Neutralization of Oxidized Phospholipids Restrains Nonalcoholic Steatohepatitis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE138419 | GEO | 2019/11/04
REPOSITORIES: GEO
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Project description:Farnesoid X receptor (FXR) agonism is emerging as an important potential therapeutic mechanism of action for multiple chronic liver diseases. The bile acid–derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of a novel, non–bile acid FXR agonist tropifexor (LJN452) in two distinct preclinical models of NASH. The efficacy of tropifexor at <1 mg/kg doses was superior to that of OCA at 25 mg/kg in the liver in both NASH models. In a chemical and dietary model of NASH (STAM model), tropifexor reversed established fibrosis and reduced nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin-resistant, obese NASH model (AMLN), tropifexor markedly reduced steatohepatitis, fibrosis, and profibrogenic gene expression. Transcriptome analysis of livers from AMLN mice revealed 461 differentially expressed genes following tropifexor treatment, which included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on the preclinical validation in animal models, tropifexor is a promising investigational therapy that is currently under phase 2 development for NASH.
2019-08-20 | GSE129389 | GEO
Project description:Hyperlipidemia is a well-established risk factor for cardiovascular diseases. Trillions of people worldwide display mildly elevated levels of plasma lipids and cholesterol due to diet and life-style. The relationship between severe hyperlipidemia and thrombosis has been extensively investigated, but the effects of the preliminary stages of hyperlipidemia on platelet function are unclear. Therefore, we investigated how moderate elevation of different plasma lipid profiles influence platelet activation and thrombus formation, as compared to higher plasma lipid concentrations. Hyperlipidemic Apoe-/- and Ldlr-/- and wild-type mice were fed a normal chow diet, resulting in mildly increased plasma cholesterol. Blood from both knockout mice was used in comparison to wild-type mice, for multiparameter ex vivo measurements of thrombus formation under flow. Whole blood (fibrin-)thrombus formation on collagen in the absence or presence of coagulation (with(out) tissue factor), indicated enhancement of the thrombotic process in both knockout mice. These effects were not further aggravated in aged mice, as well as in Apoe-/- mice on high fat diet with very high plasma cholesterol levels. Bone marrow chimeras of wild-type or Ldlr-/- platelets into irradiated Ldlr-/- recipient mice showed similar thrombus formation patterns. This suggested that hyperlipidemia itself, not the platelet LDL receptor deficiency is responsible for the altered platelet activation status in Ldlr-/- mice. Exploration of the platelet proteome revealed high similarity between the three genotypes, although some proteins showed significantly changed expression in Apoe-/- mice. Finally, platelet lipidomic analysis showed an increased lipid profile in mildly hyperlipidemic mice, which may further contribute to the observed prothrombotic phenotype
2021-01-08 | PXD020276 | Pride
Project description:Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a significant risk factor for hepatocellular carcinoma (HCC). However, a preclinical model of progressive NAFLD/NASH is largely lacking. Here, we report that mice with hepatocyte-specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. Mice with hepatic Tid1 deficiency showed impairing mitochondrial function and causing fatty acid metabolic dysregulation; meanwhile, sequentially developed fatty liver, NASH, and cirrhosis/HCC in a diethylnitrosamine (DEN) induced oxidative environment. The pathological signatures of human NASH, including cholesterol accumulation and activation of inflammatory and apoptotic signaling pathways, are also present in these mice. Clinically, low Tid1 expression was associated with unfavorable prognosis in patients with HCC. Empirically, hepatic Tid1 deficiency directly disrupts entire mitochondria that play a key role in the NASH-dependent HCC development. Overall, we established a new mouse model that develops NASH-dependent HCC and provides a promising approach to improve the treatment.
2022-06-02 | E-MTAB-9973 | biostudies-arrayexpress
Project description:Neutralization of Oxidized Phospholipids Restrains Nonalcoholic Steatohepatitis
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Project description:Inhibitors of microsomal prostaglandin E synthase-1 (mPges-1) are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis and fails to accelerate thrombogenesis, while suppressing prostaglandin (PG) E2, but increasing biosynthesis of prostacyclin (PGI2). In hyperlipidemic mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE2 accounts for its anti-atherogenic effect. However, the impact of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. To address how differential effects on PGE2 and PGI2 might modulate salt-evoked BP responses in the absence of mPges-1, we generated mice lacking the I prostanoid (Ipr) receptor or mPges-1 on a hyperlipidemic background caused by deletion of the low density lipoprotein receptor (Ldlr). Here, mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr-/- mice, whereas, despite the direct vasodilator properties of PGI2, Ipr deletion suppressed it. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1-/- mice. Suppression of PGE2 biosynthesis was enough to explain the exaggerated BP response to salt loading by either mPges-1/Ldlr depletion or by an MPGES-1 inhibitor in mice expressing human mPGES-1. However, the lack of a hypertensive response to salt in Ipr-deficient mice was attributable to reactive activation of the atrial natriuretic peptide (ANP) pathway. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high salt diet. This is attributable to the protective effect of estrogen in Ldlr-/- mice and in Ipr-/- /Ldlr-/- mice. Thus, estrogen compensates for a deficiency in PGI2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In males, by contrast, augmented formation of ANP plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. In male mice, depletion of Lactobacilius in the gut microbiome coincided with a reduction in their fecal product, indole-3-lactic acid and plasma levels of indoxyl sulfate/ tryptophan. These metabolites act via the Aryl Hydrocarbon Receptor to restrain inflammation and oxidative stress and their depletion may augment salt induced hypertension in males. Hyperlipidemic males on a high salt diet might be at risk of a hypertensive response to mPGES-1 inhibitors.
