Hepatic delivery of miroRNA-30c analog reduces plasma cholestrol in mice and monkeys and atherosclerosis in mice without causing liver injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE295365 | GEO | 2026/07/08
REPOSITORIES: GEO
Similar Datasets
Project description:Ganoderma lucidum is a traditional Chinese medicine with a variety of active compounds and possessing adequate lipid-lowering and anti-atherosclerotic effects. However, its main active components and potential mechanisms still remain unclear. Here, we evaluated the anti-hyperlipidemic effect of the adenosine extract from Ganoderma lucidum (AEGL) in high-fat-diet (HFD)-induced hyperlipidemic ApoE-/- mice and explored the underlying biological mechanism by multi-omics analysis. Treatment with AEGL for 8 weeks significantly decreased the serum levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-c) by 45.59%, 41.22%, and 39.02%, respectively, as well as reduced liver TC and TG by 44.15% and 76.23%, compared with the HFD-only group. We also observed significant amelioration of hepatic steatosis without liver and kidney damage after AEGL treatment. Regulating the expression and acetylation/crotonylation of proteins involved in the PPAR signaling pathway may be one of the potential mechanisms involved in the observed lipid-lowering effects of AEGL.
2023-03-11 | PXD036478 | Pride
Project description:Despite advances in lipid-lowering treatment, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality, underscoring the need for treatments that address residual risk. Targeting both the synthesis and clearance of triglyceride (TG)-rich lipoproteins is a promising approach. Liver X receptor (LXR) inhibition suppresses de novo lipogenesis and enhances clearance of TG-rich lipoproteins, but its clinical utility remains unexplored. Here, we demonstrate the pivotal role of LXR in lipid metabolism and metabolic diseases. In dysmetabolic animal models, LXR inverse agonists reduced plasma TG and cholesterol and improved insulin sensitivity by suppressing LXR activity and intestinal lipid absorption. Given concerns that systemic LXR inhibition may impair reverse cholesterol transport, we developed TLC-2716—an orally-administered, gut- and liver-restricted LXR inverse agonist. In human liver organoids modeling steatohepatitis, TLC-2716 reduced lipid accumulation and downregulated inflammation and fibrotic gene expression. In a Phase 1 clinical trial (NCT05483998), 14-day treatment with TLC-2716 was safe and resulted in placebo-adjusted reductions up to 38.5% in plasma TG and 60.8% in postprandial remnant cholesterol. These results highlight the safety and therapeutic potential of TLC-2716 as a novel treatment for managing dyslipidemia and reducing residual ASCVD risk.
2025-11-14 | GSE299888 | GEO
Project description:Although hypertriglyceridemia and postprandial lipemia associate with greater atherosclerosis, partially metabolized triglyceride-rich lipoproteins termed remnants rather than nascent lipoproteins have been implicated as the culprits. Whether chylomicrons are inherently atherogenic remains unclear. To test whether increased levels of nascent triglyceride-rich lipoproteins (TRLs) in the absence of markedly reduced LDL-C levels contribute to atherosclerosis, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl-/-) and LDLR knockdown (Ldlrkd) developed hypertriglyceridemia and elevated cholesterol levels; all the increased cholesterol was in chylomicrons or large VLDL. After 12 weeks on a WD, atherosclerotic lesions both in the brachiocephalic artery and the aortic root were more severe in iLpl-/-/Ldlrkd mice than control Ldlrkd mice. Aorta from hypertriglyceridemic mice had changes in the transcriptomes of endothelial cells, macrophages, and smooth muscle cells indicating vascular inflammation. Our data show that intact TRLs contribute to atherosclerosis, explain the association of postprandial lipemia and vascular disease, and prove that non-remnant TRLs are not benign.
