Fat in the skin: Triacylglycerol metabolism in keratinocytes and its role in the development of neutral lipid storage disease

Abstract

Keratinocyte differentiation is essential for skin development and the formation of the skin permeability barrier. This process involves an orchestrated remodeling of lipids. The cleavage of precursor lipids from lamellar bodies by β-glucocerebrosidase, sphingomyelinase, phospholipases and sterol sulfatase generates ceramides, non-esterified fatty acids and cholesterol for the lipid-containing extracellular matrix, the lamellar membranes in the stratum corneum. The importance of triacylglycerol (TAG) hydrolysis for the formation of a functional permeability barrier was only recently appreciated. Mice with defects in TAG synthesis (acyl-CoA:diacylglycerol acyltransferase-2-knock-out) or TAG catabolism (comparative gene identification-58, -CGI-58-knock-out) develop severe permeability barrier defects and die soon after birth because of desiccation. In humans, mutations in the CGI-58 gene also cause (non-lethal) neutral lipid storage disease with ichthyosis. As a result of defective TAG synthesis or catabolism, humans and mice lack ω-(O)-acylceramides, which are essential lipid precursors for the formation of the corneocyte lipid envelope. This structure plays an important role in linking the lipid-enriched lamellar membranes to highly cross-linked corneocyte proteins. This review focuses on the current knowledge of biochemical mechanisms that are essential for epidermal neutral lipid metabolism and the formation of a functional skin permeability barrier.

Keywords: ABHD5; ATGL; CGI-58; ceramide; ichthyosis; keratinocyte; lipids; triacylglycerol.

Figure 1

Schema depicting the role of epidermal triacylglycerol (TAG) metabolism in skin permeability barrier development. Acyl-CoA:diacylglycerol acyltransferase-2 (DGAT-2) transfers an activated fatty acid (FA-CoA) onto diacylglycerol (DAG) to generate TAG. These TAGs are hydrolyzed by a lipase, co-activated by comparative gene identification-58 (CGI-58). TAG-derived FAs are then activated and transferred by an unknown ω-(O)-acyltransferase (ω-O-AT?) onto ω-OH-(glucosyl)ceramides (ω-OH-(Glc)Cer). Acylceramides (acylCer) are glucosylated by uridine diphosphate glucose:ceramide glucosyltransferase (glucosylceramide synthase, GlcCerS). Generated acylglucosylceramides (acylGlcCer) are then covalently bound to proteins of the cornified envelope by a transesterification reaction (transglutaminase 1, TGM1), deglucosylated (β-glucocerebrosidase-GlcCer'ase) and hydrolyzed (ceramidase, Cer'ase). TAG-derived FAs may also act as ligands for nuclear hormone receptors, activating transcriptional regulators involved in epidermal differentiation. Excessive epidermal TAG accumulation (as indicated by ↑) may lead to lamellar/nonlamellar phase separation and permeability barrier dysfunction. Defects in protein function (as indicated by flashes) result in ichthyosiform phenotypes.