2020-06-01 | GSE115916 | GEO
Project description:Oxidized phospholipids (OxPLs), which arise due to oxidative stress, are proinflammatory and proatherogenic, but their roles in non-alcoholic steatohepatitis (NASH) are unknown. Here, we show that OxPLs accumulate in human and mouse NASH. Using a transgenic mouse that expresses a functional single-chain variable fragment of E06, a natural antibody that neutralizes OxPLs, we demonstrate the causal role of OxPLs in NASH. Targeting OxPLs in hyperlipidemic Ldlr-/- mice improved multiple aspects of NASH, including steatosis, inflammation, fibrosis, hepatocyte death, and progression to hepatocellular carcinoma. Mechanistically, we found that OxPLs promote ROS accumulation to induce mitochondrial dysfunction in hepatocytes. Neutralizing OxPLs in AMLN-diet-fed Ldlr-/- mice reduced oxidative stress, improved hepatic and adipose-tissue mitochondrial function, and fatty-acid oxidation. These results suggest targeting OxPLs may be an effective therapeutic strategy for NASH.
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Project description:As the central hub metabolic organ bodily, the liver is paramount to keep whole-body energy homeostasis. Further, mitochondria are the central metabolic hub within cells to connect the main catabolized, energy production, and hormonal signaling pathways. It is evident that mitochondrial dysfunction may play a critical role in the development of NASH. Accordingly, understanding the underlying mechanisms of mitochondrial dysfunction is of importance to develop therapies for NASH. Here, we report that mice with hepatocyte-specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. The hepatocellular nodules were developed in 3-month DEN-treated Tid1-/- mice. At the age of 6 months, the DEN-treated Tid1-/- mice showed a higher number of tumors and greater tumor size than the DEN-treated Tid1+/- mice, followed by the DEN-treated WT mice. To gain insights into the mRNA changes during NASH-HCC progress, we performed an RNA-seq analysis with livers collected from 6-month DEN-treated mice.
2022-07-02 | E-MTAB-9974 | biostudies-arrayexpress
Project description:This project is aimed at characterizing the interactions of SARS-CoV-2 Spike protein and its variants with multiple full-length antibodies and monitoring the accompanying conformational dynamics. Different categories of antibodies are tested that recognize different domains of the Spike protein. The project aims at identifying the effects of weak, moderate and strong neutralizing antibodies on Spike protein and decipher their mechanisms of action. In addition to the direct binding effects, distal allosteric effects are also determined. A range of biophysical experiments, biochemical assays, and molecular dynamics simulations are used as orthogonal approaches. The rationale is to identify regions on the SARS-CoV-2 Spike protein that acts as indicators for antibody binding and use these hotspots to develop better neutralizing antibodies against SARS-CoV-2 and any future viral pandemics.
2023-10-09 | PXD043818 | Pride
Project description:Title: White adipose tissue inflammation and gut permeability develop prior to NASH development, associated with increased oxidative stress, intrahepatic diacylglycerol and proinflammatory chemokines in the liver of diet-induced obese and hyperinsulinemic Ldlr-/-.Leiden mice Abstract: NAFLD progression from simple steatosis to NASH and fibrosis is driven by an intricate interplay between molecular and cellular mechanisms. These drivers are not limited to the liver itself but also white adipose tissue and gut may contribute. Current knowledge on these drivers is mostly based on studies that investigate these at a single time point (typically end-stage disease). However, such studies provide no insight into the temporal dynamics and chronology, which therefore remain poorly understood. Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) to induce obesity-associated NAFLD and compared to lean controls fed chow. Groups of mice were sacrificed after 8, 16, 28 and 38 weeks to study liver, white adipose tissue, gut and circulating factors to investigate the sequence of pathogenic events in these critical metabolically active organs as well as organ-crosstalk during NAFLD development. Ldlr-/-.Leiden mice on a HFD develop obesity, dyslipidemia and insulin resistance, essentially as observed in obese NASH patients, in this translational context WAT and gut dysfunction precede the development of NASH and liver fibrosis.
