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Project description:Purpose: Although clinical evidence suggests that high salt intake is associated with NAFLD, the underlying mechanism remains elusive. We sought to investigate whether salt-induced inflammation in liver is dependent on SIRT3 reduction. Methods: 6-week-old male SIRT3 knockout or their wild-type littermates were fed with high salt diet (HSD, containing 8% NaCl) or normal salt diet (NSD, containing 0.4% NaCl) for 4 months. And then their liver tissues were removed and total RNA was extracted to perform RNA sequencing. Results: 1850 differentially upregulated expressed genes were identified when comparing HSD group (HSD1, HSD2) to NSD group (NSD WT1, NSD2). Meanwhile, 1246 differentially upregulated expressed genes in response to SIRT3 knockout were determined (each group containing 3 samples). we observed that the common genes upregulated by both HSD and knockout of SIRT3 were enriched in immune system, including Tnf, Ccl2, etc. In addition, the common genes upregulated by knockout of SIRT3 in both NSD and HSD group were still enriched in the immune system. Conclusions: Through RNA-seq, we determined that HSD-induced hepatic inflammtion was highly similar to the effect of SIRT3 knockout, suggesting that reduction of SIRT3 expression is the main reason leading to salt-induced hepatic inflammation.
2023-09-01 | GSE183584 | GEO
Project description:Purpose: Our previous study has confirmed that reduction of SIRT3 expression is a main factor contributing to salt-induced hepatic inflammtion. Here we sought to investigate whether salt-induced SIRT3 reduction was related to epigenetic modification. Methods: 6-week-old male wild-type mice were fed with high salt diet (HSD, containing 8% NaCl) or normal salt diet (NSD, containing 0.4% NaCl) for 4 months. And then their liver tissues were removed and subjected to bilsulfate-seq. Results: Through bisulfate-seq, we did not observe any change in DNA methylation in the CpG island of Sirt3 gene promoter region. Conclusions: Salt-induced SIRT3 reduction is not related to DNA methylation on SIRT3 gene promoter.
2023-09-01 | GSE183583 | GEO
Project description:Purpose: Our previous study has confirmed that reduction of SIRT3 expression is a main factor contributing to salt-induced hepatic inflammtion. Here we sought to investigate whether salt-induced SIRT3 reduction was related to epigenetic modification. Methods: 6-week-old male SIRT3 knockout or their wild-type littermates were fed with high salt diet (HSD, containing 8% NaCl) or normal salt diet (NSD, containing 0.4% NaCl) for 4 months. And then their liver tissues were removed and subjected to ChIP-seq using antibodies against H3K27ac (ab4729), H3K4me1 (ab8895), H3K9ac (39917) and H3 (ab1791). Results: Through ChIP-seq, we observed the enrichment of H3K27ac was increased on the promoters of Sirt3 and some pro-inflammatory genes, including Ccl2, Tnf and Il6, after high salt loading. However, neither H3K4me1 nor H3K9ac displayed such phenomunum. In addition, those genes containing increased H3K27ac level in response to high salt were mainly enriched in metabolism and inflammatory pathways. And knockout of SIRT3 mainly affected genes related to AMP-activated protein kinase (AMPK) and insulin signaling pathways. Conclusions: Salt-induced SIRT3 reduction is related to the epigenetic regulation, especially H3K27ac.
2023-09-01 | GSE183582 | GEO
Project description:Salt induces hepatic inflammatory response through epigenetic modulation of SIRT3
| PRJNA761356 | ENA
Project description:Salt induces hepatic inflammatory response through epigenetic modulation of SIRT3 [ChIP-seq]
| PRJNA761358 | ENA
Project description:Salt induces hepatic inflammatory response through epigenetic modulation of SIRT3 [Bisulfite-seq]
| PRJNA761357 | ENA
Project description:Salt induces hepatic inflammatory response through epigenetic modulation of SIRT3 [RNA-seq]
| PRJNA761359 | ENA
Project description:The interaction between fat deposition and inflammation during obesity contributes to the development of non-alcoholic fatty liver disease (NAFLD). The present study examined the effects of palmitoleate, a monounsaturated fatty acid (16:1n7), on liver metabolic and inflammatory responses, and investigated the mechanisms by which palmitoleate increases hepatocyte fatty acid synthase (FAS) expression. Male wild-type C57BL/6J mice were supplemented with palmitoleate and subjected to the assays to analyze hepatic steatosis and liver inflammatory response. Additionally, mouse primary hepatocytes were treated with palmitoleate and used to analyze fat deposition, the inflammatory response, and sterol regulatory element-binding protein 1c (SREBP1c) activation. Compared with controls, palmitoleate supplementation increased the circulating levels of palmitoleate and improved systemic insulin sensitivity. Locally, hepatic fat deposition and SREBP1c and FAS expression were significantly increased in palmitoleate-supplemented mice. These pro-lipogenic events were accompanied by improvement of liver insulin signaling. In addition, palmitoleate supplementation reduced the numbers of macrophages/Kupffer cells in livers of the treated mice. Consistently, supplementation of palmitoleate decreased the phosphorylation of nuclear factor kappa B (NF-?B, p65) and the expression of proinflammatory cytokines. These results were recapitulated in primary mouse hepatocytes. In terms of regulating FAS expression, treatment of palmitoleate increased the transcription activity of SREBP1c and enhanced the binding of SREBP1c to FAS promoter. Palmitoleate also decreased the phosphorylation of NF-?B p65 and the expression of proinflammatory cytokines in cultured macrophages. Together, these results suggest that palmitoleate acts through dissociating liver inflammatory response from hepatic steatosis to play a unique role in NAFLD.
| S-EPMC3387145 | biostudies-literature
Project description:Diethylstilbestrol (DES) is an endocrine disruptor that was used to prevent adverse effects of pregnancy in women in late 1940s until early 1970s. Its use was banned following significant toxicity and negative effects not only in the mothers but also transgenerationally. Previous studies from our laboratory showed that DES induces thymic atrophy and immunosuppression in mice. In this study, we investigated the molecular mechanisms through which DES triggers thymic atrophy, specifically autophagy. To that end, we treated C57BL/6 mice with DES, and determined expression of two autophagy-related proteins, microtubule-associated protein-1 light chain 3 (LC3) and Beclin-1 (Becn1). We observed that DES-induced thymic atrophy was associated with increased autophagy in thymocytes and significant upregulation in the expression of both Becn1 and LC3. DES also caused downregulation in the expression of miR-30a in thymocytes, and transfection studies revealed that miR-30a targeted Becn1. Upon examination of methylation status of Becn1, we noted hypomethylation of Becn1 in thymocytes of mice exposed to DES. Together, these data demonstrate for the first time that DES induces autophagy in thymocytes potentially through epigenetic changes involving hypomethylation of Becn1 and down-regulation of miR-30a expression.
| S-EPMC6463288 | biostudies-literature
Project description:BackgroundSP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn's disease (CD), suggesting a role in inflammation.ResultsWe report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal mucosa.ConclusionsThis study identifies SP140 as a druggable epigenetic therapeutic target for CD.
| S-EPMC9392322 | biostudies-literature