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Fatty acid transport protein 1 can compensate for fatty acid transport protein 4 in the developing mouse epidermis.

Lin MH, Miner JH - J. Invest. Dermatol. (2014)

Bottom Line: Transgenic expression of FATP1 in suprabasal keratinocytes rescued the phenotype of Fatp4 mutants, and FATP1 sorted to the same intracellular organelles as endogenous FATP4.Thus, FATP1 and FATP4 likely have overlapping substrate specificities, enzymatic activities, and biological functions.These results suggest that increasing expression of FATP1 in suprabasal keratinocytes could normalize the skin of IPS patients and perhaps prevent the atopic manifestations.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Washington University School of Medicine, St. Louis, Missouri, USA.

ABSTRACT
Fatty acid transport protein (FATP) 4 is one of a family of six FATPs that facilitate long- and very-long-chain fatty acid uptake. Mice lacking FATP4 are born with tight, thick skin and a defective barrier; they die neonatally because of dehydration and restricted movements. Mutations in SLC27A4, the gene encoding FATP4, cause ichthyosis prematurity syndrome (IPS), characterized by premature birth, respiratory distress, and edematous skin with severe ichthyotic scaling. Symptoms of surviving patients become mild, although atopic manifestations are common. We previously showed that suprabasal keratinocyte expression of a Fatp4 transgene in Fatp4 mutant skin rescues the lethality and ameliorates the skin phenotype. Here we tested the hypothesis that FATP1, the closest FATP4 homolog, can compensate for the lack of FATP4 in our mouse model of IPS, as it might do postnatally in IPS patients. Transgenic expression of FATP1 in suprabasal keratinocytes rescued the phenotype of Fatp4 mutants, and FATP1 sorted to the same intracellular organelles as endogenous FATP4. Thus, FATP1 and FATP4 likely have overlapping substrate specificities, enzymatic activities, and biological functions. These results suggest that increasing expression of FATP1 in suprabasal keratinocytes could normalize the skin of IPS patients and perhaps prevent the atopic manifestations.

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Restoration of the skin barrier in Fatp4−/−;Tg(IVL-Fatp1) and Fatp4−/−;Tg(IVL-Fatp4) mice(a) Dorsal skin sections from E16.0 littermate embryos were subjected to in situ hybridization and counterstained with nuclear fast red. Fatp4 RNA was detected in suprabasal keratinocytes of Fatp4+/− (control) and in nuclei of some Fatp4−/− keratinocytes (top panels). Fatp1 RNA was detected in basal keratinocytes and hair follicle (asterisks) progenitors of Fatp4+/− and Fatp4−/− embryos, and additionally detected in suprabasal keratinocytes of Fatp4−/−;Tg(IVL-Fatp1) embryos (lower panels). Dashed lines demarcate the dermo-epidermal boundary. Scale bar is 50 μm. (b) E17.5 littermate embryos were tested for inward X-Gal permeability. The incomplete barrier in Fatp4−/− embryos was remedied in Fatp4−/−;Tg(IVL-Fatp1) embryos (asterisk). (c, d) Newborns were tested for outward TEWL assays. The increased TEWL in Fatp4−/− newborns compared to Fatp4+/− controls was normalized in both Fatp4−/−;Tg(IVL-Fatp1) (c) and Fatp4−/−;Tg(IVL-Fatp4) newborns (d). Numbers of samples (n) are indicated. ***P<0.001; *P<0.05. The TEWL readings in c and d were obtained from two separate Vapometers.
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Figure 1: Restoration of the skin barrier in Fatp4−/−;Tg(IVL-Fatp1) and Fatp4−/−;Tg(IVL-Fatp4) mice(a) Dorsal skin sections from E16.0 littermate embryos were subjected to in situ hybridization and counterstained with nuclear fast red. Fatp4 RNA was detected in suprabasal keratinocytes of Fatp4+/− (control) and in nuclei of some Fatp4−/− keratinocytes (top panels). Fatp1 RNA was detected in basal keratinocytes and hair follicle (asterisks) progenitors of Fatp4+/− and Fatp4−/− embryos, and additionally detected in suprabasal keratinocytes of Fatp4−/−;Tg(IVL-Fatp1) embryos (lower panels). Dashed lines demarcate the dermo-epidermal boundary. Scale bar is 50 μm. (b) E17.5 littermate embryos were tested for inward X-Gal permeability. The incomplete barrier in Fatp4−/− embryos was remedied in Fatp4−/−;Tg(IVL-Fatp1) embryos (asterisk). (c, d) Newborns were tested for outward TEWL assays. The increased TEWL in Fatp4−/− newborns compared to Fatp4+/− controls was normalized in both Fatp4−/−;Tg(IVL-Fatp1) (c) and Fatp4−/−;Tg(IVL-Fatp4) newborns (d). Numbers of samples (n) are indicated. ***P<0.001; *P<0.05. The TEWL readings in c and d were obtained from two separate Vapometers.

