Abstract
Phospholipids are required for epidermal lamellar body formation. Glycerol 3-phosphate acyltransferases (GPATs) catalyze the initial step in the biosynthesis of glycerolipids. Little is known about the expression and regulation of GPATs in epidermis/keratinocytes. Here, we demonstrate that GPAT 1, 3, and 4 are expressed in epidermis/keratinocytes, whereas GPAT2 is not detected. In mouse epidermis, GPAT 3 and 4 are mainly localized to the upper layers whereas GPAT1 is found in both the upper and lower layers. GPAT1 and 3 mRNA increase during fetal rat epidermal development. No change in GPAT expression was observed in adult mice following acute permeability barrier disruption. Calcium-induced human keratinocyte differentiation increased GPAT3 mRNA whereas both GPAT1 and 4 mRNA levels decreased. In parallel, total GPAT activity increased 2-fold in differentiated keratinocytes attributable to an increase in N-ethylmaleimide (NEM) sensitive GPAT activity localized to microsomes with little change in NEM resistant activity, consistent with an increase in GPAT3. Furthermore, PPARγ or PPARδ activators increased GPAT3 mRNA, microsomal GPAT activity, and glycerol lipid synthesis without affecting the expression of GPAT1 or 4. Finally, both PPARγ and PPARδ activators increased GPAT3 mRNA via increasing its transcription. Thus, multiple isoforms of GPAT are expressed and differentially regulated in epidermis/keratinocytes.
Highlights
Phospholipids are required for epidermal lamellar body formation
Glucosylceramides, and phospholipids, and following lamellar body secretion the glucosylceramides are metabolized to ceramides, a process catalyzed by the enzyme -glucocerebrosidase, and the phospholipids are metabolized to free fatty acids, a reaction catalyzed by secretory phospholipases [1,2,3,4]
Cig treatment did not alter incorporation into PE/PS (Fig. 6B). These results indicate that activation of nuclear receptors, in particular peroxisome proliferator-activated receptor (PPAR)␥, stimulates GPAT3 gene expression, leading to both enhanced microsomal Glycerol-3-phosphate acyltransferase (GPAT) activity and increased glycerolipid synthesis in cultured human keratinocyte (CHK)
Summary
Phospholipids are required for epidermal lamellar body formation. Glycerol 3-phosphate acyltransferases (GPATs) catalyze the initial step in the biosynthesis of glycerolipids. This permeability barrier is localized to the stratum corneum (SC), the outermost layer of the epidermis [1] This permeability barrier is mediated by extracellular lipids, primarily cholesterol, ceramides, and free fatty acids, which are delivered to the extracellular spaces of the SC by the secretion of lamellar body contents by differentiated keratinocytes [1]. Disruption of the permeability barrier leads to a marked increase in epidermal cholesterol, ceramide, and fatty acid synthesis, which enhances the formation of lamellar bodies [1, 5]. Inhibition of cholesterol, ceramides, or fatty acid synthesis in the epidermis impairs the formation of lamellar bodies, leading to the decreased delivery of lipid to the extracellular spaces of the SC and impaired permeability barrier function [6,7,8]. Both GPAT3 and GPAT4 are endoplasmic reticulum (ER)-associated, NEM-sensitive enzymes, and appear to utilize a broad range of long-chain fatty acyl-CoAs, including both saturated and unsaturated species, as their substrate [9,10,11]
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