Plaque gene expression out of the aortic root of wildtype (Con) or myeloid-derived lipin-1 KO mice after high fat diet for 8 or 12 weeks
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE151922 | GEO | 2020/07/20
REPOSITORIES: GEO
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Project description:Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. Lipin 1 appears to be highly involved in the control of fatty acid metabolism. Lipin 1 is most often located in the nucleus, but other studies suggest that lipin also has effects in the cytoplasm. However, the molecular function of lipin 1 is unclear. To evaluate the effects of activation of the lipin 1 system in liver, lipin 1beta was overexpressed in mouse liver using an adenoviral vector. We found that lipin 1 overexpression increased the expression of many genes involved in mitochondrial fatty acid oxidation while repressing expression of genes involved in lipogenesis. We believe that lipin is a transcriptional coactivator of the peroxisome proliferator-activated receptor (PPAR) complex. However, the many molecular aspects of its function remain unclear. Abstract of published manuscript follows: Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway.Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence JC Jr, Kelly DP. Center for Cardiovascular Research and Washington University School of Medicine, St. Louis, Missouri 63110; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110. Perturbations in hepatic lipid homeostasis are linked to the development of obesity-related steatohepatitis. Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. However, the molecular function of lipin 1 is unclear. Herein, we demonstrate that the expression of lipin 1 is induced by peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a transcriptional coactivator controlling several key hepatic metabolic pathways. Gain-of-function and loss-of-function strategies demonstrated that lipin selectively activates a subset of PGC-1alpha target pathways, including fatty acid oxidation and mitochondrial oxidative phosphorylation, while suppressing the lipogenic program and lowering circulating lipid levels. Lipin activates mitochondrial fatty acid oxidative metabolism by inducing expression of the nuclear receptor PPARalpha, a known PGC-1alpha target, and via direct physical interactions with PPARalpha and PGC-1alpha. These results identify lipin 1 as a selective physiological amplifier of the PGC-1alpha/PPARalpha-mediated control of hepatic lipid metabolism. Keywords: response to lipin 1 activation
2006-08-16 | GSE5538 | GEO
Project description:Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. Lipin 1 appears to be highly involved in the control of fatty acid metabolism. Lipin 1 is most often located in the nucleus, but other studies suggest that lipin also has effects in the cytoplasm. However, the molecular function of lipin 1 is unclear. To evaluate the effects of activation of the lipin 1 system in liver, lipin 1beta was overexpressed in mouse liver using an adenoviral vector. We found that lipin 1 overexpression increased the expression of many genes involved in mitochondrial fatty acid oxidation while repressing expression of genes involved in lipogenesis. We believe that lipin is a transcriptional coactivator of the peroxisome proliferator-activated receptor (PPAR) complex. However, the many molecular aspects of its function remain unclear. Abstract of published manuscript follows:; Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway.Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence JC Jr, Kelly DP. Center for Cardiovascular Research and Washington University School of Medicine, St. Louis, Missouri 63110; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110. Perturbations in hepatic lipid homeostasis are linked to the development of obesity-related steatohepatitis. Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. However, the molecular function of lipin 1 is unclear. Herein, we demonstrate that the expression of lipin 1 is induced by peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a transcriptional coactivator controlling several key hepatic metabolic pathways. Gain-of-function and loss-of-function strategies demonstrated that lipin selectively activates a subset of PGC-1alpha target pathways, including fatty acid oxidation and mitochondrial oxidative phosphorylation, while suppressing the lipogenic program and lowering circulating lipid levels. Lipin activates mitochondrial fatty acid oxidative metabolism by inducing expression of the nuclear receptor PPARalpha, a known PGC-1alpha target, and via direct physical interactions with PPARalpha and PGC-1alpha. These results identify lipin 1 as a selective physiological amplifier of the PGC-1alpha/PPARalpha-mediated control of hepatic lipid metabolism. Experiment Overall Design: Adult male C57BL6 mice were injected with adenovirus driving expression of mouse lipin 1beta or green fluorescent protein (GFP). Mice were recovered and sacrificed 6 days after injection. Total RNA was isolated and analyzed using Affymetrix microarray.
2008-06-13 | E-GEOD-5538 | biostudies-arrayexpress
Project description:Plaque gene expression out of the aortic root of wildtype (Con) or myeloid-derived lipin-1 KO mice after high fat diet for 8 or 12 weeks
| PRJNA637652 | ENA
Project description:The lipin family consists of three members (lipin-1, lipin-2 and lipin-3) that are phosphatidate phosphatases. Lipins facilitate lipid synthesis and remodeling through the conversion of phosphatidic acid to diacylglycerol. Lipin-1 and lipin-2 are also transcriptional co-regulators of peroxisome proliferator-activated receptors (PPARs). Our previous studies showed differential lipin-1 expression in numerous prostate cancer cell lines, and the lipin-1 expression was higher in cells representing advanced prostate cancer. However, the role of lipin-1 in prostate cancer cell growth is not fully understood. This study addressed the role of lipin-1 in prostate cancer cell function by performing RNA sequencing and qualitative LC-MS/MS analysis in PC-3 cells in which the gene for lipin-1 (LPIN1) was genetically inhibited. Transcriptomic and lipidomic analyses of LPIN1 knockdown PC-3 cells demonstrated alterations in the expression of numerous genes and the peak intensities of several lipids. The genes and lipids aligned with pathways that mediate focal adhesion, glycerophospholipid metabolism (GM), and PPAR signaling. Additionally, treatment of PC-3 cells with curcumin, a suggested inhibitor of lipin, decreased lipin-1 and lipin-3 expression, with no effect on lipin-2 expression. Bioinformatic analysis of prostate cancer patients demonstrated a correlation between LPIN3 mRNA expression and higher Gleason scores (8-10). These data show the novel findings that lipin-1 mediates the lipidome of castration-resistant prostate cancer cells and identified several pathways that it regulates, beyond GM and PPAR. Additionally, these data suggest that curcumin may be used to treat advanced prostate cancer that overexpresses lipin-3.
