Effect of miR-33 supression in hepatocytes in NAFLD and NASH
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE259277 | GEO | 2024/10/01
REPOSITORIES: GEO
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Project description:We perform RNAseq in NAFLD livers from WT and miR-33-AlbCRE conditional knock-out mice. Liver were isolated from mice after 3 months of feeding a choline deficient high fat diet to analyze the effect of miR-33 deficiency.
2024-10-01 | GSE220093 | GEO
Project description:Effect of miR-33 supression in hepatocytes in NAFLD and NASH
| PRJNA1080570 | ENA
Project description:Effect of miR-33 supression in hepatocytes in NAFLD
| PRJNA908790 | ENA
Project description:miR-33 is an intronic microRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve high-density lipoprotein (HDL) biogenesis in the liver and increase circulating HDL-C levels in both rodents and nonhuman primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole-body miR-33–knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function, and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardiometabolic diseases.
2021-02-11 | PXD023471 | Pride
Project description:miR-33 is an intronic miRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve HDL biogenesis in the liver and increase circulating HDL-C levels in both rodents and non-human primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole body miR-33 knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver, and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardio-metabolic diseases.
2021-01-31 | GSE164517 | GEO
Project description:In this study the effect of anti-miR-33 treatment on plasma and liver lipid profiles was examined in non-human primates. A significant increase in plasma HDL-C, and a significant decrease in plasma triglyceride levels were observed. African green monkeys on a Normal chow diet were treated with anti-miR-33 or control anti-miR for 4 weeks and were then switched to a High Carb/Med. Cholesterol diet and treated with anti-miR-33 or control anti-miR for 8 more weeks (n=6/group). Gene expression profiling was performed on liver biopsies obtained at -5 weeks (baseline), 4 weeks and 12 weeks.
2011-08-26 | E-GEOD-31177 | biostudies-arrayexpress
Project description:Mouse peritoneal macrophages were transfected with 80-120 nM miRIDIAN miRNA mimics (miR-mimic-33/miR-mimic-33*) or with 80-120 nM miRIDIAN miRNA inhibitors (anti-miR-33 ASO/anti-miR-33*ASO) Control samples were treated with an equal concentration of a non-targeting control mimics sequence (control mimic) or inhibitor negative control sequence (control aso), to control for non-specific effects in miRNA experiments.
2016-04-18 | GSE79055 | GEO
Project description:miRNA-33a/b provides a critical link between the regulation of cholesterol and fatty acid biosynthesis by SREBPs, and cholesterol efflux, high-density lipoprotein (HDL) biogenesis and fatty acid oxidation pathways. Notably, pharmacological inhibition of miR-33 elevates hepatic ABCA1 expression, thereby increasing circulating HDL-C and attenuating the progression of atherosclerosis, highlighting the therapeutic potential of miR-33 inhibitors for the treatment of cardiovascular disease. However, work with genetic models of miR-33 deficiency has clearly demonstrated that global loss of miR-33 promotes the development of obesity and metabolic dysfunction. We sought to determine if miR-33 is directly involved in regulating the activity of the AgRP and POMC neurons that promote signals of hunger and satiety, respectively. We have generated AgRP conditional KO mouse to analyze the effect of removing miR-33 in these neurons. After miR-33 removal, mice were fed a HFD and then the expression of different markers related to activiation or inhibition of AgRP neurons was analyzed by scRNAseq.
2024-02-06 | GSE222191 | GEO
Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.
2024-09-30 | GSE235179 | GEO
Project description:We used single cell RNA-sequencing of aortic CD45+ cells, combined with immunohistologic, morphometric and flow cytometric analyses to define the changes in plaque immune cell composition, gene expression and function following miR-33 inhibition. We report that anti-miR-33 treatment of Ldlr–/– mice with advanced atherosclerosis reduced plaque burden and altered the plaque immune cell landscape by shifting the balance of pro- and anti-atherosclerotic macrophage and T cell subsets. By quantifying the kinetic processes that determine plaque macrophage burden, we found that anti-miR-33 reduced levels of circulating monocytes and splenic myeloid progenitors, decreased macrophage proliferation and retention, and promoted macrophage attrition by apoptosis and efferocytotic clearance. scRNA-sequencing of aortic arch plaques showed that anti-miR-33 reduced the frequency of MHCIIhi “inflammatory” and Trem2hi “metabolic” macrophages, but not tissue resident macrophages. Furthermore, anti-miR-33 led to derepression of distinct miR-33 target genes in the different macrophage subsets: in resident and Trem2hi macrophages, anti-miR-33 relieved repression of miR-33 target genes involved in lipid metabolism (e.g., Abca1, Ncoa1, Ncoa2, Crot), whereas in MHCIIhi macrophages, anti-miR-33 upregulated target genes involved in chromatin remodeling and transcriptional regulation. Anti-miR-33 also reduced the accumulation of aortic CD8+ and CD4+ Th1 cells, and increased levels of FoxP3+ regulatory T cells in plaques, consistent with an immune-dampening effect on plaque inflammation.
2021-04-21 | GSE161494 | GEO