PNPLA1 defects in patients with autosomal recessive congenital ichthyosis and KO mice sustain PNPLA1 irreplaceable function in epidermal omega-O-acylceramide synthesis and skin permeability barrier

Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of monogenic genodermatoses that encompasses non-syndromic disorders of keratinization. The pathophysiology of ARCI has been linked to a disturbance in epidermal lipid metabolism that impaired the stratum corneum function, leading to permeability barrier defects. Functional characterization of some genes involved in ARCI contributed to the identification of molecular actors involved in epidermal lipid synthesis, transport or processing. Recently, PNPLA1 has been identified as a gene causing ARCI. While other members of PNPLA family are key elements in lipid metabolism, the function of PNPLA1 remained unclear. We identified 5 novel PNPLA1 mutations in ARCI patients, mainly localized in the putative active enzymatic domain of PNPLA1. To investigate Pnpla1 biological role, we analysed Pnpla1-deficient mice. KO mice died soon after birth from severe epidermal permeability defects. Pnpla1-deficient skin presented an important impairment in the composition and organization of the epidermal lipids. Quantification of epidermal ceramide species highlighted a blockade in the production of ω-O-acylceramides with a concomitant accumulation of their precursors in the KO. The virtually loss of ω-O-acylceramides in the stratum corneum was linked to a defective lipid coverage of the resistant pericellular shell encapsulating corneocytes, the so-called cornified envelope, and most probably disorganized the extracellular lipid matrix. Finally, these defects in ω-O-acylceramides synthesis and cornified envelope formation were also evidenced in the stratum corneum from PNPLA1-mutated patients. Overall, our data support that PNPLA1/Pnpla1 is a key player in the formation of ω-O-acylceramide, a crucial process for the epidermal permeability barrier function.

Phospholipase A2 in skin biology: new insights from gene-manipulated mice and lipidomics

“…A recent breakthrough in this research area has been the identification of PNPLA1, a member of the iPLA 2 family, as a long-sought ω-O-acylceramide synthase, whose genetic mutations in humans and dogs cause congenital [56] and deletion in mice leads to neonatal death due to excessive transepidermal dehydration resulting from severe skin barrier defect [57][58][59]. PNPLA1 catalyzes the unique transacylase reaction, whereby the LA moiety cleaved from triacylglycerol through the lipase-like reaction of this enzyme is directly transferred to the ω-hydroxy moiety of ultra-long chain fatty acid in ceramide (ω-O-hydroxyceramide), with the ω-hydroxy group, instead of water, serving as an acyl (linoleoyl) acceptor [60].…”

SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation

“…Furthermore, results inconsistent with the current line of thinking come from inactivation studies with PNPLA1, the gene that esterifies linoleate to CerOS, forming CerEOS (21)(22)(23)(24)(25). In Pnpla1-deficient mice or patients with mutations in the PNPLA1 gene, the CLE is almost absent even though CerOS and its glucosylated form are highly accumulated (22,24,25). This suggests that the prerequisite for lipoxygenase-catalyzed oxidation of CerEOS is not in order to facilitate de-esterification of the linoleate moiety and produce CerOS, but rather has a different functional role during formation of the CLE.…”

“…However, the transglutaminase(s) are not identified, and known gene knockouts do not exhibit the expected skin phenotype with absence of the CLE (19,20). Furthermore, results inconsistent with the current line of thinking come from inactivation studies with PNPLA1, the gene that esterifies linoleate to CerOS, forming CerEOS (21)(22)(23)(24)(25). In Pnpla1-deficient mice or patients with mutations in the PNPLA1 gene, the CLE is almost absent even though CerOS and its glucosylated form are highly accumulated (22,24,25).…”

Ceramides metabolism and impaired epidermal barrier in cutaneous diseases and skin aging: focus on the role of the enzyme PNPLA1 in the synthesis of ω-O-acylceramides and its pathophysiological involvement in some forms of congenital ichthyoses

“…Some of them have been addressed in many works which demonstrated their involvement in stratum corneum lipid metabolism. Recently, our group as well as others showed that PNPLA1 was a key player in the formation of v-esterified ceramides (Grond et al, 2017;Hirabayashi et al, 2017;Ohno et al, 2017;Pichery et al, 2017).…”