Mus musculus
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ABSTRACT:
PROVIDER: PRJNA145331 | ENA |
REPOSITORIES: ENA
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Project description:The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Albcre/+Mig-6f/f; Mig-6d/d). Mig-6d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6d/d mice compared to Mig-6f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease. Eight week old Mig-6f/f vs Mig-6d/d male mice after undergoing a 24 hour fast
2011-08-30 | E-GEOD-31752 | biostudies-arrayexpress
Project description:The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Albcre/+Mig-6f/f; Mig-6d/d). Mig-6d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6d/d mice compared to Mig-6f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease.
2011-08-31 | GSE31752 | GEO
Project description:Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate limiting enzyme of bile acid biosynthetic pathway to convert cholesterol to bile acids, which is a major output pathway for cholesterol catabolism. In this study, we aimed to assess the potential regulatory mechanisms of microRNA-185 (miR-185) involved in cholesterol and bile acid homeostasis. This study provides convincing evidences about the critical role of miR-185 in FoxO1 modulation at both posttranscriptional and posttranslational levels, which account for the effects on CYP7A1 gene and its mediated cholesterol-bile acid metabolism. These results suggest an important role of miR-185 as a novel atherosclerosis-protective target for drug discovery.
2023-03-26 | GSE169693 | GEO
Project description:Bile acids are not only physiological detergents facilitating nutrient absorption, but also signaling molecules regulating metabolic homeostasis. We reported recently that transgenic expression of CYP7A1 in mice stimulated bile acid synthesis and prevented Western diet-induced obesity, insulin resistance and hepatic steatosis. The aim of this experiment is to determine the impact of induction of hepatic bile acid synthesis on liver metabolism by determining hepatic gene expression profile in CYP7A1 transgenic mice. CYP7A1 transgenic mice and wild type control mice were fed either standard chow diet or high fat high cholesterol Western diet for 4 month. Hepatic gene expressions were measured by microarray analysis. Our results indicate that hepatic bile acid synthesis is closely linked to cholesterogenesis and lipogenesis, and maintaining bile acid homeostasis is improtant in hepatic metabolic homeostasis. Male aged matched (~ 12-14 weeks) CYP7A1 transgenic mice and their wild type control littermates were fed a standard chow diet or a high fat (42%) high cholesterol (0.2%) diet (Harlan Teklad #88137) for 4 month Four groups (4 mice/group) are included in the experiments: Group 1: WT _ Chow Group 2: CYP7A1-tg + chow Group 3: WT + Western diet Group 4: CYP7A1-tg _ Western diet Total liver mRNA was isolated with a RNeasy kit (Qiagen) and used for microarray analysis.
2013-08-15 | E-GEOD-38872 | biostudies-arrayexpress
Project description:Bile acids are not only physiological detergents facilitating nutrient absorption, but also signaling molecules regulating metabolic homeostasis. We reported recently that transgenic expression of CYP7A1 in mice stimulated bile acid synthesis and prevented Western diet-induced obesity, insulin resistance and hepatic steatosis. The aim of this experiment is to determine the impact of induction of hepatic bile acid synthesis on liver metabolism by determining hepatic gene expression profile in CYP7A1 transgenic mice. CYP7A1 transgenic mice and wild type control mice were fed either standard chow diet or high fat high cholesterol Western diet for 4 month. Hepatic gene expressions were measured by microarray analysis. Our results indicate that hepatic bile acid synthesis is closely linked to cholesterogenesis and lipogenesis, and maintaining bile acid homeostasis is improtant in hepatic metabolic homeostasis.
2013-08-15 | GSE38872 | GEO
Project description:Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR.