Mentions: By in situ hybridization, Fatp4 was normally expressed in fetal epidermis in suprabasal keratinocytes (upper left panel in Figure 1a) and in hair follicle and sebaceous gland progenitors (Lin et al., 2013). In contrast, Fatp4−/− mice showed nuclear localization of Fatp4 RNA in some epidermal keratinocytes, perhaps due to mislocalization of mutant transcripts caused by inclusion of the retrotransposon (upper middle panel in Figure 1a) (Lin et al., 2013). FATP1 is the FATP with the highest homology to FATP4 (Hirsch et al., 1998). Fatp1 RNA was detected in subsets of basal keratinocytes, in hair follicle progenitors (lower left panel in Figure 1a), and in subcutaneous adipocytes (data not shown) during fetal development. Its epidermal expression did not appear to be affected by the lack of FATP4 (lower middle panel in Figure 1a). Thus, Fatp4 and Fatp1 are expressed in nearly complementary compartments in fetal mouse skin.


Fatty acid transport protein 1 can compensate for fatty acid transport protein 4 in the developing mouse epidermis.

Lin MH, Miner JH - J. Invest. Dermatol. (2014)

Restoration of the skin barrier in Fatp4−/−;Tg(IVL-Fatp1) and Fatp4−/−;Tg(IVL-Fatp4) mice(a) Dorsal skin sections from E16.0 littermate embryos were subjected to in situ hybridization and counterstained with nuclear fast red. Fatp4 RNA was detected in suprabasal keratinocytes of Fatp4+/− (control) and in nuclei of some Fatp4−/− keratinocytes (top panels). Fatp1 RNA was detected in basal keratinocytes and hair follicle (asterisks) progenitors of Fatp4+/− and Fatp4−/− embryos, and additionally detected in suprabasal keratinocytes of Fatp4−/−;Tg(IVL-Fatp1) embryos (lower panels). Dashed lines demarcate the dermo-epidermal boundary. Scale bar is 50 μm. (b) E17.5 littermate embryos were tested for inward X-Gal permeability. The incomplete barrier in Fatp4−/− embryos was remedied in Fatp4−/−;Tg(IVL-Fatp1) embryos (asterisk). (c, d) Newborns were tested for outward TEWL assays. The increased TEWL in Fatp4−/− newborns compared to Fatp4+/− controls was normalized in both Fatp4−/−;Tg(IVL-Fatp1) (c) and Fatp4−/−;Tg(IVL-Fatp4) newborns (d). Numbers of samples (n) are indicated. ***P<0.001; *P<0.05. The TEWL readings in c and d were obtained from two separate Vapometers.
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Figure 1: Restoration of the skin barrier in Fatp4−/−;Tg(IVL-Fatp1) and Fatp4−/−;Tg(IVL-Fatp4) mice(a) Dorsal skin sections from E16.0 littermate embryos were subjected to in situ hybridization and counterstained with nuclear fast red. Fatp4 RNA was detected in suprabasal keratinocytes of Fatp4+/− (control) and in nuclei of some Fatp4−/− keratinocytes (top panels). Fatp1 RNA was detected in basal keratinocytes and hair follicle (asterisks) progenitors of Fatp4+/− and Fatp4−/− embryos, and additionally detected in suprabasal keratinocytes of Fatp4−/−;Tg(IVL-Fatp1) embryos (lower panels). Dashed lines demarcate the dermo-epidermal boundary. Scale bar is 50 μm. (b) E17.5 littermate embryos were tested for inward X-Gal permeability. The incomplete barrier in Fatp4−/− embryos was remedied in Fatp4−/−;Tg(IVL-Fatp1) embryos (asterisk). (c, d) Newborns were tested for outward TEWL assays. The increased TEWL in Fatp4−/− newborns compared to Fatp4+/− controls was normalized in both Fatp4−/−;Tg(IVL-Fatp1) (c) and Fatp4−/−;Tg(IVL-Fatp4) newborns (d). Numbers of samples (n) are indicated. ***P<0.001; *P<0.05. The TEWL readings in c and d were obtained from two separate Vapometers.