2023-03-20 | GSE209762 | GEO
Project description:Objective: To define the role of epigenetics, particularly DNA methylation in adaptive vascular growth in hyperlipidemic and type 2 diabetic mouse models of hind limb ischemia Methods: Unilateral hindlimb ischemia was induced by ligating femoral artery proximal to the bifurcation of superficial and deep femoral artery. DNA was isolated from ischemic muscles collected at day 7 after ischemia induction using DNeasy Tissue kit (Qiagen). 5 µg of genomic DNA was sheared into small fragments with a mean size of 150 bp by using a Covaris⢠S2 sonicator System. Quality of the fragmentation was analyzed with Bioanalyzer. Fragmented DNA samples were used for preparation of DNA fragment libraries and sequenced on the SOLiD4 sequencing instrument on one flow cell for 50 bp reads. The sequencing reads were mapped to mus musculus genome build mm9. Data was analyzed by using Bioscope. The samples were normalized with the MEDIPS package in R/B Bioconductor. The analysis of CpG methylation was done primarily in the proximal promoter regions encompassing a region of â1kb upstream of the transcription start site (TSS) and +500 bp downstream of the TSS. Comparisons were performed between hyperlipidemic versus controls and diabetic versus controls to detect differentially methylated regions. R package Limma was used for performing the statistical testing between the groups. Results: When visualizing the whole normalized data the samples did not cluster according to the sample groups. Especially two samples from hyperlipidemic and diabetic ischemic muscles differed clearly from the rest of the samples. To detect the differentially methylated genes, stringent thresholds for p-values and fold change values were chosen to list a reasonable number of genes. Upon filtering, significant differences in the methylation patterns of the sample groups were observed. More importantly, when clustering only the filtered genes, the samples clustered clearly according to the sample groups giving evidence of condition-dependent behavior. Using a threshold of methylation fold change of >1.2 and p value <0.05, we identified 397 and 446 genes to be hypomethylated in hyperlipidemic and diabetic ischemic muscles respectively compared to controls. There were 46 genes commonly shared, but still having a unique pattern of hypomethylation in 371 and 394 genes in hyperlipidemic and diabetic ischemic muscles respectively compared to controls. Similarly, there were 371 and 394 genes hypermethylated in hyperlipidemic and diabetic ischemic respectively compared to controls. Interestingly, we found 264 genes to be commonly hypermethylated, whereas 107 and 130 genes were uniquely hypermethylated in hyperlipidemic and diabetic ischemic muscles respectively. Thus, proximal promoter methylation suggested a shared, yet distinct pattern of DNA methylation in ischemic muscles of hyperlipidemic and type 2 diabetic mice compared to controls. Out of 397 genes that were hypomethylated in hyperlipidemic ischemic muscle, 68 genes were shown to be upregulated in âproinflammatory M1 macrophagesâ as shown by recent studies. Similarly, out of the 371 hypermethylated genes 93 genes were shown to be upregulated in âanti-inflammatory and proangiogenic M2 macrophagesâ as described recently. Out of 446 hypomethylated genes in diabetic ischemic muscle, 65 genes were shown to be upregulated in âproinflammatory M1 macrophagesâ as shown recently. Similarly, out of 394 hypermethylated genes 105 genes were specifically upregulated in âanti-inflammatory and proangiogenic M2 macrophagesâ as shown recently. qRT-PCR analysis suggested an inverse relationship between proximal promoter hypermethylation and mRNA expression in a subset of M2 macrophage specific genes in hyperlipidemic and type 2 diabetic ischemic muscles compared to control ischemic muscles. Conclusions: Our results suggest a role of epigenetics particularly proximal promoter DNA methylation in macrophage polarization and their contribution to angiogenesis and tissue repair in hyperlipidemic and type 2 diabetic mouse models of hind limb ischemia. Epigenetics at the level of DNA methylation may act as a deciding factor in promoting a pro or anti-inflammatory phenotype of macrophages critical in cardiovascular diseases. Ischemic skeletal muscle DNA methylation sequencing of triplicate samples from C57BL/6J (WT) mice, hyperlipidemic mice (LDLR-/-ApoB100/100 , C57BL/6J background) and type 2 diabetic mice (IGF-II/LDLR-/-ApoB100/100 , C57BL/6J background) using SoliD4 sequencing platform
2015-12-21 | E-GEOD-42092 | biostudies-arrayexpress