2025-09-15 | GSE307653 | GEO
Project description:The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. Owing to their central role in controlling hepatic lipid and lipoprotein metabolism their activity is tightly coordinated, and accordingly dysregulation of the SREBP pathway is associated with development of dyslipidemia and non-alcoholic fatty liver disease. Using a suite of genome-wide genetic screens we have recently identified SPRING (C12ORF49) as a novel post-transcriptional regulator of SREBP activation in vitro. Our previous work demonstrated that constitutive ablation of Spring in mice is embryonically lethal. Here we show that inducible global deletion of Spring is also untolerated, and therefore to interrogate the physiological role of SPRING in controlling hepatic lipid metabolism we developed liver-specific Spring knockout mice (LKO). Liver transcriptomics and proteomics analysis revealed severely attenuated SREBP signaling in livers and in hepatocytes of LKO mice, which was associated with marked effects on both plasma and hepatic lipid levels. In plasma, total cholesterol levels were dramatically reduced in both male and female LKO mice, apparent in both the LDL and HDL fractions, while triglyceride levels remained largely unaffected. In liver, loss of Spring diminished cholesterol and triglyceride biosynthesis resulting in decreased hepatic cholesterol and triglyceride content. This coincided with reduced secretion of VLDL into the circulation. Consistent with diminished hepatic de novo lipogenesis, LKO mice were protected from developing hepatosteatosis when challenged with a fructose-rich diet. Supporting the significance of our findings in mice, we identified common and rare SPRING genetic variants that are strongly associated with circulating HDL-c and ApoA1 levels in humans. Collectively, our study positions SPRING as a core component of hepatic SREBP signaling, and consequently of systemic lipid metabolism in mice and humans.
2023-08-01 | GSE236045 | GEO
Project description:ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis. Mixed dyslipidemia, characterized by elevated triglyceride and apoC-III levels and low HDL cholesterol level, with or without elevated LDL cholesterol, increases cardiovascular disease risk and is commonly treated with combined statin and fibrate therapy. We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Association between genotyed SNPs and APOC3 response to therapy was conducted
2012-01-11 | GSE34945 | GEO
Project description:ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis. Mixed dyslipidemia, characterized by elevated triglyceride and apoC-III levels and low HDL cholesterol level, with or without elevated LDL cholesterol, increases cardiovascular disease risk and is commonly treated with combined statin and fibrate therapy. We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Association between genotyed SNPs and APOC3 response to therapy was conducted We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Genomic DNA extracted from peripheral blood was genotyped using a custom GoldenGate bead array encompassing 384 SNPs (Illumina). Multivariate linear regression and 2-way ANOVA for percent change in apoC-III level were performed between the groups receiving FA alone compared with FA+statin compared with statin alone.
2012-01-11 | E-GEOD-34945 | biostudies-arrayexpress
Project description:In previous in vitro study, we reported potential mechanism of cholesterol-lowering effect of Lactobacillus brevis119-2 (119-2) isolated from turnip “Tsuda kabu” is due to incorporation of cholesterol into 119-2 cell. In this study, we analyzed serum cholesterol and hepatic gene expression of Sprague-Dawley (SD) rat fed diet containing cholesterol with or without 119-2 for 2 weeks, to evaluate the cholesterol-lowering effect of 119-2 in vivo. Serum cholesterol of SD rat fed diet with 119-2 significantly decreased compared to SD rat fed diet without 119-2, and both viable and dead 119-2 indicated the effect. The result of hepatic gene analysis using DNA microarray suggested that potential mechanism of the cholesterol-lowering effect of 119-2 in vivo is inhibiting the activity of 3-hydroxy-3-methylglutaryl-CoA reductase by Insig (insulin induced gene) that is endoplasmic reticulum membrane protein, and catabolizing cholesterol to bile acid by Cyp7a1 (cytochrome P450 a1) that is the rate-limiting enzyme in the synthesis of bile acid from cholesterol. In addition, we concluded feeding 119-2 decreased serum low density lipoprotein (LDL) cholesterol by overexpression of Ldlr (LDL receptor gene). On the other hand, feeding Lactobacillus acidophilus ATCC43121 (ATCC) increased high density lipoprotein (HDL) cholesterol by over expression of Abca1 (ATP binding cassette sub-family A member 1 gene) and Angplt3 (Angiopoietin-like 3). These results suggested that 119-2 decrease the risk of atherosclerosis by serum cholesterol-lowering effect and improving effect of fatty liver and the LH (LDL cholesterol / HDL cholesterol) ratio.
