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1.
FIGURE 3.

FIGURE 3. From: Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity.

Ultrastructural changes in alveolar type 2 cells from Insig1/2Δ/Δ mice. A, ultrastructure of alveolar type 2 cells from Insig1flox/flox/Insig2−/− was not altered. In contrast, large electron lucent lipid droplets were present in the cytoplasm of a subset of Insig1/2Δ/Δ alveolar type 2 cells (B and C). Some lipid droplets lacked limiting membranes (arrow); others contained membranous phospholipid material (black arrowhead). Small lamellar bodies were also present in the cytoplasm of Insig1Δ/Δ alveolar type 2 cells (white arrowhead).

Laurent Plantier, et al. J Biol Chem. 2012 March 23;287(13):10099-10114.
2.
FIGURE 10.

FIGURE 10. From: Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity.

mRNAs induced in type 2 cells from Insig1/2Δ/Δ mice were functionally enriched in the lipid metabolism and immune/inflammatory response. The regulatory relationships linking the two categories of genes were identified through literature mining using Ingenuity knowledge base. Red and green nodes represent the genes induced or repressed in Insig1/2Δ/Δ versus control, respectively. Triangular nodes are genes induced in Insig1/2Δ/Δ and repressed in ScapΔ/Δ mice (22). Color range indicates the relative fold change (the darker the color, the larger the fold change).

Laurent Plantier, et al. J Biol Chem. 2012 March 23;287(13):10099-10114.
3.
FIGURE 4.

FIGURE 4. From: Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity.

Concentrations of PC, triacylglycerol (TAG), and cholesterol ester (CE). Lipid concentrations are shown for lavaged lungs (A), isolated alveolar type 2 cells (B), isolated lamellar body preparations (C), and BALF from Insig1flox/flox/Insig2−/− (open bars) and Insig1/2Δ/Δ mice (closed bars) (D) *, p < 0.05. n = 6. E, precursor scan of m/z 369 shows that BALF and serum BALF cholesterol ester compositions were distinct, indicating that BALF cholesterol ester was not blood-derived. F demonstrates that decreased PC16:0/16:0 was the major contributor to the lower total BALF PC concentration in Insig1/2Δ/Δ mice, n = 6, p < 0.05.

Laurent Plantier, et al. J Biol Chem. 2012 March 23;287(13):10099-10114.
4.
FIGURE 1.

FIGURE 1. From: Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity.

Respiratory epithelium-specific deletion of Insig1 in Insig2−/−mice increased SREBP. A, schematic of Insig1 deletion strategy in the alveolar epithelium is shown. In utero treatment with doxycycline induced Cre-mediated deletion of exon 1 of the Insig1 gene in SFTPC-rtTAWT/Tg/(tetO)7CMV-CreWT/Tg/Insig1flox/flox mice, termed Insig1Δ/Δ. These mice were bred into Insig2−/− mice. Mice lacking either SFTPC-rtTA or (tetO)7CMV-Cre are termed Insig1flox/flox. B, aSREBP1 (72 kDa) was ∼2-fold higher in the lungs of Insig1/2Δ/Δ mice compared with Insig1flox/flox/Insig2−/− mice. A representative Western blot is shown. GAPDH was used as an internal control, n = 4 in each group, mean ± S.E., *, p < 0.05. DOX, doxycycline; rtTA, reverse tetracycline transactivator; CRE, Cre-recombinase.

Laurent Plantier, et al. J Biol Chem. 2012 March 23;287(13):10099-10114.
5.
FIGURE 2.

FIGURE 2. From: Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity.

Cytoplasmic accumulation of neutral lipids in alveolar type 2 cells of Insig1/2Δ/Δ mice. A, alveolar cells from Insig1/2Δ/Δ mice were enlarged and contained optically empty vacuoles after staining with pentachrome. Vacuoles contained neutral lipids as shown by Oil Red O staining. Photomicrographs are representative of n = 5. Insets show higher magnification. B, lungs were double-stained with a pro-SP-C antibody, a marker of alveolar type 2 cells (green color), and Nile Red (red color). C, alveolar type 2 cells were stained with Nile Red and counted in Insig1flox/flox/Insig2−/− mice (open bars) and Insig1/2Δ/Δ mice (closed bars) at 2 and 6 months of age and expressed as a percentage, n = 3, *, p < 0.05.

Laurent Plantier, et al. J Biol Chem. 2012 March 23;287(13):10099-10114.
6.
FIGURE 6.

FIGURE 6. From: Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity.

RNA microarray data from alveolar type 2 cells isolated from Insig1/2Δ/Δ mice. A, two-dimensional hierarchical clustering identified 650 mRNAs that were significantly altered in type 2 cells isolated from Insig1/2Δ/Δ compared with Insig1flox/flox/Insig2−/− mice. The intensity in the red and green color ranges indicates increased versus decreased mRNAs, respectively. Each row represents a single mRNA, and each column represents a biological replicate. B, RT-PCR analysis confirmed RNA microarray data demonstrating decreased expression of Insig1 and increased expression of Hmgcs1, Fasn, and Stard4 in Insig1/2Δ/Δ in cells from Insig1/2Δ/Δ mice (filled bars) compared with control (open bars), n = 3, *, p < 0.05. C, Western blot analysis confirmed increased expression of FASN in lung homogenates from the Insig1/2Δ/Δ mice, n = 4. GAPDH was used as a loading control.

