Cytosolic StAR-related lipid transfer domain 4 (STARD4) protein influences keratinocyte lipid phenotype and differentiation status.
BACKGROUND
Terminally differentiating keratinocytes actively synthesize and accumulate cholesterol, which is a key constituent of intercellular lipid lamellae which contribute to the epidermal permeability barrier. While the pathway for cholesterol biosynthesis is established, intracellular transport mechanisms for this lipid are poorly understood, despite their importance in regulating organelle sterol content, keratinocyte differentiation status and the activity of lipid-responsive transcription factors involved in skin health, repair and disease. Recent data implicate proteins containing a steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain in cellular cholesterol homeostasis.


OBJECTIVE
To investigate gene expression of cytosolic, cholesterol-binding StAR-related lipid transfer domain 4 (STARD4) protein in primary human keratinocytes and differentiating HaCaT keratinocytes and, by overexpression of this protein, the function of STARD4 in HaCaT keratinocyte lipid phenotype and differentiation status.


METHODS
Quantitative polymerase chain reaction was utilized to measure gene expression of STARD4 relative to the housekeeping gene GAPDH. Following transient (48 h) overexpression of STARD4, keratinocyte lipid mass and lipogenesis were measured, along with expression of genes involved in cholesterol homeostasis and those encoding a range of keratinocyte differentiation markers.


RESULTS
Cholesterol-binding protein STARD4 is expressed in both primary and immortalized HaCaT keratinocytes, and is repressed during Ca(2+) -dependent differentiation of the latter. Transient overexpression of STARD4 reduces endogenous [(14) C]cholesterol and cholesteryl ester biosynthesis, and triggers increased expression of SREBF2, ABCG4 and LOR, while repressing expression of ABCA1.


CONCLUSIONS
The cytosolic cholesterol-sensing protein STARD4 modulates both keratinocyte cholesterol homeostasis and differentiation status, increasing the efficiency of cholesterol trafficking within the cell, and amplifying and 'fine-tuning' cellular responses to this sterol. Modulation of expression of STARD4, and other members of the START family of lipid trafficking proteins, may prove useful in resolving imbalances in lipid metabolism associated with loss of epidermal barrier function in psoriasis and atopic dermatitis.
Department of Biological and Biomedical Sciences, Glasgow Caledonian University, UK.
H M
HM
Elbadawy
F
F
Borthwick
C
C
Wright
P E
PE
Martin
A
A
Graham
D064286:ATP Binding Cassette Transporter 1; D000070996:ATP Binding Cassette Transporter, Subfamily G; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002784:Cholesterol / Q000096:biosynthesis; D020869:Gene Expression Profiling; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D008055:Lipids / Q000032:analysis*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism
C577836:ABCA1 protein, human; C439766:ABCG4 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070996:ATP Binding Cassette Transporter, Subfamily G; D018528:ATP-Binding Cassette Transporters; D008055:Lipids; D026901:Membrane Transport Proteins; C497390:SREBF2 protein, human; C456544:STARD4 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol