ABCC3: ATP binding cassette subfamily C member 3; ACAD(V)L: (very) long-chain specific acyl-CoA dehydrogenase, mitochondrial; ACOX1: acyl-CoA oxidase 1; ACPP (ACP3): acid phosphatase 3; AKR1B1: aldo-keto reductase family 1 member B; ALOX: lipoxygenase; ATP10B: ATPase phospholipid transporting 10B; ATP12A: ATPase H+/K+ transporting non-gastric alpha2 subunit; ARL8B: ADP ribosylation factor like GTPase 8B; AXL: AXL receptor tyrosine kinase; BDH1: 3-hydroxybutyrate dehydrogenase 1; CAT: catalase; CCDC50: coiled-coil domain containing 50; CCN: cyclin; CD: cluster of differentiation; CDKN1C: cyclin dependent kinase inhibitor 1C; CHPT1: choline C phosphotransferase 1; CIDEA: cell death inducing DFFA like effector A; CNFN: cornifelin; CRABP2: cellular retinoic acid binding protein 2; CYP51: lanosterol 14α-demethylase; DCN: decorin; DHC7 (DNAH1): dynein axonemal heavy chain 1; DUSP3: dual specificity phosphatase 3; ECHB (HADHB): hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta; EGFR: epidermal growth factor receptor; EHF: ETS homologous factor; EID1: EP300 interacting inhibitor of differentiation 1; EPS: epidermal growth factor receptor pathway substrate; FABP: fatty acid binding protein; FBLN1: fibulin 1; FDFT1: farnesyl-diphosphate farnesyltransferase 1; FDPS: farnesyl diphosphate synthase; FGFBP1: fibroblast growth factor binding protein 1; FXR1: FMR1 autosomal homolog 1; GAB2: GRB2 associated binding protein 2; GAS7: growth arrest specific 7; GDPD3: glycerophosphodiester phosphodiesterase domain containing 3; GGH: gamma-glutamyl hydrolase; GM2A: GM2 ganglioside activator; GPD1L: glycerol-3-phosphate dehydrogenase 1 like; GSPT1: G1 to S phase transition 1; HAS3: hyaluronan synthase 3; HB-EGF: heparin-binding EGF-like growth factor; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCS1: 3-hydroxy-3-methylglutaryl-CoA synthase 1; IL: interleukin; INV: involucrin; KLF6: kruppel like factor 6; KRT: keratin; LASS6 (CERS6): ceramide synthase 6; LDLR: low density lipoprotein receptor; LFNG: LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase; LIFR: LIF receptor subunit alpha; LSS: lanosterol synthase; MAP4K4: mitogen-activated protein kinase kinase kinase kinase 4; MAPK13: mitogen-activated protein kinase 13; MCC: MCC regulator of WNT signaling pathway; MMP9: matrix metalloproteinase 9; MREG: melanoregulin; MTCP1: mature T cell proliferation 1; MVD: mevalonate diphosphate decarboxylase; NENF: neudesin neurotrophic factor; OACT5 (LPCAT3): lysophosphatidylcholine acyltransferase 3; OSR2: odd-skipped related transcription factor 2; PDGFC: platelet derived growth factor C; PDGFRA: platelet derived growth factor receptor alpha; PDK: pyruvate dehydrogenase kinase; PIK3IP1: phosphoinositide-3-kinase interacting protein 1; PLA2G3: phospholipase A2 group III; PRKAB2: protein kinase AMP-activated non-catalytic subunit beta 2; RAI14: retinoic acid induced 14; RBL2: RB transcriptional corepressor like 2; REEP5: receptor accessory protein 5; RHOC: ras homolog family member C; S100A: S100 calcium-binding protein A; SERINC1: serine incorporator 1; SOD2: superoxide dismutase 2; SPRR1B: small proline rich protein 1B; SQLE: squalene epoxidase; STAT: signal transducer and activator of transcription; TACC1: transforming acidic coiled-coil containing protein 1; TGFBR: transforming growth factor beta receptor; TGM: transglutaminase; TTC3: tetratricopeptide repeat domain 3; UCK2: uridine-cytidine kinase 2; XPC: XPC complex subunit, DNA damage recognition and repair factor. The PPARD/Ppard gene is upregulated in lesional skin of patients with psoriasis vulgaris ^{[5][43][44][45][46][47][48]}[5,31,61,62,63,64,65] and of mouse models of psoriasis ^[46][47][63,64]. However, although PPARD has been identified as a putative pathogenic gene in psoriasis ^[48][65], variants at the PPARD genomic locus have not been associated with psoriasis. In psoriatic plaques, PPARδ accumulates in KC nuclei in all epidermal layers [5]; however, subcellularly, PPARδ is found both in the cytoplasm and nucleus of KCs in the basal layer and in the stratum spinosum, whereas it is strictly found in nuclei in KCs in the stratum