Expression data from murine skin of tamoxifen-induced Ugcgfl/fl K14CreERT2 vs. Ugcgfl/fl
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE47789 | GEO | 2013/06/12
SECONDARY ACCESSION(S): PRJNA208005
REPOSITORIES: GEO
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Project description:Tamoxifen-induced deletion of endogenous GlcCer-synthesizing enzyme UDP-glucose:ceramide glucosyltransferase (UGCG) in keratin K14-positive cells results in epidermal GlcCer depletion. We used microarrays to investigate the molecular consequences of Ugcg-depleted mouse epidermis. Ugcgfl/fl K14CreERT2 vs. Ugcgfl/fl samples taken at day 21 post tamoxifen induction
2013-06-12 | E-GEOD-47789 | biostudies-arrayexpress
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Project description:Recent studies have reported that glycosphingolipids (GSL) might be involved in obesity induced insulin resistance. Those reports suggested that inhibition of GSL biosynthesis in animals ameliorated insulin sensitivity accompanied with improved glycemic control leading to decreased liver steatosis in obese mice. In addition, GSL depletion altered hepatic secretory function. In those studies, ubiquitously acting inhibitors for GSL-biosynthesis have been used to inhibit function of the enzyme Ugcg (UDP-glucose:ceramide glucosyltransferase), catalyzing the first step of the glucosylceramide based GSL-synthesis pathway. In the present study, a genetic approach for GSL deletion in hepatocytes was chosen to achieve full inhibition of GSL synthesis and to prevent possible adverse effects caused by Ugcg-inhibitors. Using the Cre/loxP system under control of the albumin promoter, GSL biosynthesis in hepatocytes and their release into the plasma could be effectively blocked. Deletion of GSL in hepatocytes did not change quantity of bile excretion through the biliary duct. Total bile salt content in bile-, feces- and plasma from mutant mice showed no difference as compared to control animals. Cholesterol concentration in liver-, bile-, feces- and plasma-samples remained unaffected. Lipoprotein concentration in plasma-samples in mutant animals reached similar levels as in their control littermates. No alteration in glucose tolerance after intraperitoneal application of glucose and insulin appeared in mutant animals. A preventive effect of GSL-deficiency on development of liver steatosis after high fat diet feeding could not be observed. Conclusion: The data suggest that GSL in hepatocytes are not essential for sterol, glucose and lipoprotein metabolism and do not prevent high fat diet-induced liver steatosis, indicating that Ugcg inhibitors exert their effect on hepatocytes either independently of GSL or mediated by other (liver) cell types. Comparison of wildtype mouse liver function versus Ugcg-deficient
2010-05-14 | E-GEOD-19316 | biostudies-arrayexpress
Project description:Recent studies have reported that glycosphingolipids (GSL) might be involved in obesity induced insulin resistance. Those reports suggested that inhibition of GSL biosynthesis in animals ameliorated insulin sensitivity accompanied with improved glycemic control leading to decreased liver steatosis in obese mice. In addition, GSL depletion altered hepatic secretory function. In those studies, ubiquitously acting inhibitors for GSL-biosynthesis have been used to inhibit function of the enzyme Ugcg (UDP-glucose:ceramide glucosyltransferase), catalyzing the first step of the glucosylceramide based GSL-synthesis pathway. In the present study, a genetic approach for GSL deletion in hepatocytes was chosen to achieve full inhibition of GSL synthesis and to prevent possible adverse effects caused by Ugcg-inhibitors. Using the Cre/loxP system under control of the albumin promoter, GSL biosynthesis in hepatocytes and their release into the plasma could be effectively blocked. Deletion of GSL in hepatocytes did not change quantity of bile excretion through the biliary duct. Total bile salt content in bile-, feces- and plasma from mutant mice showed no difference as compared to control animals. Cholesterol concentration in liver-, bile-, feces- and plasma-samples remained unaffected. Lipoprotein concentration in plasma-samples in mutant animals reached similar levels as in their control littermates. No alteration in glucose tolerance after intraperitoneal application of glucose and insulin appeared in mutant animals. A preventive effect of GSL-deficiency on development of liver steatosis after high fat diet feeding could not be observed. Conclusion: The data suggest that GSL in hepatocytes are not essential for sterol, glucose and lipoprotein metabolism and do not prevent high fat diet-induced liver steatosis, indicating that Ugcg inhibitors exert their effect on hepatocytes either independently of GSL or mediated by other (liver) cell types.
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Project description:Keratin cytoskeletal proteins are crucial for the maintenance of skin integrity. Mutations in genes coding for K5 and K14 cause the human skin disorder epidermolysis bullosa simplex (EBS) leading to substantial alterations in keratin assembly and collapse of keratin filaments into cytoplasmic protein aggregates. The phenotypic consequences of K5 and K14 mutations comprise fragility of basal keratinocytes and skin blistering upon mild mechanical trauma. Treatment of EBS is only supportive and consists primarily of wound care and avoidance of mechanical stress. Besides symptomatic care, no efficient therapeutic treatment is available for EBS. In the present study, we used patient-derived keratinocytes carrying the most frequent K14.R125C mutation as a reproducible EBS model to understand EBS pathomechanisms and to develop a therapy approach aimed to restore a functional keratin network. Numerous post-translational modifications (PTMs) such as phosphorylation have been reported to occur on keratins, which affect the organization of keratin networks. Whether keratin mutations affect the occurrence of PTMs and thereby keratin aggregation in EBS is yet unknown. We find that the K14.R125C mutation alters keratin and keratin-associated protein PTMs in distinct ways and suggest that disease mutations and altered PTMs aggravate keratin aggregation. We reason that chemical compounds affecting the interplay of mutations and PTMs enable the reformation of a keratin cytoskeleton from aggregates are potential candidates for combating EBS.
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Project description:Lysosomal autophagy inhibition (LAI) with hydroxychloroquine or DC661 can enhance cancer therapy, but tumor regrowth is common. To elucidate LAI resistance, proteomics and immunoblotting demonstrated that LAI induced lipid metabolism enzymes in multiple cancer cell lines. Lipidomics showed that LAI increased cholesterol, sphingolipids, and glycosphingolipids. These changes were associated with striking levels of GM1+ membrane microdomains (GMM) in plasma membranes and lysosomes. Inhibition of cholesterol/sphingolipid metabolism proteins enhanced LAI cytotoxicity. Targeting UDP-glucose ceramide glucosyltransferase (UGCG) synergistically augmented LAI cytotoxicity. While UGCG inhibition decreased LAI-induced GMM and augmented cell death, UGCG overexpression led to LAI resistance. Melanoma patients with high UGCG expression had significantly shorter disease-specific survival. The FDA-approved UGCG inhibitor eliglustat combined with LAI significantly inhibited tumor growth and improved survival in syngeneic tumors and a therapy-resistant patient-derived xenograft. These findings nominate UGCG as a new cancer target, and clinical trials testing UGCG inhibition in combination with LAI are warranted.
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Project description:Analysis of whole transcript in mice with overexpression of 4-1BB under the control of keratin 14 promoter. The study analyze the whole transcript from all eye tissue obtained from C57/BL6 (WT control), K14-4-1BB (355) low copy number mice, K14-4-1BB (389) full blown disease mice (uveitis and cataract) and K14-4-1BB (389) onset of disease mice (eye inflammation).
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