Lipoxygenases (LOX) and cyclooxygenase (COX) are the main enzymes for PUFA metabolism to highly bio‐active prostaglandins, leukotrienes, thromboxanes, lipoxins, resolvins and protectins. LOX and COX pathways are important for the regulation of pro‐inflammatory or pro‐resolving metabolite synthesis and metabolism for various inflammatory diseases such as atopic dermatitis (AD). In this study, we determined PUFAs and PUFA metabolites in serum as well as affected and non‐affected skin samples from AD patients and the dermal expression of various enzymes, binding proteins and receptors involved in these LOX and COX pathways. Decreased EPA and DHA levels in serum and reduced EPA level in affected and non‐affected skin were found; in addition, n3/n6‐PUFA ratios were lower in affected and non‐affected skin and serum. Mono‐hydroxylated PUFA metabolites of AA, EPA, DHA and the sum of AA, EPA and DHA metabolites were increased in affected and non‐affected skin. COX1 and ALOX12B expression, COX and 12/15‐LOX metabolites as well as various lipids, which are known to induce itch (12‐HETE, LTB4, TXB2, PGE2 and PGF2) and the ratio of pro‐inflammatory vs pro‐resolving lipid mediators in non‐affected and affected skin as well as in the serum of AD patients were increased, while n3/n6‐PUFAs and metabolite ratios were lower in non‐affected and affected AD skin. Expression of COX1 and COX‐metabolites was even higher in non‐affected AD skin. To conclude, 12/15‐LOX and COX pathways were mainly upregulated, while n3/n6‐PUFA and metabolite ratios were lower in AD patients skin. All these parameters are a hallmark of a pro‐inflammatory and non‐resolving environment in affected and partly in non‐affected skin of AD patients.

Adiponectin is an adipocyte-derived adipokine with potent antidiabetic, anti-inflammatory, and antiatherogenic activity. Long-term, high-fat diet results in gain of body weight, adiposity, further inflammatory-based cardiovascular diseases, and reduced adiponectin secretion. Vitamin A derivatives/retinoids are involved in several of these processes, which mainly take place in white adipose tissue (WAT). In this study, we examined adiponectin expression as a function of dietary high-fat and high–vitamin A conditions in mice. A decrease of adiponectin expression in addition to an up-regulation of aldehyde dehydrogenase A1 (ALDH1A1), retinoid signaling, and retinoic acid response element signaling was selectively observed in WAT of mice fed a normal–vitamin A, high-fat diet. Reduced adiponectin expression in WAT was also observed in mice fed a high–vitamin A diet. Adipocyte cell culture revealed that endogenous and synthetic retinoic acid receptor (RAR)α- and RARγ-selective agonists, as well as a synthetic retinoid X receptor agonist, efficiently reduced adiponectin expression, whereas ALDH1A1 expression only increased with RAR agonists. We conclude that reduced adiponectin expression under high-fat dietary conditions is dependent on 1) increased ALDH1A1 expression in adipocytes, which does not increase all-trans-retinoic acid levels; 2) further RAR ligand–induced, WAT-selective, increased retinoic acid response element–mediated signaling; and 3) RAR ligand–dependent reduction of adiponectin expression.—Landrier, J.-F., Kasiri, E., Karkeni, E., Mihály, J., Béke, G., Weiss, K., Lucas, R., Aydemir, G., Salles, J., Walrand, S., de Lera, A. R., Rühl, R. Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue.

Lycopene is the red pigment in tomatoes and tomato products and is an important dietary carotenoid found in the human organism. Lycopene-isomers, oxidative lycopene metabolites and apo-lycopenoids are found in the food matrix. Lycopene intake derived from tomato consumption is associated with alteration of lipid metabolism and a lower incidence of cardiovascular diseases (CVD). Lycopene is mainly described as a potent antioxidant but novel studies are shifting towards its metabolites and their capacity to mediate nuclear receptor signalling. Di-/tetra-hydro-derivatives of apo-10´-lycopenoic acid and apo-15´-lycopenoic acids are potential novel endogenous mammalian lycopene metabolites which may act as ligands for nuclear hormone mediated activation and signalling. In this review, we postulate that complex lycopene metabolism results in various lycopene metabolites which have the ability to mediate transactivation of various nuclear hormone receptors like RARs, RXRs and PPARs. A new mechanistic explanation of how tomato consumption could positively modulate inflammation and lipid metabolism is discussed.

TSLP is an important trigger and initiator for various atopic diseases mainly atopic dermatitis (AD). Activators of nuclear hormone receptors like bioactive vitamin A and D derivatives are known to induce TSLP up-regulation in the skin. In this study, various combinations of synthetic specific agonists and antagonists of the retinoic acid receptors (RARs), retinoid X receptors (RXRs) and vitamin D receptor (VDR) were topically administered to mice. The aim of the study was to elucidate via which nuclear hormone receptor pathways TSLP is regulated and how this regulation is connected to the development and phenotype of atopic dermatitis. TSLP expression was monitored using QRT-PCR and serum TSLP levels using ELISA. Synthetic agonists of the VDR and RARγ as well as the natural agonist all-trans retinoic acid (ATRA) increased TSLP expression in the skin, while an RXR agonist was not active. Treatments with antagonists of RXRs and RARs in addition to RARα-agonists reduced skin TSLP expression. Strong activation was found after a combination of a VDR and an RXR agonist (ca. 5 times induction) and even stronger by an RARγ and an RXR agonist treatment (ca. 48 times induction). We conclude that besides VDR-mediated signaling mainly RARγ-RXR mediated pathways in the skin are important patho-physiological triggers for increased skin TSLP expression. We conclude that topical synthesized retinoids stimulated by internal or external triggers or topically applied induce TSLP production and are thereby important triggers for atopic dermatitis prevalence.