Liver X Receptor α Activation Enhances Cholesterol Secretion in Lactating Mammary Epithelium
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PROVIDER: PRJNA498520 | ENA |
REPOSITORIES: ENA
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Project description:We profiled differential gene expression in vivo between pregnant day 14 (secretory differentiation) and lactation day 4 (established secretory activation) using isolated mouse mammary epithelial cells depleted of the mammary adipocytes. Liver-X-Receptors are ligand-dependent transcription factors activated by cholesterol metabolites. These receptors induce a suite of target genes required for de novo synthesis of triglycerides and cholesterol transport in many tissues. Two different isoforms -LXRα and LXRβ- have been well characterized in liver, adipocytes, macrophages and intestinal epithelium among others, but their contribution to cholesterol and fatty acid efflux in the lactating mammary gland is poorly understood. We hypothesize that LXR regulates lipogenesis during milk fat production in lactation. Global mRNA analysis of mouse mammary epithelial cells (MECs) revealed multiple LXR/RXR targets are upregulated sharply at the onset of lactation compared to mid-pregnancy. LXRα is the primary isoform and its protein levels increase throughout lactation in MECs. The LXR agonist GW3965 markedly induced several genes involved in cholesterol transport and lipogenesis and enhanced cytoplasmic lipid droplet accumulation in the HC11 MEC cell line. Importantly, in vivo pharmacological activation of LXR increased the milk cholesterol percentage and induced Srebp1c and Abca7 expression in MECs. Cumulatively, our findings identify LXRα as an important regulator of cholesterol incorporation into the milk through key nodes of de novo lipogenesis, suggesting a potential therapeutic target in women with difficulty initiating lactation.
2019-03-05 | GSE121819 | GEO
Project description:Liver X receptors (LXRs) are ligand-dependent transcription factors activated by cholesterol metabolites. These receptors induce a suite of target genes required for de novo synthesis of triglycerides and cholesterol transport in many tissues. Two different isoforms, LXRα and LXRβ, have been well characterized in liver, adipocytes, macrophages, and intestinal epithelium among others, but their contribution to cholesterol and fatty acid efflux in the lactating mammary epithelium is poorly understood. We hypothesize that LXR regulates lipogenesis during milk fat production in lactation. Global mRNA analysis of mouse mammary epithelial cells (MECs) revealed multiple LXR/RXR targets upregulated sharply early in lactation compared with midpregnancy. LXRα is the primary isoform, and its protein levels increase throughout lactation in MECs. The LXR agonist GW3965 markedly induced several genes involved in cholesterol transport and lipogenesis and enhanced cytoplasmic lipid droplet accumulation in the HC11 MEC cell line. Importantly, in vivo pharmacological activation of LXR increased the milk cholesterol percentage and induced sterol regulatory element-binding protein 1c (Srebp1c) and ATP-binding cassette transporter a7 (Abca7) expression in MECs. Cumulatively, our findings identify LXRα as an important regulator of cholesterol incorporation into the milk through key nodes of de novo lipogenesis, suggesting a potential therapeutic target in women with difficulty initiating lactation.
| S-EPMC6620573 | biostudies-literature
Project description:Thyroid hormone responsive protein Spot 14 has been consistently associated with de novo fatty acid synthesis activity in multiple tissues, including the lactating mammary gland, which synthesizes large quantities of medium chain fatty acids (MCFAs) exclusively via FASN. However, the molecular function of Spot14 remains undefined during lactation. Spot14-null mice produce milk deficient in total triglyceride and de novo MCFA that does not sustain optimal neonatal growth. The lactation defect was rescued by provision of a high fat diet to the lactating dam. Transgenic mice overexpressing Spot14 in mammary epithelium produced total milk fat equivalent to controls, but with significantly greater MCFA. Spot14-null dams have no diminution of metabolic gene expression, enzyme protein levels, or intermediate metabolites that accounts for impaired de novo MCFA. When [(13)C] fatty acid products were quantified in vitro using crude cytosolic lysates, native FASN activity was 1.6-fold greater in control relative to Spot14-null lysates, and add back of Spot14 partially restored activity. Recombinant FASN catalysis increased 1.4-fold and C = 14:0 yield was enhanced 4-fold in vitro following addition of Spot14. These findings implicate Spot14 as a direct protein enhancer of FASN catalysis in the mammary gland during lactation when maximal MCFA production is needed.
| S-EPMC4031937 | biostudies-literature
Project description:Chronic islet inflammation is a hallmark of type 2 diabetes (T2D) and involves in the dysfunction of β cells. However, how β cells participate in this process remains unclear. Here, we report that the immune checkpoint molecule B7-H4(B7S1, B7x, VTCN1) expressed in β cells is critical to maintain β cell mass and insulin secretion. Lesion of B7-H4 in β cells results in glucose intolerance due to less β cell mass and deficient insulin secretion with upregulated cytokines and activated signal transducer and activator of transcription 5 (Stat5) signaling, while overexpression of B7-H4 in β cells ameliorates glucose intolerance in high-fat diet (HFD)-treated mice. Mechanistically, B7-H4 deficiency actives the Stat5 signaling, which inhibits the expression of Apolipoprotein F (ApoF), leading to reduced cholesterol efflux and accumulated cholesterol in β cells, thereby impairing the insulin processing and secretion. Inhibiting Stat5 activity or overexpression of ApoF in β cells can rescue the glucose intolerance and insulin secretion deficiency in β-cell-specific B7-H4 knockout (B7-H4 cKO) mice. Our study demonstrates that β cell expressed immune checkpoint molecule B7-H4 is essential for islet immune homeostasis and β cell function maintenance, and for the first time unravels the mechanism by which B7-H4 regulates insulin secretion through regulating cholesterol metabolism via Stat5 signaling, which may shed new light on the development of novel strategies for T2D treatment.
