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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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Amelioration of skin phenotypes in Fatp4−/−;Tg(IVL-Fatp1) miceDorsal skin sections from E16.0 embryo littermates were subjected to hematoxylin and eosin staining (top row) and immunohistochemical analyses followed by counterstaining with hematoxylin (bottom three rows). The thickened epidermis phenotype seen in Fatp4−/− newborns was normalized in Fatp4−/−;Tg(IVL-Fatp1) newborns (top row). The HA-tagged FATP1 encoded by the transgene was detected primarily in granular keratinocytes in Fatp4−/−;Tg(IVL-Fatp1) mice (second row). The ectopic expression of keratin 6 seen in Fatp4−/− newborns was diminished in Fatp4−/−;Tg(IVL-Fatp1) mice (third row). The nuclear localization of pSTAT3 shown in Fatp4−/− newborns was also diminished in Fatp4−/−;Tg(IVL-Fatp1) mice (bottom row). Dashed lines demarcate the dermo-epidermal boundary. Scale bar is 50 μm.
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Figure 2: Amelioration of skin phenotypes in Fatp4−/−;Tg(IVL-Fatp1) miceDorsal skin sections from E16.0 embryo littermates were subjected to hematoxylin and eosin staining (top row) and immunohistochemical analyses followed by counterstaining with hematoxylin (bottom three rows). The thickened epidermis phenotype seen in Fatp4−/− newborns was normalized in Fatp4−/−;Tg(IVL-Fatp1) newborns (top row). The HA-tagged FATP1 encoded by the transgene was detected primarily in granular keratinocytes in Fatp4−/−;Tg(IVL-Fatp1) mice (second row). The ectopic expression of keratin 6 seen in Fatp4−/− newborns was diminished in Fatp4−/−;Tg(IVL-Fatp1) mice (third row). The nuclear localization of pSTAT3 shown in Fatp4−/− newborns was also diminished in Fatp4−/−;Tg(IVL-Fatp1) mice (bottom row). Dashed lines demarcate the dermo-epidermal boundary. Scale bar is 50 μm.

Mentions: Fatp4−/− fetuses display epidermal hyperplasia that results from an increased number of proliferating suprabasal cells (Lin et al., 2010). The hyperplasia is associated with epidermal activation of keratin 6 expression, epidermal growth factor receptor (EGFR) signaling, and phosphorylation and nuclear translocation of STAT3, a downstream effector of EGFR signaling. Pharmacological inhibition of EGFR and STAT3 activation reduce skin thickening and partially suppress the barrier abnormalities (Lin et al., 2010). Consistent with the RNA expression pattern of the Fatp1 transgene, HA-tagged FATP1 was detected specifically in suprabasal keratinocytes (second row in Figure 2). The transgenic FATP1 prevented the epidermal hyperplasia observed in Fatp4−/− mice (top row in Figure 2). In addition, the ectopic activation of keratin 6 and STAT3 in Fatp4−/− epidermis was diminished by Fatp1 transgene expression (bottom two rows in Figure 2). This amelioration of Fatp4−/− skin phenotypes is reminiscent of the effects of suprabasal Fatp4 transgene expression (Moulson et al., 2007).


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)

Amelioration of skin phenotypes in Fatp4−/−;Tg(IVL-Fatp1) miceDorsal skin sections from E16.0 embryo littermates were subjected to hematoxylin and eosin staining (top row) and immunohistochemical analyses followed by counterstaining with hematoxylin (bottom three rows). The thickened epidermis phenotype seen in Fatp4−/− newborns was normalized in Fatp4−/−;Tg(IVL-Fatp1) newborns (top row). The HA-tagged FATP1 encoded by the transgene was detected primarily in granular keratinocytes in Fatp4−/−;Tg(IVL-Fatp1) mice (second row). The ectopic expression of keratin 6 seen in Fatp4−/− newborns was diminished in Fatp4−/−;Tg(IVL-Fatp1) mice (third row). The nuclear localization of pSTAT3 shown in Fatp4−/− newborns was also diminished in Fatp4−/−;Tg(IVL-Fatp1) mice (bottom row). Dashed lines demarcate the dermo-epidermal boundary. Scale bar is 50 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4289464&req=5

Figure 2: Amelioration of skin phenotypes in Fatp4−/−;Tg(IVL-Fatp1) miceDorsal skin sections from E16.0 embryo littermates were subjected to hematoxylin and eosin staining (top row) and immunohistochemical analyses followed by counterstaining with hematoxylin (bottom three rows). The thickened epidermis phenotype seen in Fatp4−/− newborns was normalized in Fatp4−/−;Tg(IVL-Fatp1) newborns (top row). The HA-tagged FATP1 encoded by the transgene was detected primarily in granular keratinocytes in Fatp4−/−;Tg(IVL-Fatp1) mice (second row). The ectopic expression of keratin 6 seen in Fatp4−/− newborns was diminished in Fatp4−/−;Tg(IVL-Fatp1) mice (third row). The nuclear localization of pSTAT3 shown in Fatp4−/− newborns was also diminished in Fatp4−/−;Tg(IVL-Fatp1) mice (bottom row). Dashed lines demarcate the dermo-epidermal boundary. Scale bar is 50 μm.
Mentions: Fatp4−/− fetuses display epidermal hyperplasia that results from an increased number of proliferating suprabasal cells (Lin et al., 2010). The hyperplasia is associated with epidermal activation of keratin 6 expression, epidermal growth factor receptor (EGFR) signaling, and phosphorylation and nuclear translocation of STAT3, a downstream effector of EGFR signaling. Pharmacological inhibition of EGFR and STAT3 activation reduce skin thickening and partially suppress the barrier abnormalities (Lin et al., 2010). Consistent with the RNA expression pattern of the Fatp1 transgene, HA-tagged FATP1 was detected specifically in suprabasal keratinocytes (second row in Figure 2). The transgenic FATP1 prevented the epidermal hyperplasia observed in Fatp4−/− mice (top row in Figure 2). In addition, the ectopic activation of keratin 6 and STAT3 in Fatp4−/− epidermis was diminished by Fatp1 transgene expression (bottom two rows in Figure 2). This amelioration of Fatp4−/− skin phenotypes is reminiscent of the effects of suprabasal Fatp4 transgene expression (Moulson et al., 2007).

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