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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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Subcellular localization of endogenous FATP4 and transgenic FATP1 in granular keratinocytesGranular keratinocytes from the epidermis of newborns (a–i′, m–o′) or 1.5 (j–l′) or 5.5-day-old (p–u′) pups were subjected to double immunofluorescence staining with the indicated antibodies. Merged confocal images of low and high magnification are shown in the right two columns. The mesh-like pattern of FATP4 staining in Fatp4+/+ cells colocalized partially with the mitochondrial membrane protein ATP synthase (a–c′; arrowheads in c′) and mainly with the ER luminal protein calreticulin (d–f′), but not with the plasma membrane protein interleukin 1 receptor 1 (g–i′). The mesh-like pattern of FATP4 localization was similar to the staining pattern of calreticulin around the filaggrin-positive granules (j–l′). The HA-tagged FATP1 in Fatp4+/+;Tg(IVL-Fatp1) cells also showed a mesh-like staining pattern that colocalized with endogenous FATP4 (s–u′). The HA-tagged FATP1 was not detected in Fatp4+/+ cells (m–o′). Endogenous FATP4 was not detected in Fatp4−/−;Tg(IVL-Fatp1) cells (p–r′). Scale bar is 10 μm.
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Figure 5: Subcellular localization of endogenous FATP4 and transgenic FATP1 in granular keratinocytesGranular keratinocytes from the epidermis of newborns (a–i′, m–o′) or 1.5 (j–l′) or 5.5-day-old (p–u′) pups were subjected to double immunofluorescence staining with the indicated antibodies. Merged confocal images of low and high magnification are shown in the right two columns. The mesh-like pattern of FATP4 staining in Fatp4+/+ cells colocalized partially with the mitochondrial membrane protein ATP synthase (a–c′; arrowheads in c′) and mainly with the ER luminal protein calreticulin (d–f′), but not with the plasma membrane protein interleukin 1 receptor 1 (g–i′). The mesh-like pattern of FATP4 localization was similar to the staining pattern of calreticulin around the filaggrin-positive granules (j–l′). The HA-tagged FATP1 in Fatp4+/+;Tg(IVL-Fatp1) cells also showed a mesh-like staining pattern that colocalized with endogenous FATP4 (s–u′). The HA-tagged FATP1 was not detected in Fatp4+/+ cells (m–o′). Endogenous FATP4 was not detected in Fatp4−/−;Tg(IVL-Fatp1) cells (p–r′). Scale bar is 10 μm.

Mentions: By hematoxylin staining, granular keratinocytes isolated from control mice were filled with keratohyalin granules (lower left panel in Figure 4). Compared to controls, granular keratinocytes from Fatp4−/− newborns were smaller, and the granules were less distinct (middle column in Figure 4). In contrast, these abnormalities were remedied in Fatp4−/−;Tg(IVL-Fatp4) cells and Fatp4−/−;Tg(IVL-Fatp1) cells (right column in Figure 4). By double immunofluorescence staining, endogenous FATP4 in control cells was detected in a mesh-like pattern that colocalized mainly with the ER luminal protein calreticulin (Figure 5d–f′) and partially with the mitochondrial membrane protein ATP synthase (Figure 5a–c′; arrowheads in c′). The FATP4 signals were also observed at the nuclear surface, which is very likely the ER membrane that is contiguous with the nuclear membrane. Using interleukin 1 receptor 1 as a marker, we could not detect FATP4 at the plasma membrane (Figure 5g–i′). The mesh-like pattern of FATP4 staining was similar to the inter-granular staining of calreticulin (Figure 5j–l′). FATP4 was not detected in Fatp4−/− cells (Figure 5p–r′ and data not shown).


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)

Subcellular localization of endogenous FATP4 and transgenic FATP1 in granular keratinocytesGranular keratinocytes from the epidermis of newborns (a–i′, m–o′) or 1.5 (j–l′) or 5.5-day-old (p–u′) pups were subjected to double immunofluorescence staining with the indicated antibodies. Merged confocal images of low and high magnification are shown in the right two columns. The mesh-like pattern of FATP4 staining in Fatp4+/+ cells colocalized partially with the mitochondrial membrane protein ATP synthase (a–c′; arrowheads in c′) and mainly with the ER luminal protein calreticulin (d–f′), but not with the plasma membrane protein interleukin 1 receptor 1 (g–i′). The mesh-like pattern of FATP4 localization was similar to the staining pattern of calreticulin around the filaggrin-positive granules (j–l′). The HA-tagged FATP1 in Fatp4+/+;Tg(IVL-Fatp1) cells also showed a mesh-like staining pattern that colocalized with endogenous FATP4 (s–u′). The HA-tagged FATP1 was not detected in Fatp4+/+ cells (m–o′). Endogenous FATP4 was not detected in Fatp4−/−;Tg(IVL-Fatp1) cells (p–r′). Scale bar is 10 μm.
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Figure 5: Subcellular localization of endogenous FATP4 and transgenic FATP1 in granular keratinocytesGranular keratinocytes from the epidermis of newborns (a–i′, m–o′) or 1.5 (j–l′) or 5.5-day-old (p–u′) pups were subjected to double immunofluorescence staining with the indicated antibodies. Merged confocal images of low and high magnification are shown in the right two columns. The mesh-like pattern of FATP4 staining in Fatp4+/+ cells colocalized partially with the mitochondrial membrane protein ATP synthase (a–c′; arrowheads in c′) and mainly with the ER luminal protein calreticulin (d–f′), but not with the plasma membrane protein interleukin 1 receptor 1 (g–i′). The mesh-like pattern of FATP4 localization was similar to the staining pattern of calreticulin around the filaggrin-positive granules (j–l′). The HA-tagged FATP1 in Fatp4+/+;Tg(IVL-Fatp1) cells also showed a mesh-like staining pattern that colocalized with endogenous FATP4 (s–u′). The HA-tagged FATP1 was not detected in Fatp4+/+ cells (m–o′). Endogenous FATP4 was not detected in Fatp4−/−;Tg(IVL-Fatp1) cells (p–r′). Scale bar is 10 μm.
Mentions: By hematoxylin staining, granular keratinocytes isolated from control mice were filled with keratohyalin granules (lower left panel in Figure 4). Compared to controls, granular keratinocytes from Fatp4−/− newborns were smaller, and the granules were less distinct (middle column in Figure 4). In contrast, these abnormalities were remedied in Fatp4−/−;Tg(IVL-Fatp4) cells and Fatp4−/−;Tg(IVL-Fatp1) cells (right column in Figure 4). By double immunofluorescence staining, endogenous FATP4 in control cells was detected in a mesh-like pattern that colocalized mainly with the ER luminal protein calreticulin (Figure 5d–f′) and partially with the mitochondrial membrane protein ATP synthase (Figure 5a–c′; arrowheads in c′). The FATP4 signals were also observed at the nuclear surface, which is very likely the ER membrane that is contiguous with the nuclear membrane. Using interleukin 1 receptor 1 as a marker, we could not detect FATP4 at the plasma membrane (Figure 5g–i′). The mesh-like pattern of FATP4 staining was similar to the inter-granular staining of calreticulin (Figure 5j–l′). FATP4 was not detected in Fatp4−/− cells (Figure 5p–r′ and data not shown).

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