2023-11-17 | GSE247919 | GEO
Project description:The lipin phosphatidate phosphatase (PAP) enzymes (lipin 1, lipin 2, and lipin 3) catalyze a step in triglyceride and phospholipid biosynthesis, and genetic lipin deficiencies cause human disease that is triggered by metabolic stress, such as fasting. We assessed the protein interactome of lipins 1, 2, and 3 in hepatocytes, and identified unique protein associations between lipin 1 and U2 mRNA spliceosome components. Lpin1–/– mouse liver exhibited aberrant mRNA splicing in the fasted state, including mRNAs involved in mRNA processing and liver maturation. Aberrant splicing could be induced in cultured hepatocytes by lipin 1 knockdown or elevated phosphatidic acid levels, suggesting a role for lipin 1 PAP activity in splicing fidelity. Refeeding Lpin1–/– animals after fasting largely restored mRNA splicing fidelity. Reduced levels of ESRP2 splicing factor exclusively in the fasted state of Lpin1–/– liver was associated with widespread aberrant exon inclusion. These findings connect lipid homeostasis with mRNA splicing, and identify aberrant mRNA splicing in lipin 1 deficiency as a potential contributor to disease symptoms triggered by fasting.
2021-09-15 | GSE160984 | GEO
Project description:Lipin-1 affects the expression levels of many genes during TLR4 stimulation of macrophages. Gene expression analysis of peritoneal macrophages from four control (hetorozygotes) mice and four lipin-1 mutant (fatty liver distrophy, fld) mice stimulated with 100 ng/ml LPS for 5 hours.
2014-10-01 | E-GEOD-54155 | biostudies-arrayexpress
Project description:This project consists of two experiments. The first is mapping the binding interface between the isolated m-lip domain of mouse lipin and liposomes. The second experiments is mapping the binding interface between full length mouse lipin and liposomes. Looking at the isolated m-lip domain, we found that residues 470-490 and 500-550 showed decreases in exchange upon liposome binding. The full-length lipin experiment saw decreases in exchnage in these same regions, as well as in the very C-terminus and very N-terminus regions of the protein. An order-disorder experiment was done on full length lipin where the protein was exposed to a short pulse of deuterium and compared to the fully-deuterated protein. In this instance, we established that the majority of the protein is relatively disordered and does not have secondary structure with high stability
2021-06-29 | PXD022172 | Pride
Project description:Lipin-1 affects the expression levels of many genes during TLR4 stimulation of macrophages.
2014-10-01 | GSE54155 | GEO
Project description:HDX-MS analysis of Lipin binding to anionic membranes
2020-03-18 | PXD017575 | Pride
Project description:Apolipoprotein E-knock out (apoE-KO) mouse is known as a model animal for atherosclerosis accompanied by spontaneous hypercholesterolemia. When apoE-KO mice were fed a chow supplemented with 1.25% cholesterol (high-Chol diet), cholesterol and bile acids were highly increased in the liver within a week. However, the amount of triacylglycerol (TG) in very low-density lipoprotein (VLDL), but not in the liver, was reduced by 78%. The epididymal adipose tissue was almost diminished in the long term. Cholesterol metabolism is tightly regulated by both cholesterol and its metabolites in the mammalian liver, but the regulatory mechanism of TG synthesis remains to be elucidated. To evaluate the impact of high-Chol diet for 1 week on gene expression in the liver of apoE-KO mice, DNA microarray analysis was performed with comparison to apoE-KO mice fed a normal chow. We found that mRNA expression related to lipid metabolism was suppressed by the high-Chol diet in the liver of apoE-KO mice, which includes beta-oxidation and glycerol-3-phosphate (G3P) pathway for TG synthesis. In particular, the mRNA and protein expression of lipin-1 and lipin-2 was markedly decreased. PGC-1?, which up-regulates the transcription of lipin-1, was also suppressed. Lipin is reported to function as a coactivator of PGC-1? and is an inducible amplifier of PPAR?, indicating that the suppression of genes involved in beta-oxidation could be induced by suppression of the lipins. These data using apoE-KO mice indicate that cholesterol and its metabolites are involved in regulating TG metabolism through a suppression of lipin-1 and lipin-2 in the liver. This research provides evidence for the mechanism of lipin expression in the liver. Apo E-KO mice at 10 weeks of age were fed normal chow (control) or high-Chol diet containing 1.25% cholesterol for 1 week. Three independent experiments were performed at each diet.
2011-08-07 | E-GEOD-27457 | biostudies-arrayexpress