granulosum ^[5][47][5,64]. This suggests that PPARδ is constitutively activated by endogenous ligands in granular KCs of the epidermis in patients with psoriatic lesions ^[47][64]. Accordingly, endogenous PPARδ ligands can be produced in psoriatic lesions from the oxidation of arachidonic acid via ALOX8 (mouse) or ALOX12 (mouse and human) ^[47][49][64,66], two enzymes located in the stratum granulosum ^[49][50][51][66,67,68]. FABP5 is a fatty acid-binding protein expressed in the epidermis and has been shown to deliver endogenous lipid ligands to PPARδ in KC nuclei and to be a PPARδ target gene ^[52][69]. The expression of FABP5 parallels that of PPARδ at both the mRNA and protein levels in psoriasis ^[5][46][5,63]. Thus, in the suprabasal epidermis of psoriatic lesions, it is likely that PPARδ is constitutively activated by endogenous ligands such as arachidonic acid or its derivatives (eicosanoids), which are transported by FABP5 to the nucleus of granular KCs to promote PPARδ–mediated KC terminal differentiation and lipid β-oxidation. Specific overexpression and activation of human PPARδ in suprabasal mouse epidermis has been achieved by generating transgenic mice expressing a Cyp1A1-driven expression of human PPARD in KCs followed by topical treatment with the PPARδ agonist GW501516 ^[45][62]. Interestingly, these mice developed psoriasis-like inflammation associated with an increased Th17 immune response ^[45][62]. In this model, sustained activation of the STAT3 pathway is critically involved in the development of psoriasis-like disease ^[45][62]. The constitutive activation of PPARδ in suprabasal epidermis not only promotes terminal KC differentiation but also the production, in KCs, of IL-36 and the pleiotropic pro-inflammatory cytokine IL-1β. The latter can contribute to the activation of skin dendritic cells, which can in turn, skew naïve T cells toward a Th17 phenotype ^[45][62]. Moreover, suprabasal mouse KCs overexpressing the constitutively activated human PPARδ probably secrete soluble factors able to trigger the proliferation of basal KCs ^[45][62]. In addition, in psoriatic plaques, some PPARδ localize to nuclei in basal KCs to potentially sustain KC proliferation ^[5][47][5,64]. In line with this, previous work suggested that upregulation of PPARδ in the epidermis of psoriatic lesions might contribute to KC hyperproliferation via the upregulation of heparin-binding EGF-like growth factor (HB-EGF) at the mRNA and protein levels ^[43][31]. HB-EGF is a ligand that activates EGFR and is expressed in the basal layer of the epidermis, where it has been shown to accelerate wound healing ^[53][70]. This might be relevant for psoriasis because disease flares can be induced by physical trauma (the isomorphic or Koebner phenomenon) among other causes. Pioneering work on the pathogenesis of psoriasis showed increased levels of antimicrobial peptides in psoriatic skin breaks the innate tolerance to self-DNA which ultimately drives autoimmunity ^[54][71]. Moreover, human genomic DNA fragments enhance TNFA and HBEGF expression as well as KC proliferation, hence mimicking the KC phenotype in psoriatic skin lesions ^[55][72]. Thus, we can speculate that PPARδ in the basal epidermis of psoriatic plaques sustains KC proliferation via mechanisms involving HB-EGF. NF-kB has been shown to inhibit PPARδ-dependent transactivation. However, in lesional psoriasis, p65 NF-kB is sequestered in the cytoplasm of basal KCs, which might allow PPARδ to exert its transcriptional regulation on various genes, including those involved in KC proliferation [5]. PPARδ is upregulated in the epidermis of lesional atopic dermatitis when compared to non-lesional skin but to a lesser extent than in psoriatic lesions ^[43][31]. The expression of FABP5 parallels that of PPARδ in psoriasis and atopic dermatitis ^[43][56][31,73]. Notably, the expression of Ppard and Fabp5 is markedly increased in the epidermis of mouse models of lesional atopic dermatitis ^[57][58][38,74]. Similar to psoriasis, FABP5 is mainly localized to the nuclei of suprabasal KCs, suggesting efficient local generation of PPARδ ligands to sustain