Mentions: By in situ hybridization, Fatp4 was normally expressed in fetal epidermis in suprabasal keratinocytes (upper left panel in Figure 1a) and in hair follicle and sebaceous gland progenitors (Lin et al., 2013). In contrast, Fatp4−/− mice showed nuclear localization of Fatp4 RNA in some epidermal keratinocytes, perhaps due to mislocalization of mutant transcripts caused by inclusion of the retrotransposon (upper middle panel in Figure 1a) (Lin et al., 2013). FATP1 is the FATP with the highest homology to FATP4 (Hirsch et al., 1998). Fatp1 RNA was detected in subsets of basal keratinocytes, in hair follicle progenitors (lower left panel in Figure 1a), and in subcutaneous adipocytes (data not shown) during fetal development. Its epidermal expression did not appear to be affected by the lack of FATP4 (lower middle panel in Figure 1a). Thus, Fatp4 and Fatp1 are expressed in nearly complementary compartments in fetal mouse skin.

Bottom Line: Transgenic expression of FATP1 in suprabasal keratinocytes rescued the phenotype of Fatp4 mutants, and FATP1 sorted to the same intracellular organelles as endogenous FATP4.Thus, FATP1 and FATP4 likely have overlapping substrate specificities, enzymatic activities, and biological functions.These results suggest that increasing expression of FATP1 in suprabasal keratinocytes could normalize the skin of IPS patients and perhaps prevent the atopic manifestations.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Washington University School of Medicine, St. Louis, Missouri, USA.

ABSTRACT
Fatty acid transport protein (FATP) 4 is one of a family of six FATPs that facilitate long- and very-long-chain fatty acid uptake. Mice lacking FATP4 are born with tight, thick skin and a defective barrier; they die neonatally because of dehydration and restricted movements. Mutations in SLC27A4, the gene encoding FATP4, cause ichthyosis prematurity syndrome (IPS), characterized by premature birth, respiratory distress, and edematous skin with severe ichthyotic scaling. Symptoms of surviving patients become mild, although atopic manifestations are common. We previously showed that suprabasal keratinocyte expression of a Fatp4 transgene in Fatp4 mutant skin rescues the lethality and ameliorates the skin phenotype. Here we tested the hypothesis that FATP1, the closest FATP4 homolog, can compensate for the lack of FATP4 in our mouse model of IPS, as it might do postnatally in IPS patients. Transgenic expression of FATP1 in suprabasal keratinocytes rescued the phenotype of Fatp4 mutants, and FATP1 sorted to the same intracellular organelles as endogenous FATP4. Thus, FATP1 and FATP4 likely have overlapping substrate specificities, enzymatic activities, and biological functions. These results suggest that increasing expression of FATP1 in suprabasal keratinocytes could normalize the skin of IPS patients and perhaps prevent the atopic manifestations.

Show MeSH
Related in: MedlinePlus