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PubMed | Thomas Jefferson University, Northwestern University, The Research Center for Digestive Tract and Liver Diseases, Trinity College Dublin and 3 more.
Type: | Journal: Experimental dermatology | Year: 2016

SVEP1 is a recently identified multi-domain cell adhesion protein, homologous to the mouse polydom protein, which has been shown to mediate cell-cell adhesion in an integrin dependent-manner in osteogenic cells. In the present study, we characterized SVEP1 function in the epidermis. SVEP1 was found by qRT-PCR to be ubiquitously expressed in human tissues, including the skin. Confocal microscopy revealed that SVEP1 is normally mostly expressed in the cytoplasm of basal and suprabasal epidermal cells. Down-regulation of SVEP1 expression in primary keratinocytes resulted in decreased expression of major epidermal differentiation markers. Similarly, SVEP1 down-regulation was associated with disturbed differentiation and marked epidermal acanthosis in three-dimensional skin equivalents. In contrast, the dispase assay failed to demonstrate significant differences in adhesion between keratinocytes expressing normal vs. low levels of SVEP1. Homozygous Svep1 knockout mice were embryonic lethal. Thus, to assess the importance of SVEP1 for normal skin homeostasis in vivo, we down regulated SVEP1 in zebra fish embryos with a Svep1-specific splice morpholino. Scanning electron microscopy revealed a rugged epidermis with perturbed microridge formation in the center of the keratinocytes of morphant larvae. Transmission electron microscopy analysis demonstrated abnormal epidermal cell-cell adhesion with disadhesion between cells in Svep1-deficient morphant larvae compared to controls. In summary, our results indicate that SVEP1 plays a critical role during epidermal differentiation. This article is protected by copyright. All rights reserved.

PubMed | Thomas Jefferson University, Tel Aviv Sourasky Medical Center, The Research Center for Digestive Tract and Liver Diseases, University of Dundee and 4 more.
Type: | Journal: The Journal of investigative dermatology | Year: 2016

Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin, but its expression was dramatically reduced in the patients skin. The downregulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. Small interfering RNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture, and downregulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using exvivo live imaging, small interfering RNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared with controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that its absence may aggravate the clinical manifestations of ABCA12 mutations.

Lisiansky V.,The Integrated Cancer Prevention Center | Lisiansky V.,Tel Aviv University | Kraus S.,The Integrated Cancer Prevention Center | Kraus S.,Tel Aviv University | And 17 more authors.
International Journal of Biological Markers | Year: 2014

Background: Inflammatory bowel disease (IBD) results from an inappropriate inflammatory response in which genetic, immune, and environmental factors all play important roles. Recently, single nucleotide polymorphisms (SNPs) in the CD24 gene have been associated with the development of several autoimmune diseases. Aim: To evaluate whether CD24 SNPs, are associated with risk of ulcerative colitis (UC) and Crohn's disease (CD). Methods: The CD24 polymorphisms C170T (rs8734), TG1527del (rs3838646), A1626G (rs1058881), and A1056G (rs1058818) were assessed in a case-control study of an Israeli cohort comprising 117 IBD patients and 105 age and gender-matched healthy controls. Restriction fragment length polymorphism (RFLP) analysis was performed using BstX1, Bsr1, Mfe1, and BstU1 restriction enzymes. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression models. Results: Carriers of the C170T SNP were at increased risk of IBD (OR=3.022, 95% CI: 1.748-5.223, p=0.001), UC (OR=3.002, 95% CI: 1.661-5.427, p=0.001) and CD (OR=3.077, 95% CI: 1.334-7.095, p=0.008). Carrying the A1626G and A1056G SNPs was found to be a risk factor for IBD (OR=2.460, 95% CI: 1.420-4.259, p=0.001 and OR=1.856, 95% CI: 1.011- 3.405, p=0.01), UC (OR=2.218, 95% CI: 1.207-4.075, p=0.01 and OR=1.944, 95% CI: 0.995-3.798, p=0.01) but not for CD (p=0.086 and p=0.299). The A1626G and TG1527del were found to be associated with younger age of IBD onset (p=0.022 and p=0.027, respectively). Conclusions: The CD24 C170T polymorphism is associated with IBD risk. The A1626G and A1056G SNPs might be associated only with UC risk. These findings suggest CD24 as a new genetic susceptibility factor, with clinical implications in the prediction of IBD prognosis and therapy. © 2014 Wichtig Publishing.