2013-04-24 | GSE41734 | GEO
Project description:McAuley2012 - Whole-body Cholesterol Metabolism
Lipid metabolism has a key role to play in human longevity and healthy aging. A whole-body mathematical model of cholesterol metabolism that explores the changes in both the rate of intestinal cholesterol absorption and the hepatic rate of clearance of LDL-C from the plasma, has been presented here. The model showed that of these two mechanisms, changes to the rate of LDL-C removal from the plasma with age had the most significant effect on cholesterol metabolism.
The original SBML model file was generated using MathSBML 2.5.1.
This model is described in the article:
A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation.
Mc Auley MM, Wilkinson DJ, Jones JJ, Kirkwood TT.
BMC Syst Biol. 2012 Oct 10;6(1):130.
Abstract:
BACKGROUND: Global demographic changes have stimulated marked interest in the process of ageing. There has been, and will continue to be, an unrelenting rise in the number of the oldest old ( >85 years of age). Together with an ageing population there comes an increase in the prevalence of age related disease. Of the diseases of ageing, cardiovascular disease (CVD) has by far the highest prevalence. It is regarded that a finely tuned lipid profile may help to prevent CVD as there is a long established relationship between alterations to lipid metabolism and CVD risk. In fact elevated plasma cholesterol, particularly Low Density Lipoprotein Cholesterol (LDL-C) has consistently stood out as a risk factor for having a cardiovascular event. Moreover it is widely acknowledged that LDL-C may rise with age in both sexes in a wide variety of groups. The aim of this work was to use a whole-body mathematical model to investigate why LDL-C rises with age, and to test the hypothesis that mechanistic changes to cholesterol absorption and LDL-C removal from the plasma are responsible for the rise. The whole-body mechanistic nature of the model differs from previous models of cholesterol metabolism which have either focused on intracellular cholesterol homeostasis or have concentrated on an isolated area of lipoprotein dynamics. The model integrates both current and previously published data relating to molecular biology, physiology, ageing and nutrition in an integrated fashion.
RESULTS: The model was used to test the hypothesis that alterations to the rate of cholesterol absorption and changes to the rate of removal of LDL-C from the plasma are integral to understanding why LDL-C rises with age. The model demonstrates that increasing the rate of intestinal cholesterol absorption from 50% to 80% by age 65 years can result in an increase of LDL-C by as much as 34mg/dL in a hypothetical male subject. The model also shows that decreasing the rate of hepatic clearance of LDL-C gradually to 50% by age 65 years can result in an increase of LDL-C by as much as 116mg/dL.
CONCLUSIONS: Our model clearly demonstrates that of the two putative mechanisms that have been implicated in the dysregulation of cholesterol metabolism with age, alterations to the removal rate of plasma LDL-C has the most significant impact on cholesterol metabolism and small changes to the number of hepatic LDL receptors can result in a significant rise in LDL-C. This first whole-body systems based model of cholesterol balance could potentially be used as a tool to further improve our understanding of whole-body cholesterol metabolism and its dysregulation with age. Furthermore, given further fine tuning the model may help to investigate potential dietary and lifestyle regimes that have the potential to mitigate the effects aging has on cholesterol metabolism.
