Reduced adiponectin expression after high-fat diet is associated with selective up-regulation of ALDH1A1 and further retinoic acid receptor signaling in adipose tissue.

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.

The association of medication-related osteonecrosis of the jaw with Actinomyces spp. infection.

Medication-related osteonecrosis of the jaw (MRONJ) represents a complication of bisphosphonate treatment that responds poorly to standard treatment. In a retrospective cohort study we investigated a possible role of Actinomyces spp. in the pathogenesis of MRONJ. Deep biopsies of necrotic bone were collected during surgical treatment of MRONJ and evaluated by histology and microbiology for the presence of Actinomyces spp. Microbiological, demographic and clinicpathological data were analyzed for risk of Actinomyces-associated MRONJ. Between 2005 and 2014, 111 patients suffering from histologically-confirmed MRONJ were identified. Actinomyces spp. were detected in 99 cases (89%) by histology and in six further patients by microbiological culture. A diverse microbial flora was found in all specimens without association with Actinomyces spp. Demographic and clinicopathological characteristics did not separate significantly Actinomyces-positive from Actinomyces-negative cases. Our observations confirm previous reports of a high prevalence of Actinomyces spp. in MRONJ in the single largest cohort available up to now. The high prevalence of Actinomyces spp. and the lack of clinicopathological risk factors underline the prominent role of Actinomyces spp. in MRONJ and may change the current understanding of MRONJ. Established prolonged antimicrobial treatment regimens against Actinomyces spp. infection could therefore be a mainstay of future MRONJ management.

Effect of high versus low doses of fat and vitamin A dietary supplementation on fatty acid composition of phospholipids in mice.

Dietary fat and vitamin A provide important precursors for potent bioactive ligands of nuclear hormone receptors, which regulate various enzymes involved in lipid homeostasis, metabolism and inflammation. We determined the effects of dietary fat and dietary vitamin A on hepatic expression of two fatty acid metabolizing enzymes, elongase 6 (ELOVL6) and stearoyl-coenzyme A desaturase 1 (SCD1) and the concentration of saturated fatty acids (SAFA) and monounsaturated fatty acid (MUFA) of phospholipids in serum and liver. Mice (n = 6) were fed 4 weeks with diets containing 2, 5 and 25 % of fat or vitamin A (0, 2,500 and 326,500 RE/kg as retinyl palmitate). MUFAs and SAFAs were measured using GC and ESI-MS/MS. Hepatic expression of metabolizing enzymes was determined using QRT-PCR. ELOVL6 was significantly down-regulated in response to a high-fat diet (p < 0.001) and significantly up-regulated in response to low-fat diet (p < 0.05). SCD1 expression was significantly lower in high- versus low-fat diet (p < 0.05). The vitamin A content in the diet did not influence the hepatic expression of both enzymes. In plasma, the amounts of MUFAs bound to phospholipids significantly decreased in response to a high-fat diet and increased after a low-fat diet. This tendency was also observed in the liver for various phospholipids sub-classes. In summary, this study shows that fat content in the diet has a stronger impact than the content of vitamin A on hepatic gene expression of SCD1 and ELOVL6 and thereby on MUFA and SAFA concentrations in liver and plasma.

Reduced retinoid signaling in the skin after systemic retinoid-X receptor ligand treatment in mice with potential relevance for skin disorders.

Retinoid-X receptor (RXR)- and retinoic acid receptor (RAR)-mediated signaling is induced by retinoic acids (RA), which are involved in the regulation of skin permeability, differentiation and immune response. Dysregulation of retinoid signaling is present in various skin disorders. Topically and systemically administered synthetic RAR or RXR agonists might influence retinoid-mediated signaling in the skin of RARE reporter animals and gene expression analysis for retinoid, skin homeostasis and skin inflammation marker genes and local retinoid concentrations. Mice were treated orally and topically with synthetic ligands and bioimaging, QRT-PCR and retinoid analysis were performed. Topical application of the synthetic RAR ligand AM580 significantly enhanced retinoid signaling in skin while topical application of the RXR ligand LG268 did not influence retinoic acid receptor response elements (RARE)-mediated signaling. Systemic treatments with LG268 decreased the expression of genes involved in skin homeostasis, RA synthesis and skin RA concentrations, while it increased various markers for skin inflammation and RA degradation, which corresponds to decreased skin RARE signaling. We conclude from these observations that increased systemic concentrations of an RXR -ligand may be one reason for reduced retinoid signaling, -reduced all-trans RA levels in the skin, reduced epidermal homeostasis and increased skin inflammation marker expression with potential relevance for various skin disorders, like atopic dermatitis.