the activation of PPARδ ^[57][38]. Interestingly, the amounts of arachidonic acid, PGF2α and 5-HETE (PPARδ endogenous ligands) are increased in lesional skin of atopic dermatitis patients when compared to healthy skin ^[59][75]. The increased cleavage of membrane phospholipids via cPLA2 in the stratum granulosum can significantly contribute to the accumulation of arachidonic acid and its derivatives in lesional atopic dermatitis skin as well as in psoriatic lesions ^[60][61][62][76,77,78]. The role of PPARδ has been less investigated in atopic dermatitis than in psoriasis. However, in both diseases, PPARδ might induce KC hyperproliferation, enhance differentiation and contribute to inflammatory processes. However, PPARδ can also be envisaged as a key regulator of metabolism, especially in the metabolic shift toward anaerobic glycolysis that has been recently evidenced in psoriatic and atopic lesions ^[57][63][64][38,79,80]. The production of lactate is largely increased in the epidermis of flaky tail mice and mice treated with MC903, two mouse models of lesional atopic dermatitis ^[57][38] and of mice treated with imiquimod, a mouse model of psoriasis ^[65][81]. Interestingly, the PPARδ ligand GW610742, when orally administered to ob/ob mice, induces lactate accumulation in the liver ^[66][82]. Indeed, PPARδ has been shown to regulate the expression of key enzymes involved in glucose metabolism, including in KCs (Table 2) ^[67][68][69][83,84,85]. PPARδ can promote anaerobic glycolysis by upregulating PDK, an enzyme that inactivates pyruvate dehydrogenase (PDH) via phosphorylation. PDH is the rate-limiting enzyme involved in pyruvate uptake in mitochondria, which ultimately favors oxidative phosphorylation ^[70][86]. Thus, inactivation of PDH by PPARδ-induced PDK inhibits pyruvate uptake in mitochondria, which, in turn, promotes anaerobic glycolysis ^[71][87]. In the epidermis of flaky tail mice, there is a shift toward anaerobic glycolysis associated with an enhanced PPARδ pathway including increased PDK1. In line with this, mitochondrial function is not enhanced in the epidermis of flaky tail mice despite a dramatic need for energy to sustain forced KC proliferation and to dampen inflammation ^[57][38]. These results are in line with previous work showing that PPARδ antagonism favors mitochondrial function ^[72][88]. PPARδ promotes β-oxidation of fatty acids in all cell types, including KCs (Table 2) ^[69][73][74][85,89,90]. In flaky tail mice, peroxisomal β-oxidation is upregulated when compared to that of healthy mice, with marked increases in the mRNA, protein and activity levels of ACOX1 ^[57][38], a well-known PPARδ downstream target ^[73][74][89,90]. This profile has been observed in another mouse model of lesional atopic dermatitis, i.e., mice topically treated with MC903 ^[57][38]. This treatment is associated with decreased proportions of very-long chain fatty acids and ceramides, especially with 24 and 26 carbons ^[57][38], as observed in the epidermis of patients with lesional atopic dermatitis ^[75][91]. Interestingly, C24 and C26 fatty acids are exclusively oxidized in peroxisomes via ACOX1 ^[76][77][92,93]. Thus, the upregulation of PPARδ in the epidermis of patients with lesional atopic dermatitis might promote peroxisomal β-oxidation of very- and ultra-long-chain fatty acids and ceramides, hence significantly contributing to disease pathogenesis. Indeed, the efficacy of the stratum corneum barrier depends, to a large part, on the lipid composition of the lipid matrix surrounding the corneocytes, which consists of more than 50% fatty acids with 24 and 26 carbons. Interestingly, the proportion of very-long-chain ceramides is also decreased in the epidermis of psoriatic lesions ^[78][94] and is associated with increased ACOX1 ^[57][38] and PPARδ (see above), thus corroborating the key role of the PPARδ pathway in lipid abnormalities in both lesional atopic dermatitis and psoriasis. In contrast to lesional AD ^[57][38], mitochondrial β-oxidation might be increased in psoriasis as suggested by previous work ^[27][46] and might further contribute to lipid abnormities.