This model is hosted on BioModels Database
and identified by: MODEL1206010000
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
2024-09-02 | BIOMD0000000434 | BioModels
Project description:In previous in vitro study, we reported potential mechanism of cholesterol-lowering effect of Lactobacillus brevis119-2 (119-2) isolated from turnip M-bM-^@M-^\Tsuda kabuM-bM-^@M-^] is due to incorporation of cholesterol into 119-2 cell. In this study, we analyzed serum cholesterol and hepatic gene expression of Sprague-Dawley (SD) rat fed diet containing cholesterol with or without 119-2 for 2 weeks, to evaluate the cholesterol-lowering effect of 119-2 in vivo. Serum cholesterol of SD rat fed diet with 119-2 significantly decreased compared to SD rat fed diet without 119-2, and both viable and dead 119-2 indicated the effect. The result of hepatic gene analysis using DNA microarray suggested that potential mechanism of the cholesterol-lowering effect of 119-2 in vivo is inhibiting the activity of 3-hydroxy-3-methylglutaryl-CoA reductase by Insig (insulin induced gene) that is endoplasmic reticulum membrane protein, and catabolizing cholesterol to bile acid by Cyp7a1 (cytochrome P450 a1) that is the rate-limiting enzyme in the synthesis of bile acid from cholesterol. In addition, we concluded feeding 119-2 decreased serum low density lipoprotein (LDL) cholesterol by overexpression of Ldlr (LDL receptor gene). On the other hand, feeding Lactobacillus acidophilus ATCC43121 (ATCC) increased high density lipoprotein (HDL) cholesterol by over expression of Abca1 (ATP binding cassette sub-family A member 1 gene) and Angplt3 (Angiopoietin-like 3). These results suggested that 119-2 decrease the risk of atherosclerosis by serum cholesterol-lowering effect and improving effect of fatty liver and the LH (LDL cholesterol / HDL cholesterol) ratio. Lactobacillus brevis119-2 (119-2) was isolated from turnip M-bM-^@M-^\Tsuda kabuM-bM-^@M-^] harvested in Matsue city, Shimane Prefecture, Japan, and was stored at Shimane Institute for industrial Technology. Male Jcl: SD rat (4 weeks of age) were obtained from CLEA Japan, Inc. (Tokyo, Japan). Rats were maintained under controlled environmental conditions (temperature 23 M-BM-1 3 M-KM-^ZC, relative humidity 55% M-BM-1 25%, 12/12hr light - dark cycle) and given food and water ad libitum. All rats were acclimated 1 week prior to the experiment. Two groups of 11 rats each were treated respective group diets for 2weeks. Control group was fed high-cholesterol diet containing 10 g cholesterol/kg, 5 g cholic acid/kg, 985 g mouse & rat & rabbit diet (CRF-1) /kg obtained from Oriental yeast Co., Ltd (Tokyo, Japan). The other group was fed same highcholesterol diet with 10 g freeze-dried viable 119-2 /kg. This study and all procedures were approved by regulations and code of ethics in experimental animals Chitose Japan Food Research Laboratories.
2013-04-24 | E-GEOD-41734 | biostudies-arrayexpress
Project description:The effect of perfluoroalkyl sulfonates on lipoprotein metabolism was investigated in APOE*3-Leiden.CETP mice with a humanized lipoprotein profile. Perfluorohexane sulfonate and perfluorooctane sulfonate markedly reduced both plasma TG and TC by decreasing nonHDL-C and HDL-C accompanied by a reduction in apoAI. Mechanistic studies showed that these effects were mainly caused by impaired lipoprotein production. Male E3L.CETP mice on a C57Bl/6 background were fed a Western-type diet, containing 0.25% (w/w) cholesterol, 1% (w/w) corn oil and 14% (w/w) bovine fat (Western-type diet) (Hope Farms, Woerden, The Netherlands) for 4 to 6 weeks in three independent experiments. Upon randomization according to total plasma cholesterol (TC) and TG levels, mice received the Western-type diet without or with PFBS (30 mg/kg/day), PFHxS (6 mg/kg/day) or PFOS (3 mg/kg/day) during 4-6 weeks. The effects of these PFAS on plasma lipids and lipoproteins were determined. In addition, PFAS levels were determined in plasma and livers were isolated for hepatic lipid analysis and hepatic gene expression analysis using an Affymetrix technology platform and Affymetrix GeneChip® mouse genome 430 2.0 arrays.
2011-01-01 | E-GEOD-22940 | biostudies-arrayexpress