The expression profiling comparison of mice with Scap and Insig deletion from perinatal lung (E17.5-PN1)
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Yan Xu
PROVIDER: E-GEOD-53397 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:In this study, we studied the genomic responses of the Insig and Scap deletion from perinatal lung. Through comprehensive data analysis and integration, time dependent effects of epithelial SCAP/INSIG/SREBP deletion and defined SCAP/INSIG/SREBP-associated genes, bioprocesses and downstream pathways were identified.
2014-07-10 | GSE53397 | GEO
Project description:Background: Lung function is dependent upon the precise regulation of the synthesis, storage, and catabolism of tissue and alveolar lipids. Results: Activation of SREBP (Sterol Response Element Binding Protein) induced lipogenesis in alveolar epithelial cells, causing neutral lipid accumulation, lung inflammation, and tissue remodeling. Conclusions: The accumulation of neutral lipids in type II epithelial cells and alveolar macrophages caused lung inflammation, consistent with findings in lipid storage disorders. Significance: Pulmonary lipotoxicity may contribute to the pathogenesis of lung dysfunction associated with diabetes, obesity, and other metabolic disorders. Genome-wide transcription profiling comparison between doxycycline-exposed SFTPC-rtTAWT/Tg/(tetO)7CMV-CreWT/Tg/Insig1flox/flox/Insig2-/- mice (i.e., Insig1/2∆/∆ ) and Insig1flox/flox/Insig2-/- . Three independent pooled RNA from isolated lung type 2 cells of each genotype were used.
2012-03-01 | E-GEOD-31797 | biostudies-arrayexpress
Project description:Indomethacin (an inhibitor of prostaglandin synthesis) and RU486 (mifepristone, progesterone receptor antagonist) are well known compounds which impair follicle rupture in rats, nevertheless the histopahotlogical figures of these follicle were different in detail due to the difference of the pathway which each compound inhibits. To characterize these unruptured follicles further and to investigate the genes which were altered in each rat treated with indomethacin or mifepristone, gene expression profile in ovarian follicle were analyzed in female sprague-Dawley rats. Peri- or post ovulatory follicles were collected by laser microdissection and extracted RNA was analyzed by genechip after single dosage of mifepristone or indomethacin. Animals were singly administered orally Indomethacin (IM) at 4mg/kg at 16:00 or RU486 (RU) at 100 mg/kg at 10:00 on the proestrus day, and sacrificed by exsanguination under anesthesia at 22:00 on the proestrus day (PeF: peri-ovulatory follicle), and 10:00 on the estrus day (PoF: post-ovulatory follicle). Ovaries were also collected from untreated rats at 22:00 on the proestrus day, and 10:00 on the estrus day as control groups. Three animals were contained per each treatment group at each timing. The ovaries were removed and embedded in OCT (Tissue-Tek, Sakura Finetek, Torrance, CA), frozen in dry-ice-cold isopentan, and stored at -70 C until used. Frozen sections (8 micro meter thick) were mounted on the membrane slides (MMI, Glatteburg, Zurich, Switzerland), and stained with HistogeneTM LCM frozen section staining kit (Arcturus Engineering, Mountain View, CA). Then, 15 follicles in each phase were retrieved by Laser Micro Dissection system (LMD, CellCut Plus, MMI). The collected follicle sections were lysed by the buffer RLT in the collection tube supplied in RNeasy Micro Kit (Qiagen, Hilden, Germany), and total RNA was extracted according to manufacturer's instructions.
2014-02-01 | E-GEOD-54584 | biostudies-arrayexpress
Project description:A population genetic study identified that the asialoglycoprotein receptor 1 (ASGR1) mutation carriers had significantly lower non-HDL-c levels and reduced risks of cardiovascular diseases. However, the mechanism behind this phenomenon remained unclear. Here, we established Asgr1 knockout mice that represented a plasma lipid profile with significantly lower non-HDL-c and triglyceride caused by decreased secretion and increased uptake of VLDL/LDL. These two phenotypes were linked with the decreased expression of microsomal triglyceride transfer protein (MTTP) and proprotein convertase subtilisin/kexin type 9 (PCSK9), two key target genes of the sterol regulatory element-binding proteins (SREBPs). Furthermore, there were less nSREBPs on account of more SREBPs being trapped in endoplasmic reticulum, which was caused by an increased expression of insulin-induced gene 1 (INSIG1), an anchor of SREBPs. Logically, two rescue experiments were conducted in ASGR1 deficient condition. Both INSIG1 knockdown and ASGR1 rescue independently reversed the ASGR1-mutated phenotypes, restoring the SREBP signaling manifested by improved APOB secretion and reduced LDL uptake. Our observation demonstrated a novel axis of ASGR1-INSIG1-SREBPs regulating lipid hemostasis, and hypomorphic manipulation of ASGR1 leads to significant reduction of lipid content via less nSREBPs. It provides multiple potential targets, including ASGR, for lipid-lowering drug development.
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Project description:Lipid accumulation in the renal tubules is a major determinant of diabetic kidney disease (DKD), and activation of SREBPs plays a central role in this process. Our study aimed to explore whether HSPA8, a molecular chaperone, is the master regulator of INSIG/SREBPs function in DKD. Here, we showed that tubular epithelial cell (TEC)-specific knockout of HSPA8 upregulated the phosphorylation of INSIG1 and INSIG2, which disrupted the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, and the activation of SREBPs. TEC-specific overexpression of HSPA8 restrained these changes. INSIG1 and INSIG2 can be phosphorylated by protein kinase R (PKR), while HSPA8 can recognize PKR and recruit the E3 ubiquitin ligase (CHIP) to promote PKR ubiquitination and degradation. SREBP1 transcriptionally activated HSPA8 expression under temporary hyperglycemic stimulation. However, persistent hyperglycemia reduced HSPA8 levels by promoting nuclear factor (NF)-κB-mediated transcriptional inhibition and reducing USP43-mediated deubiquitination of HSPA8. Collectively, these findings indicate that the molecular chaperone HSPA8 serves as a negative feedback regulator of SREBPs, lipogenesis, and DKD development.
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Project description:Pulmonary function after birth is dependent upon surfactant lipids that reduce surface tension in the alveoli. The sterol-responsive element-binding proteins (SREBPs) are transcription factors regulating expression of genes controlling lipid homeostasis in many tissues. To identify the role of SREBPs in the lung, we conditionally deleted the SREBP cleavage-activating protein gene, Scap, in respiratory epithelial cells (Scap∆/∆) in vivo. Prior to birth (E18.5), deletion of Scap decreased the expression of both SREBPs and a number of genes regulating fatty acid and cholesterol metabolism. Nevertheless, Scap∆/∆ mice survived postnatally, surfactant and lung tissue lipids being substantially normalized in adult Scap∆/∆ mice. Although phospholipid synthesis was decreased in type II cells from adult Scap∆/∆ mice, lipid storage, synthesis, and transfer by lung lipofibroblasts were increased. mRNA microarray data indicated that SCAP influenced two major gene networks, one regulating lipid metabolism and the other stress-related responses. Deletion of the SCAP/SREBP pathway in respiratory epithelial cells altered lung lipid homeostasis and induced compensatory lipid accumulation and synthesis in lung lipofibroblasts. To identify the role of SREBPs in the lung, we conditionally deleted the SREBP cleavage-activating protein gene, Scap, in respiratory epithelial cells (Scap∆/∆) in vivo.Lung cRNA was hybridized to the murine genome MOE430 V2 chips.
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