2016-02-04 | GSE77529 | GEO
Project description:Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR
2016-02-04 | GSE77507 | GEO
Project description:Biliary reverse cholesterol transport (RCT) plays a crucial role in cholesterol clearance and regulation of atherogenesis. San-wei-tan-xiang capsule (SWTX), a traditional Chinese medicine, has shown potential in inhibiting atherogenesis by increasing high-density lipoprotein (HDL) cholesterol levels and promoting macrophage-mediated cholesterol efflux. However, the specific role of HDL-driven cholesterol metabolism in the anti-atherogenic effects of SWTX remains unclear. In this study, liquid chromatography coupled with tandem mass spectrometry was used to analyze the circulating metabolic profile, and RNA sequencing was performed on liver samples from ApoE−/− mice fed a cholesterol-enriched diet. We found that SWTX treatment induced significantly differential expression of metabolites and genes involved in cholesterol and lipid metabolism, as well as bile secretion pathways, which are critical for HDL-driven biliary RCT. Furthermore, alterations in L-carnitine and choline metabolism induced by SWTX treatment was involved in the atheroprotective effects of SWTX. Notably, SWTX treatment led to a significant increase in the expression of cholesterol 7α-hydroxylase (CYP7A1), a key enzyme involved in bile acid synthesis during atherogenesis. Additionally, the expression of CYP7A1 and CYP7A1-mediated bile acid secretion were enhanced by the addition of choline in hepatic cells, suggesting that SWTX-induced elevation of choline metabolic products may contribute to the upregulation of CYP7A1 and CYP7A1-mediated biliary RCT. Overall, SWTX demonstrated its ability to attenuate atherosclerotic plaque formation, which can be attributed to alterations in carnitine and choline metabolism, as well as the modulation of CYP7A1-mediated HDL-driven biliary RCT.
2024-06-12 | GSE236672 | GEO
Project description:Deoxycholic acid (DCA) is a secondary bile acid produced by a small number of commensal species of bacteria present in the mammalian gut. Elevated DCA concentration correlates with disease states including colon cancer and cholesterol gallstones, but the associated mechanisms are not fully understood. Both primary and secondary bile acids are also capable of affecting gene expression through nuclear receptors such as FXR. To better understand the impact of a commensal-derived secondary bile acid on host metabolism we fed DCA to germ-free (GF) mice, which normally lack DCA, and compared the hepatic transcriptomes of bile acid fed GF mice to GF mice receiving a control diet, as well as to those of conventionally housed control animals. Interestingly, the feeding of DCA to GF mice, but not the feeding of cholic acid (CA) from which DCA is derived, results in an up-regulation of genes of cholesterol biosynthetic pathways. GF mice normally have elevated hepatic cholesterol compared to conventionally housed mice. Despite increase in the expression of cholesterol biosynthetic genes, the DCA fed GF mice showed a markedly decreased level of hepatic cholesterol equivalent to the hepatic cholesterol concentration of conventionally colonized animals. Total cholesterol in the serum was unaffected by DCA, but there was a decrease in the HDL lipoprotein fraction as well as an increase in the non-HDL lipoprotein fraction of the serum cholesterol. DCA, but not CA, is sufficient to modulate host lipoprotein metabolism. Taken together, these results suggests that a minor component of the gut microbiome has a significant impact on cholesterol homeostasis through secondary metabolism of bile acids and suggests a possible therapeutic intervention route through the microbial metabolic pathways. two mouse strains, three diets, one time point
2015-01-08 | E-GEOD-34730 | biostudies-arrayexpress
Project description:Morphine and its pharmacological derivatives are the most prescribed analgesics for moderate to severe pain management. However, chronic use of morphine reduces pathogen clearance and induces bacterial translocation across the gut barrier. The enteric microbiome has been shown to play a critical role in the preservation of the mucosal barrier function and metabolic homeostasis. Here, we show for the first time, using bacterial 16s rDNA sequencing, that chronic morphine treatment significantly alters the gut microbial composition and induces preferential expansion of the gram-positive pathogenic and reduction of bile-deconjugating bacterial strains. A significant reduction in both primary and secondary bile acid levels was seen in the gut, but not in the liver with morphine treatment. Morphine induced microbial dysbiosis and gut barrier disruption was rescued by transplanting placebo-treated microbiota into morphine-treated animals, indicating that microbiome modulation could be exploited as a therapeutic strategy for patients using morphine for pain management. In this study, we establish a link between the two phenomena, namely gut barrier compromise and dysregulated bile acid metabolism. We show for the first time that morphine fosters significant gut microbial dysbiosis and disrupts cholesterol/bile acid metabolism. Changes in the gut microbial composition is strongly correlated to disruption in host inflammatory homeostasis13,14 and in many diseases (e.g. cancer/HIV infection), persistent inflammation is known to aid and promote the progression of the primary morbidity. We show here that chronic morphine, gut microbial dysbiosis, disruption of cholesterol/bile acid metabolism and gut inflammation; have a linear correlation. This opens up the prospect of devising minimally invasive adjunct treatment strategies involving microbiome and bile acid modulation and thus bringing down morphine-mediated inflammation in the host.
2016-06-01 | E-MTAB-3722 | biostudies-arrayexpress