Laurent Plantier, et al. J Biol Chem. 2012 March 23;287(13):10099-10114.
7.
FIGURE 9.

FIGURE 9. From: Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity.

Accumulation of lipid-laden alveolar macrophages and inflammatory mediators in Insig1/2Δ/Δ mice. A, BALF cell counts; B, percentage of BALF cells stained with Oil Red O in 2- and 6-month-old Insig1flox/flox/Insig2−/− (white) and Insig1/2Δ/Δ mice (black). C, percentage of BALF cells stained with an antibody against arginase-1 (ARG1). D, expression of mRNAs for Arg1 and Nos2 in BALF cells from 2-month-old Insig1flox/flox/Insig2−/− and Insig1/2Δ/Δ mice. E, PGE2 in BALF; F, IL-6, IL-1β, TNF-α, keratinocyte chemoattractant, and MIP2 in lung homogenates of 2-month-old Insig1flox/flox/Insig2−/− and Insig1/2Δ/Δ mice, n = 6; *, p < 0.05. mRNA was isolated from alveolar macrophages isolated after lung lavage from 8-week-old control (n = 10) and Insig1/2Δ/Δ mice, n = 5. G, IL-1b and IL-12b mRNAs were measured by RT-PCR and were normalized to 18 S RNA levels. Bars represent means ± S.D., and differences were assessed by two-tailed Student t test.

Laurent Plantier, et al. J Biol Chem. 2012 March 23;287(13):10099-10114.
8.
FIGURE 7.

FIGURE 7. From: Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity.

Quantitation of mRNAs in distinct alveolar type 2 cell subpopulations. A, alveolar type 2 cells of Insig1/2Δ/Δ mice were sorted according to their neutral lipid content as determined by Nile Red staining. Phospholipid-rich cells were detected using a 660/20-nm emission filter, neutral lipid-rich cells using a 545/30-nm emission filter. Neutral lipid negative (NL) and neutral lipid positive (NL+) cell populations were sorted. Gene expression was determined by RT-PCR in Insig1flox/flox/Insig2−/− alveolar type 2 cells (empty bars), in NL (gray bars), and NL+ (filled bars) cells from Insig1/2Δ/Δ mice. B, Insig1 mRNA was strongly reduced in NL+ cells but not in NL cells. C, genes related to lipid biosynthesis and surfactant metabolism were induced in NL+ but not in NL cells from Insig1/2Δ/Δ mice. D, mRNAs related to lipid transport, catabolism, and leukocyte recruitment were induced in NL cells. Figure represents n = 5, $, p < 0.05 versus Insig1flox/flox/Insig2−/− (empty) alveolar type 2 cells and NL cells (gray); *, p < 0.05 versus Insig1flox/flox/Insig2−/− and NL+ alveolar type 2 cells.

Laurent Plantier, et al. J Biol Chem. 2012 March 23;287(13):10099-10114.
9.
FIGURE 5.

FIGURE 5. From: Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity.

Lipid concentrations and incorporation of [methyl-9-2H]choline and secretion of BALF PC. A, fractional incorporation of [methyl-9-2H]choline into lavaged lungs, purified lamellar bodies, and isolated alveolar type 2 cells was unaltered in Insig1/2Δ/Δ mice (closed bars) compared with Insig1flox/flox/Insig2−/− (open bars) but was significantly increased in BALF PC. B, correcting the incorporation of [methyl-9-2H]choline in BALF PC for the enrichment of stable isotope label in the substrate lamellar body pool suggested the rate of PC secretion into BALF was unaltered in Insig1/2Δ/Δ mice, n = 7, *, p < 0.05. C, comparison of the molecular species compositions of [methyl-9-2H]choline incorporation into BALF PC (closed bars) with endogenous PC compositions (open bars) demonstrated that there was an initial synthesis of unsaturated species with fatty acyl groups containing 18 or more carbon atoms (Unsat PC) for both Insig1/2Δ/Δ and Insig1flox/flox/Insig2−/− mice, with increased acyl remodeling to PC16:0/16:1 compared with PC16:0/16:0 in the Insig1/2Δ/Δ mice.

Laurent Plantier, et al. J Biol Chem. 2012 March 23;287(13):10099-10114.
10.
FIGURE 8.

FIGURE 8. From: Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity.

Inflammation and alveolar remodeling in Insig1/2Δ/Δ mice. The lungs of Insig1/2Δ/Δ mice are shown at 6 and 8 months of age. Focal accumulation of enlarged foamy multinuclear alveolar macrophages are shown by Movat's pentachrome stain (A), and peribronchial infiltrates include T lymphocytes demonstrated by CD3 immunostaining (B). C, inflammation was accompanied by alveolar type 2 cell hyperplasia shown by pro-SP-C immunostaining. Lungs of Insig1flox/flox/Insig2−/− mice were normal (data not shown). Immunostaining shown with nickel-diaminobenzidine appears brown; nuclei were counterstained with nuclear Fast Red. D, photomicrographs are representative of n = 9 mice of each genotype. At 10 months of age, extensive lesions were observed in the lungs of Insig1Δ/Δ/Insig2−/− mice, with prominent foamy macrophage infiltration, and cholesterol clefts (arrowhead). Bars, 100 μm. Insets show higher magnification.

Laurent Plantier, et al. J Biol Chem. 2012 March 23;287(13):10099-10114.

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