We previously isolated a novel autosomal recessive mouse mutation which we call wrinkle free (wrfr). wrfr mice are born with taut, shiny skin, a thickened epidermis, and a defective skin barrier. The mice die during their first day of life because their skin is so tight they are unable to breathe or suckle. There are also joint and facial defects that are likely secondary to the taut skin. We found by positional cloning that Slc27a4, the gene which encodes fatty acid transport protein 4 (FATP4), is mutated in wrfr-/- mice. FATP4 increases uptake of long and very long chain fatty acids by promoting their esterification to CoA via acyl-CoA synthetase activity. FATP4 is widely expressed and has been hypothesized to be important for intestinal uptake of dietary fatty acids. Our preliminary data show that the wrfr defect stems directly from the lack of FATP4 in the developing skin, and that the absence of FATP4 causes increased proliferation suprabasally, as well as widespread alterations in keratinocyte gene expression. Analysis of these changes suggests a premature activation of the keratinocyte differentiation program that is responsible for barrier formation during fetal maturation, yet the barrier is defective. FATP4-mediated events thus represent an important unexplored pathway regulating keratinocyte proliferation and differentiation. We hypothesize that the lack of FATP4 and the associated acyl-CoA synthetase activity leads to an alteration in lipid profiles that initiates a cascade of abnormal keratinocyte gene expression that contributes to the wrfr phenotype. We also hypothesize that FATP4 has later spatially and temporally distinct roles in lipid trafficking and metabolism that are required for barrier formation and sebaceous gland structure and function. To test these hypotheses, we propose to use new and existing FATP transgenic mice, mass spectrometric analysis of lipids, ultrastructural analysis of lamellar bodies and lamellar bilayers, analysis of sebum function and composition, and grafting of wrfr mutant skin to nude mice. With these approaches, we will determine the function of FATP4 in the skin and define novel mechanisms whereby lipids influence keratinocyte proliferation and differentiation. A number of human genetic skin diseases have been shown to stem from defects in genes that encode proteins involved in lipid trafficking. FATP4 clearly plays an important role in development of skin and appendages. A better understanding of how FATP4 functions in mice will lead to an overall better understanding of how lipid trafficking is involved in normal development of human skin and its barrier and appendages. PROJECT NARRATIVE (

Public Health Relevance

): A number of human genetic skin diseases have been shown to stem from defects in genes that encode proteins involved in lipid trafficking. FATP4 clearly plays an important role in development of skin and appendages. A better understanding of how FATP4 functions in mice will lead to an overall better understanding of how lipid trafficking is involved in normal development of human skin and its barrier and appendages.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049269-08
Application #
8310018
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2002-12-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$317,814
Indirect Cost
$108,726
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Lin, Meei-Hua; Miner, Jeffrey H (2015) Fatty acid transport protein 1 can compensate for fatty acid transport protein 4 in the developing mouse epidermis. J Invest Dermatol 135:462-70
Lin, Meei-Hua; Khnykin, Denis (2014) Fatty acid transporters in skin development, function and disease. Biochim Biophys Acta 1841:362-8
Li, Songhua; Lee, Jungsoo; Zhou, Yongdong et al. (2013) Fatty acid transport protein 4 (FATP4) prevents light-induced degeneration of cone and rod photoreceptors by inhibiting RPE65 isomerase. J Neurosci 33:3178-89
Lin, Meei-Hua; Hsu, Fong-Fu; Miner, Jeffrey H (2013) Requirement of fatty acid transport protein 4 for development, maturation, and function of sebaceous glands in a mouse model of ichthyosis prematurity syndrome. J Biol Chem 288:3964-76
Mishima, Takuya; Miner, Jeffrey H; Morizane, Mayumi et al. (2011) The expression and function of fatty acid transport protein-2 and -4 in the murine placenta. PLoS One 6:e25865
Lin, Meei-Hua; Chang, Kuo-Wei; Lin, Shu-Chun et al. (2010) Epidermal hyperproliferation in mice lacking fatty acid transport protein 4 (FATP4) involves ectopic EGF receptor and STAT3 signaling. Dev Biol 344:707-19
Miner, Jeffrey H (2010) Restrictive dermopathy and ZMPSTE24 mutations in Mennonites: Evidence for allelic heterogeneity. Am J Med Genet A 152A:2140-1; author reply 2142
Shim, Jien; Moulson, Casey L; Newberry, Elizabeth P et al. (2009) Fatty acid transport protein 4 is dispensable for intestinal lipid absorption in mice. J Lipid Res 50:491-500
Demehri, Shadmehr; Liu, Zhenyi; Lee, Jonghyeob et al. (2008) Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. PLoS Biol 6:e123
Moulson, Casey L; Lin, Meei-Hua; White, J Michael et al. (2007) Keratinocyte-specific expression of fatty acid transport protein 4 rescues the wrinkle-free phenotype in Slc27a4/Fatp4 mutant mice. J Biol Chem 282:15912-20

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