Similar Datasets
Project description:Effect of NEK7 hepatocyte knock-out on gene expression in the mice livers.
| PRJNA1135198 | ENA
Project description:The NLRP3 inflammasome, a pivotal component of innate immunity, has been implicated in various inflammatory disorders. The ubiquitin-editing enzyme A20 is well known to regulate inflammation and maintain homeostasis. However, the precise molecular mechanisms by which A20 modulates the NLRP3 inflammasome remain poorly understood. Here our study revealed that macrophages deficient in A20 exhibit increased protein abundance and elevated mRNA level of NIMA-related kinase 7 (NEK7). Importantly, A20 directly binds with NEK7, mediating its K48-linked ubiquitination, thereby targeting NEK7 for proteasomal degradation. Our results demonstrate that A20 enhance the ubiquitination of NEK7 at K189 and K293 ubiquitinated sites, with K189 playing a crucial role in the binding of NEK7 to A20, albeit not significantly influencing the interaction between NEK7 and NLRP3. Furthermore, A20 disrupts the association of NEK7 with the NLRP3 complex, potentially through the OTU domain and/or synergistic effect of ZnF4 and ZnF7 motifs. Significantly, NEK7 deletion markedly attenuates the activation of the NLRP3 inflammasome in A20-deficient conditions, both in vitro and in vivo. This study uncovers a new mechanism by which A20 inhibits the NLRP3 inflammasome.
2024-07-03 | GSE253265 | GEO
Project description:Human hepatocyte metaplasia in injured humanized mouse livers
| PRJNA253143 | ENA
Project description:In this study we sought to determine if the knockout of hepatocyte PPARgamma expression alter transcriptomics of the livers of mice with diet-induced NASH, and if there was a hepatocyte-specific PPARgamma dependent regulation of gene expression in TZD treated mice. Specifically, adult PPARg floxed male mice were fed a high fat, cholesterol and fructose (HFCF) diet for 24 weeks. After this period of time, half of the mice were injected with AAV8-TBG-Cre to knockout PPARgamma in hepatocytes (KO mice). The other half of the mice were injected with AAV8-TBG-Null, and served as controls (C mice). A subset of PPARg floxed mice were fed a low fat, cholesterol and fructose (LFCF) diet, and they were injected with AAV8-TBG-Null to generate LFCF-controls. Two weeks after AAV8 injections, half of the HFCF-fed mice in each group (C and KO) were switched to a HFCF diet containing rosiglitazone maleate (TZD, 50mg/kg of diet) for eight additional weeks. Mice were kept in their respective diets for 8 additional weeks too. At the end of the study, the livers were collected to assess hepatic gene expression with RNA-seq (performed by Novogen, Inc.)
2021-01-15 | GSE162276 | GEO
Project description:To explore the circadian regulations of Bmal1, we examined the transcriptome changes in mouse livers upon Bmal1 knock out at two circadian time points, CT0 and CT12.
2016-09-21 | GSE73271 | GEO
Project description:Purpose: Nuclear Factor I B (NFIB) has been reported to promote tumor growth, metastasis, and liver regeneration, but its mechanism in liver cancer is not fully elucidated. The present study aims to reveal the role of NFIB in hepatocellular carcinogenesis Methods:In our study, we constructed hepatocyte-specific NFIB gene knockout mice with CRISPR/Cas9 technology (Nfib-/-; Alb-cre), and induced liver cancer mouse model by intraperitoneal injection of DEN/CCl4 Results: First, we found that Nfib-/-; Alb-cre mice developed more tumor nodules and had heavier livers than wild-type mice. H&E staining indicated that the liver histological severity of Nfib-/- group was more serious than that of WT group. Then we found that the differentially expressed genes in the tumor tissue between Nfib-/- mice and wild type mice were enriched in urea cycle. Furthermore, ASS1 and CPS1, the core enzymes of the urea cycle, were significantly upregulated in Nfib-/- tumors. Subsequently, we validated that the expression of ASS1 and CPS1 increased after knockdown of NFIB by lentivirus in normal hepatocytes and also promoted cell proliferation in vitro. In addition, ChIP assay confirmed that NFIB can bind with promoter region of both ASS1 and CPS1 gene Conclusions:Our study reveals for the first time that hepatocyte-specific knock-out of Nfib aggravates hepatocellular tumor development by enhancing the urea cycle.
