Mouse Liver LeXis overexpression
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE77802 | GEO | 2016/03/31
SECONDARY ACCESSION(S): PRJNA311590
REPOSITORIES: GEO
Similar Datasets
Project description:Consequences of hepatic Lexis overexpression Mouse livers treated with AdLeXis or AdGFP
2016-03-31 | E-GEOD-77802 | biostudies-arrayexpress
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:Abstract: The LXR and SREBP transcription factors are key regulators of cellular and systemic cholesterol homeostasis. The molecular mechanisms that integrate these pathways are incompletely understood. Here we show that ligand activation of LXRs in liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as an unexpected mediator of this effect. LeXis is robustly induced in mouse liver in response to western diet feeding or pharmacologic LXR activation. Expression of LeXis in liver inhibits cholesterol biosynthesis and lowers plasma cholesterol levels. Reciprocally, knockdown of LeXis increases hepatic cholesterol content and raises plasma cholesterol levels. LeXis interacts with the heterogeneous nuclear ribonucleoprotein Raly and regulates its binding to cholesterol biosynthetic gene promoters. These studies outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms orchestrating systemic sterol homeostasis. Global RNA expression from primary hepatocytes treated with or without GW3965 were compared by RNA-Seq.
2016-02-10 | E-GEOD-77793 | biostudies-arrayexpress
Project description:Abstract: The LXR and SREBP transcription factors are key regulators of cellular and systemic cholesterol homeostasis. The molecular mechanisms that integrate these pathways are incompletely understood. Here we show that ligand activation of LXRs in liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as an unexpected mediator of this effect. LeXis is robustly induced in mouse liver in response to western diet feeding or pharmacologic LXR activation. Expression of LeXis in liver inhibits cholesterol biosynthesis and lowers plasma cholesterol levels. Reciprocally, knockdown of LeXis increases hepatic cholesterol content and raises plasma cholesterol levels. LeXis interacts with the heterogeneous nuclear ribonucleoprotein Raly and regulates its binding to cholesterol biosynthetic gene promoters. These studies outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms orchestrating systemic sterol homeostasis.
2016-02-10 | GSE77793 | GEO
Project description:RNAseq analysis was conducted to complement the targeted and untargeted metabolomics analysis of livers overexpressing the CoA-degrading enzyme Nudt7 or GFP (control). Lipid metabolism requires coenzyme A (CoA), which is found in multiple subcellular compartments including the peroxisomes. In the liver, CoA levels are dynamically adjusted between the fed and fasted states. The elevation in CoA levels that occurs during fasting is driven by increased synthesis but also correlates with decreased expression of Nudt7, the major CoA-degrading enzyme in the liver. Nudt7 resides in the peroxisomes and we overexpressed this enzyme in mouse livers to determine its effect on the size and composition of the hepatic CoA pool in the fed and fasted states. Nudt7 overexpression did not change total CoA levels but decreased the concentration of short-chain acyl-CoAs and choloyl-CoA in fasted livers, when endogenous Nudt7 activity was lowest. The effect on these acyl-CoAs correlated with a significant decrease in the hepatic bile acid content and in the rate of peroxisomal fatty acid oxidation, as estimated by targeted and untargeted metabolomics, combined with the measurement of fatty acid oxidation in intact hepatocytes. Identification of the CoA species and metabolic pathways affected the overexpression on Nudt7 in vivo supports the conclusion that the nutritionally-driven modulation of Nudt7 activity could contribute to the regulation of the peroxisomal CoA pool and peroxisomal lipid metabolism.
2019-03-08 | GSE125237 | GEO
Project description:Phosphohistidine signaling in mammalian biological systems has not been well characterized. In this study, we investigated the impact of phosphohistidine phosphatase 1 (PHPT1) expression on the hepatic proteome profile in vivo. PHPT1 overexpression was carried out using adenoviral-based transgene delivery for liver-specific overexpression of PHPT1 while a heterozygous knockout was used as a model of PHPT1 deficiency. These two models were characterized using mass spectrometry-based proteomics and label-free relative quantitation. In conjunction with bioinformatic analysis, PHPT1-induced changes in several key proteins and pathways were identified in the liver. Implementation of these models in future studies will lead to far greater insight into the role of phosphohistidine signaling and PHPT1 regulation in mammalian cells.
2020-07-29 | PXD008323 | Pride
Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to evaluate the effects of liver-specific E4BP4 overexpression under mouse albumin promoter on the muscle glucose and lipid metabolism. Methods: We generated transgenic mice (TG) with liver-specific E4BP4 overexpression. Gasrocnemius muscles were isolated at Zeitgeber Time (ZT) 0 or 12 from transgenic mice and WT littermates, and total RNA was extracted. Muscle RNA profiles were generated by deep sequencing for four groups with three mouse samples each. Results: There were no significant differences between WT and transgenic mice at both ZT0 and 12. Conclusions: Muscle metabolism was not altered at the transcription level by liver specific overexpression of E4BP4.
2021-05-01 | GSE150987 | GEO
Project description:The translocation of macromolecules across the mammalian intestinal epithelial barrier is enhanced in early life before ceasing at what has been termed gut closure. However, the translocated macromolecules, the mechanism of translocation, and the functional consequences for the neonatal liver, which is still a hematopoietic organ at this age in mice, have not been defined. Microbiota profiling identified a transiently increased abundance of small intestinal lipopolysaccharide (LPS)-producing g-Proteobacteria early after birth. Orally administered LPS was translocated across the mucosal barrier during this early postnatal window, resulting in increased hepatic cytokine expression. LPS translocation was independent of disabled homolog 2 (Dab2)-mediated endocytosis by fetal-like enterocytes, but was mediated by the fatty acid translocase CD36, which showed transient overexpression early after birth. Postnatal LPS exposure altered hepatic haematopoiesis, innate immune reactivity and the bacterial clearance capacity of the neonatal liver. Taken together, our results identify and characterise a postnatal time window of hepatic tissue stimulation by gut-derived LPS as a novel immune priming event in early life.
2024-12-22 | GSE282969 | GEO
Project description:A genetic variant in PNPLA3 (PNPLA3(I148M)), a triacylglycerol (TAG) hydrolase, is a major risk factor for nonalcoholic fatty liver disease (NAFLD); however, the mechanism underlying this association is not known. To develop an animal model of PNPLA3-induced fatty liver disease, we generated transgenic mice that overexpress similar amounts of wild-type PNPLA3 (PNPLA3(WT)) or mutant PNPLA3 (PNPLA3(I148M)) either in liver or adipose tissue. Overexpression of the transgenes in adipose tissue did not affect liver fat content. Expression of PNPLA3(I148M), but not PNPLA3(WT), in liver recapitulated the fatty liver phenotype as well as other metabolic features associated with this allele in humans. Metabolic studies provided evidence for 3 distinct alterations in hepatic TAG metabolism in PNPLA3(I148M) transgenic mice: increased formation of fatty acids and TAG, impaired hydrolysis of TAG, and relative depletion of TAG long-chain polyunsaturated fatty acids. These findings suggest that PNPLA3 plays a role in remodeling TAG in lipid droplets, as they accumulate in response to food intake, and that the increase in hepatic TAG levels associated with the I148M substitution results from multiple changes in hepatic TAG metabolism. The development of an animal model that recapitulates the metabolic phenotype of the allele in humans provides a new platform in which to elucidate the role of PNLPA3(I148M) in NAFLD.
| S-EPMC3484461 | biostudies-literature