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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 the elevated level of free fatty acids in Fatp4−/−;Tg(IVL-Fatp1) and Fatp4−/−;Tg(IVL-Fatp4) epidermisFree, extractable lipids from the epidermis of newborn mice were resolved by TLC and visualized by charring the plate. The elevated level of free fatty acids seen in Fatp4−/− mice was reduced to normal in Fatp4−/−;Tg(IVL-Fatp1) (a) and Fatp4−/−;Tg(IVL-Fatp4) mice (b). Components of the lipid standards and origin of sample application are indicated on the left of a. Lipid species of the epidermis are indicated between the panels.
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Figure 3: Amelioration of the elevated level of free fatty acids in Fatp4−/−;Tg(IVL-Fatp1) and Fatp4−/−;Tg(IVL-Fatp4) epidermisFree, extractable lipids from the epidermis of newborn mice were resolved by TLC and visualized by charring the plate. The elevated level of free fatty acids seen in Fatp4−/− mice was reduced to normal in Fatp4−/−;Tg(IVL-Fatp1) (a) and Fatp4−/−;Tg(IVL-Fatp4) mice (b). Components of the lipid standards and origin of sample application are indicated on the left of a. Lipid species of the epidermis are indicated between the panels.

Mentions: To investigate this hypothesis, we performed lipid analyses by thin layer chromatography (TLC) using total free, extractable lipids isolated from newborn epidermis. Compared to controls, Fatp4−/− epidermis showed a significantly increased amount of free fatty acids (Figure 3). Quantification of free fatty acids in separate studies revealed 4.44 ± 0.82 μg/mg dry tissue in controls (n=4) vs. 8.80 ± 1.75 μg/mg in mutants (n=4), P<0.01 (Table S1a); and 3.96 ± 1.06 μg/mg dry tissue in controls (n=6) vs. 6.54 ± 0.82 μg/mg in mutants (n=6), P<0.001 (Table S1b). Furthermore, these increases were ameliorated in both Fatp4−/−;Tg(IVL-Fatp1) mice (Figure 3a and Table S1a) and Fatp4−/−;Tg(IVL-Fatp4) mice (Figure 3b and Table S1b). In contrast, the levels of cholesteryl ester, triacyglycerol, and free cholesterol in the newborn epidermis were not significantly affected by FATP4 deficiency (Figure 3 and Table S1).


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 the elevated level of free fatty acids in Fatp4−/−;Tg(IVL-Fatp1) and Fatp4−/−;Tg(IVL-Fatp4) epidermisFree, extractable lipids from the epidermis of newborn mice were resolved by TLC and visualized by charring the plate. The elevated level of free fatty acids seen in Fatp4−/− mice was reduced to normal in Fatp4−/−;Tg(IVL-Fatp1) (a) and Fatp4−/−;Tg(IVL-Fatp4) mice (b). Components of the lipid standards and origin of sample application are indicated on the left of a. Lipid species of the epidermis are indicated between the panels.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4289464&req=5

Figure 3: Amelioration of the elevated level of free fatty acids in Fatp4−/−;Tg(IVL-Fatp1) and Fatp4−/−;Tg(IVL-Fatp4) epidermisFree, extractable lipids from the epidermis of newborn mice were resolved by TLC and visualized by charring the plate. The elevated level of free fatty acids seen in Fatp4−/− mice was reduced to normal in Fatp4−/−;Tg(IVL-Fatp1) (a) and Fatp4−/−;Tg(IVL-Fatp4) mice (b). Components of the lipid standards and origin of sample application are indicated on the left of a. Lipid species of the epidermis are indicated between the panels.
Mentions: To investigate this hypothesis, we performed lipid analyses by thin layer chromatography (TLC) using total free, extractable lipids isolated from newborn epidermis. Compared to controls, Fatp4−/− epidermis showed a significantly increased amount of free fatty acids (Figure 3). Quantification of free fatty acids in separate studies revealed 4.44 ± 0.82 μg/mg dry tissue in controls (n=4) vs. 8.80 ± 1.75 μg/mg in mutants (n=4), P<0.01 (Table S1a); and 3.96 ± 1.06 μg/mg dry tissue in controls (n=6) vs. 6.54 ± 0.82 μg/mg in mutants (n=6), P<0.001 (Table S1b). Furthermore, these increases were ameliorated in both Fatp4−/−;Tg(IVL-Fatp1) mice (Figure 3a and Table S1a) and Fatp4−/−;Tg(IVL-Fatp4) mice (Figure 3b and Table S1b). In contrast, the levels of cholesteryl ester, triacyglycerol, and free cholesterol in the newborn epidermis were not significantly affected by FATP4 deficiency (Figure 3 and Table S1).

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