome (23).…”