PubMed | The Research Center for Digestive Tract and Liver Diseases
Type: Journal Article | Journal: Digestive diseases and sciences | Year: 2013

Rodent obesity models have been shown to display impaired bile secretory functions. We have shown that glucagon-like peptide 1 (GLP-1) attenuates hepatic lipogenesis, and in the present study we investigated whether GLP-1 also improves high fat diet-associated cholestatic injury.Wild type (WT) and dipeptidyl peptidase 4-deficient rats (DPP4-) with chronic elevated serum levels of active GLP-1 were fed regular chow and a Western diet for 2months. Primary hepatocytes were used to assess GLP-1 effects on mRNA expression and transcription of genes encoding bile acid synthesis enzymes and transporters.DPP4- exhibited attenuated liver injury as expressed by lower serum AST and ALT after 2months of a Western diet. In addition, DPP4- had better insulin sensitivity, lower serum triglycerides, cholesterol and bile acids. Hepatic expression of cyp7A1, the rate limiting enzyme in conversion of cholesterol into bile acids, was strongly attenuated in DPP4- fed with a Western diet. Moreover, hepatic expression of bile transporter, ABCB11, was increased, facilitating a higher rate of bile secretion. Mechanistically, we showed that GLP-1 directly reduced basal and LXR-induced cyp7A1 mRNA expression and suppressed cyp7A1 transcription in transient transfection assays in primary hepatocytes. However, GLP-1 and its analog exendin 4 also induced mRNA expression of bile acid transporter ABCC3 in primary rat hepatocyte cultures.Our data suggest that GLP-1 analogs may serve as a novel therapeutic drug to alleviate obesity-induced liver injury by reducing bile acid synthesis and improving liver bile secretory function.

PubMed | The Research Center for Digestive Tract and Liver Diseases
Type: Journal Article | Journal: Liver international : official journal of the International Association for the Study of the Liver | Year: 2011

Hepatitis B virus (HBV) is a small DNA virus responsible for significant morbidity and mortality worldwide. The liver, which is the main target organ for HBV infection, provides the virus with the machinery necessary for persistent infection and propagation, a process that might ultimately lead to severe liver pathologies such as chronic hepatitis, cirrhosis and liver cancer. HBV gene expression is regulated mainly at the transcriptional level by recruitment of a whole set of cellular transcription factors (TFs) and co-activators to support transcription. Over the years, many of these TFs were identified and interestingly enough most are associated with the bodys nutritional state. These include the hepatocyte nuclear factors, forkhead Box O1, Farnesoid X receptor, cyclic-AMP response element-binding (CREB), CCAAT/enhancer-binding protein (C/EBP) and glucocorticoid receptor TFs and the transcription coactivator PPAR coactivator-1. Consequently, HBV gene expression is linked to hepatic metabolic processes such as glucose and fat production and utilization as well as bile acids production and secretion. Furthermore, recent evidence indicates that HBV actively interferes with some of these hepatic metabolic processes by manipulating key TFs, such as CREB and C/EBP, to meet its requirements. The discovery of the mechanisms by which HBV is controlled by the hepatic metabolic milieu may broaden our understanding of the unique regulation of HBV expression and may also explain the mechanisms by which HBV induces liver pathologies. The emerging principle of the intimate link between HBV and liver metabolism can be further exploited for host-targeted therapeutic strategies.

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