2022-06-23 | GSE200708 | GEO
Project description:Aberrant NLRP3 inflammasome activation is linked to many inflammatory diseases, driving the search for therapeutics inhibiting this pathway. NEK7 is proposed to mediate NLRP3 inflammasome assembly and activation by bridging adjacent NLRP3 subunits. Hence, reduction of NEK7 protein may block NLRP3 activation. We identified NK7-902, a potent and selective CRBN glue degrader of NEK7. NK7-902 degraded NEK7 in human immune cells and whole blood. However, full NEK7 degradation completely blocked NLRP3-dependent IL-1β release in vitro only in certain donors and experimental conditions. Unlike most CRBN glue degraders, NK7-902 effectively degraded NEK7 in murine cells and inhibited IL-1β release in mouse in vivo. By contrast, oral administration of NK7-902 in cynomolgus monkey caused long-lasting NEK7 degradation but only transiently blocked IL-1β in blood. These findings suggest NEK7 contributes to but is not absolutely required for NLRP3 activation in monkeys and humans.
2025-06-18 | PXD057229 | Pride
Project description:The goal of this experiment was to test whether human hepatocytes could give rise to biliary-like progenitor cells in an in vivo context. Here Fah-/- Il2ry-/- Rag2-/-NOD mouse livers were humanized with human hepatocytes. Only hepatocytes engraft in the Fah-/- mouse at detectable levels in this model. Then animals were given chronic liver injury with 0.1% ddc. After injury we measured human-specific transcripts to determine whether the phenotype of the human cells had changed. Specifically, we evaluated the relative levels of human biliary duct markers such as Spp1, Sox9, Krt7, etc. and hepatocyte markers such as Alb, Ttr, Fah, etc.
2014-09-01 | GSE58679 | GEO
Project description:The goal of this experiment was to test whether human hepatocytes could give rise to biliary-like progenitor cells in an in vivo context. Here Fah-/- Il2ry-/- Rag2-/-NOD mouse livers were humanized with human hepatocytes. Only hepatocytes engraft in the Fah-/- mouse at detectable levels in this model. Then animals were given chronic liver injury with 0.1% ddc. After injury we measured human-specific transcripts to determine whether the phenotype of the human cells had changed. Specifically, we evaluated the relative levels of human biliary duct markers such as Spp1, Sox9, Krt7, etc. and hepatocyte markers such as Alb, Ttr, Fah, etc. 3 DDC treated chimeras and 6 untreated chimeras are included. Additional controls include a normal human liver biopsy, FACS sorted primary intrahepatic human bile duct cells, mouse hepatocytes, and mouse intrahepatic biliary cells in ddc treated animal.
2014-09-01 | E-GEOD-58679 | biostudies-arrayexpress
Project description:The role of PPARα in gene regulation in mouse liver is well characterized. However, less is known about the effect of PPARα activation in human liver. The aim of the present study was to better characterize the impact of PPARα activation on gene regulation in human liver by combining transcriptomics with the use of hepatocyte humanized livers. To that end, chimeric mice containing hepatocyte humanized livers were given an oral dose of 300 mg/kg fenofibrate daily for 4 days. Livers were collected and analysed by hematoxilin and eosin staining, qPCR, and transcriptomics. Transcriptomics data were compared with existing datasets on fenofibrate treatment in normal mice. The human hepatocytes exhibited excessive lipid accumulation. Fenofibrate increased the size of the mouse but not human hepatocytes, and tended to reduce steatosis in the human hepatocytes. Quantitative PCR indicated that induction of PPARα targets by fenofibrate was less pronounced in the human hepatocytes than in the residual mouse hepatocytes. Transcriptomics analysis indicated that, after filtering, a total of 282 genes was significantly different between fenofibrate- and control-treated mice (P<0.01). 123 genes were significantly lower and 159 genes significantly higher in the fenofibrate-treated mice, including many established PPARα targets such as FABP1, HADHB, HADHA, VNN1, PLIN2, ACADVL and HMGCS2. According to gene set enrichment analysis, fenofibrate upregulated interferon/cytokine signaling-related pathways in hepatocyte humanized liver, but downregulated these pathways in normal mouse liver. Also, fenofibrate downregulated pathways related to DNA synthesis in hepatocyte humanized liver but not in normal mouse liver. The results support the major role of PPARα in regulating hepatic lipid metabolism, and underscore the more modest effect of PPARα activation on gene regulation in human liver compared to mouse liver. The data suggest that PPARα may have a suppressive effect on DNA synthesis in human liver, and a stimulatory effect on interferon/cytokine signalling.
2018-05-28 | GSE107041 | GEO