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1.
J Invest Dermatol ; 125(6): 1228-35, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16354193

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.


Subject(s)
Epidermis/pathology , Epidermis/physiology , Fatty Acid Transport Proteins/deficiency , Fatty Acid Transport Proteins/genetics , Animals , Epidermis/drug effects , Fatty Acid Transport Proteins/metabolism , Female , Genotype , Keratinocytes/cytology , Keratinocytes/drug effects , Keratinocytes/pathology , Mice , Mice, Knockout , Tamoxifen/pharmacology
2.
J Mol Med (Berl) ; 82(1): 39-48, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14618243

ABSTRACT

Patients suffering from hereditary hemochromatosis (HH) show progressive iron overload as a consequence of increased duodenal iron absorption. It has been hypothesized that mutations in the HH gene HFE cause misprogramming of the duodenal enterocytes towards a paradoxical iron-deficient state, resulting in increased iron transporter expression. Previous reports concerning gene expression levels of the duodenal iron transporters DMT1 and IREG1 in HH patients and animal models are controversial, however, and in many cases only mRNA expression levels were investigated. To analyze the duodenal expression of DMT1, Ireg1, Dcytb, and hephaestin and the association with iron overload in adult Hfe(-/-) mice, an Hfe(-/-) mouse line was generated. Duodenal DMT1 and Ireg1 protein levels, duodenal DMT1, Ireg1, Dcytb, hephaestin, and TfR1 mRNA levels, and hepatic hepcidin mRNA levels were quantified and the correlation to liver iron contents was calculated. We report that duodenal DMT1 and Ireg1 mRNA levels and DMT1 and Ireg1 protein levels remained unaffected by the Hfe deletion. Furthermore, duodenal hephaestin and TfR1 mRNA expression and hepatic hepcidin mRNA expression remained unaltered, while the duodenal mRNA expression of the brush border ferric reductase Dcytb was significantly increased in Hfe(-/-) mice. We found no correlation between the expression level of any of the analyzed transcripts and the liver iron content. In conclusion, the lack of correlation between DMT1 and Ireg1 protein expression and the liver iron content suggests that elevated duodenal iron transporter expression is not required for high liver iron overload. Hfe(-/-) mice do not necessarily display features of iron deficiency in the duodenum, indicated by an increase in mRNA and protein levels of DMT1 and Ireg1. Rather, the duodenal ferric reductase Dcytb may act as a possible mediator of iron overload in Hfe deficiency.


Subject(s)
Cation Transport Proteins/metabolism , Histocompatibility Antigens Class I/metabolism , Iron-Binding Proteins/metabolism , Iron/metabolism , Membrane Proteins/metabolism , Animals , Antimicrobial Cationic Peptides/genetics , Antimicrobial Cationic Peptides/metabolism , Cation Transport Proteins/genetics , Duodenum/metabolism , Hemochromatosis/genetics , Hemochromatosis/physiopathology , Hemochromatosis Protein , Hepcidins , Histocompatibility Antigens Class I/genetics , Humans , Iron-Binding Proteins/genetics , Liver/metabolism , Membrane Proteins/genetics , Mice , Mice, Knockout
3.
J Cell Biol ; 161(6): 1105-15, 2003 Jun 23.
Article in English | MEDLINE | ID: mdl-12821645

ABSTRACT

The fatty acid transport protein family is a group of evolutionarily conserved proteins that are involved in the cellular uptake and metabolism of long and very long chain fatty acids. However, little is known about their respective physiological roles. To analyze the functional significance of fatty acid transport protein 4 (Fatp4, Slc27a4), we generated mice with a targeted disruption of the Fatp4 gene. Fatp4-null mice displayed features of a neonatally lethal restrictive dermopathy. Their skin was characterized by hyperproliferative hyperkeratosis with a disturbed epidermal barrier, a flat dermal-epidermal junction, a reduced number of pilo-sebaceous structures, and a compact dermis. The rigid skin consistency resulted in an altered body shape with facial dysmorphia, generalized joint flexion contractures, and impaired movement including suckling and breathing deficiencies. Lipid analysis demonstrated a disturbed fatty acid composition of epidermal ceramides, in particular a decrease in the C26:0 and C26:0-OH fatty acid substitutes. These findings reveal a previously unknown, essential function of Fatp4 in the formation of the epidermal barrier.


Subject(s)
Epidermis/abnormalities , Epidermis/metabolism , Fatty Acids/metabolism , Membrane Proteins/deficiency , Membrane Transport Proteins , Skin Abnormalities/metabolism , Skin Diseases, Genetic/metabolism , Animals , Body Weight/genetics , Carrier Proteins/genetics , Ceramides/biosynthesis , Disease Models, Animal , Epidermis/pathology , Fatty Acid Transport Proteins , Female , Gene Targeting , Genes, Lethal/genetics , Head/abnormalities , Head/pathology , Joints/abnormalities , Joints/pathology , Lipid Metabolism , Lung/abnormalities , Lung/pathology , Lung/ultrastructure , Male , Membrane Proteins/genetics , Mice , Mice, Knockout , Microscopy, Electron , Mutation/genetics , Phenotype , Skin Abnormalities/genetics , Skin Diseases, Genetic/genetics
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