Effect of synthetic ligands of PPAR α, ß/δ, γ, RAR, RXR and LXR on the fatty acid composition of phospholipids in mice.

Nuclear hormone receptors are transcription factors that can be activated by nutrition-derived ligands and alter the expression of various specific target genes. Stearoyl-Coenzyme A desaturase (SCD1) converts palmitic acid (16:0) to palmitoleic acid (16:1n-7) as well as stearic acid (18:0) to oleic acid (18:1n-9). At the same time, elongase 6 (ELOVL6) elongates 16:1n-7 and 18:1n-9 to vaccenic acid (18:1n-7) and eicosenoic acid (20:1n-9). We examined how synthetic selective ligands of nuclear hormone receptors alter the gene expression of hepatic enzymes in mice. In addition, we examined how the regulation of these two enzymes influences fatty acid composition of phospholipids in liver and plasma. Mice were gavaged daily for 1 week with synthetic ligands of peroxisome proliferator-activated receptor (PPAR) α, ß/δ, γ, liver X receptor (LXR), retinoic acid receptor (RAR) and retinoid-X receptor (RXR) for 1 week. Phospholipids from liver and plasma were analysed using ESI-MS/MS and GC after saponification. Hepatic gene expression of SCD1 and ELOVL6 was measured using QRT-PCR. SCD1 and ELOVL6 expression increased after the gavage of LXR and RXR ligands. The analysis of fatty acid composition of total phospholipids in plasma and liver showed increased percentage contributions of the SCD1 and ELOVL6 products 18:1n-9, 18:1n-7 and 20:1n-9 after LXR and RXR ligand application. Analysis of total phospholipids from plasma and liver revealed a significant increase in monounsaturated fatty acids bound in phosphatidylcholine (PtdCho) and lysophosphatidylcholine (PtdEtn) after LXR and RXR ligand administration. Increased hepatic gene expression of SCD1 and ELOVL6 after gavage of selective RXR or LXR ligands to mice resulted in increased concentrations of their metabolic products in phospholipids of liver and plasma.

Modulation of Cyp3a11 mRNA expression by alpha-tocopherol but not gamma-tocotrienol in mice.

Metabolism of vitamin E is initiated by cytochrome P450 (CYP) enzymes usually involved in the metabolism of xenobiotics. Like other CYP substrates, vitamin E induced a reporter gene under the control of the pregnane X receptor (PXR) which regulates the expression of CYPs including CYP3A4. gamma-Tocotrienol, the most effective PXR activator, also induced endogenous CYP3A4 mRNA in HepG2 cells. Since these findings imply an interference of vitamin E with drug metabolism it was deemed necessary to investigate their in vivo relevance. Therefore, mice were grown for 3 months with alpha-tocopherol-deficient, -adequate, and -supranutritional diet, i.e. 2, 20 and 200 mg RRR-alpha-tocopheryl acetate/kg diet, respectively. Half of them received 250 microg gamma-tocotrienol/day for the last 7 days. After 3 months, hepatic levels of Cyp3a11 mRNA, the murine homolog to human CYP3A4, were about 2.5-fold higher in the 20 and 200 mg alpha-tocopherol groups than in the 2 mg group. After feeding 200 mg alpha-tocopherol for 9 months, Cyp3a11 mRNA was 1.7-fold higher than after 3 months. In contrast, gamma-tocotrienol did not induce Cyp3a11 mRNA. This could be explained by its high metabolism as demonstrated by the 20- to 25-fold increase in the urinary excretion of gamma-CEHC, the final metabolite of gamma-tocotrienol degradation. In conclusion, alpha-tocopherol maintains an adequate level of xenobiotic-metabolizing enzymes. If fed in supranutritional dosages, especially for longer times, alpha-tocopherol induces Cyp3a11 to levels which might interfere with drug metabolism.