2024-12-19 | GSE268688 | GEO
Project description:Nutrition affects milk composition influencing its nutritional properties. Nutrition also modifies the expression of mammary genes, whose regulation is not completely known. MicroRNAs (miRNA) are small non-coding RNA that work as important post-transcriptional gene expression regulators by targeting messenger RNAs. Our goal was to characterize miRNA whose expression is regulated by nutrition in the lactating goat mammary gland, and which may give clues to decipher the regulations of milk components biosynthesis and secretion. Using high-throughput sequencing technology, miRNomes of the lactating mammary gland have been established from 4 goats fed ad libitum and 6 goats food deprived during 48h. Food deprivation affected the expression of 30 miRNA (padj<0.1), 16 were downregulated and 14 were upregulated. Prediction tools Diana-microT suggests a potential role of several nutriregulated miRNA in the lipid metabolism. Among putative targets 19 differently expressed genes (DEG) previously identified in the same sample, were found. Functions of these 19 DEG revealed their involvement in tissue remodeling. This study constitutes the first evidence of nutriregulated miRNA in the ruminant mammary gland. The characterization of these 30 miRNA could contribute to a better understanding of genes regulations in the mammary gland in response to nutrition.
2015-07-01 | GSE61025 | GEO
Project description:Animal nutrition considerably affects milk composition that influences its nutritional quality. Milk component synthesis and secretion by the mammary gland involve expression of a large number of genes whose nutritional regulation remains poorly defined. In this study, we examined the effect of food deprivation (FD) on the expression of 8379 genes in caprine mammary gland using a bovine oligonucleotide microarray. Twelve lactating goats were assigned to 2 groups based on their feeding level (control diet ad libitum vs. 48-h FD). We identified 161 genes whose expression was altered by FD. Most of these genes (88%) were downregulated, suggesting a stress response by the mammary gland. In particular, the decrease in expression of genes involved in milk protein, lactose, and lipid metabolism could contribute together with the shortage of nutrients to the drop in milk protein, lactose, and fat secretion. In addition, this study highlights modification of the expression of at least 14 genes that could be responsible for a slowdown in mammary cell proliferation and differentiation and/or an increase in programmed cell death in response to 48-h FD in goats. Keywords: Response to nutritional factor
2007-02-21 | GSE6380 | GEO
Project description:Nutrition affects milk composition influencing its nutritional properties. Nutrition also modifies the expression of mammary genes, whose regulation is not completely known. MicroRNAs (miRNA) are small non-coding RNA that work as important post-transcriptional gene expression regulators by targeting messenger RNAs. Our goal was to characterize miRNA whose expression is regulated by nutrition in the lactating goat mammary gland, and which may give clues to decipher the regulations of milk components biosynthesis and secretion. Using high-throughput sequencing technology, miRNomes of the lactating mammary gland have been established from 4 goats fed ad libitum and 6 goats food deprived during 48h. Food deprivation affected the expression of 30 miRNA (padj<0.1), 16 were downregulated and 14 were upregulated. Prediction tools Diana-microT suggests a potential role of several nutriregulated miRNA in the lipid metabolism. Among putative targets 19 differently expressed genes (DEG) previously identified in the same sample, were found. Functions of these 19 DEG revealed their involvement in tissue remodeling. This study constitutes the first evidence of nutriregulated miRNA in the ruminant mammary gland. The characterization of these 30 miRNA could contribute to a better understanding of genes regulations in the mammary gland in response to nutrition. MicroRNA profiles of mammary glands from 10 Alpine goats at the peak of lactation (48 ± 2 days post-partum) generated by a HiSeq 2500 using Illumina Solexa technic.
2015-07-01 | E-GEOD-61025 | biostudies-arrayexpress
Project description:Background: The mammary gland is a dynamic organ that undergoes important physiological changes during reproductive cycles. Until now, data regarding the characterisation of miRNA in the mammary gland have been scarce and mainly focused on their abnormal expression in breast cancer. Our goal was to characterise the microRNA (miRNA) involved in mechanisms regulating the mammary function, with particular focus on the lactation stage Methodology/principal findings: Using high-throughput sequencing technology, an exhaustive repertoire of miRNA (miRNome) expressed in mouse and bovine mammary glands during established lactation was identified, characterised and compared. Furthermore, in order to obtain more information on miRNA loading in the RNA-induced silencing complex (RISC), the miRNome was compared with that obtained from RNA associated with the AGO2 protein (AGO2-miRNome) in mouse lactating mammary gland. This study enabled the identification of 164 and 167 miRNA in mouse and bovine, respectively. Among the 30 miRNA most highly expressed in each species, 24 were common to both species and six of them tended to be more highly expressed in lactating than in non-lactating mammary gland. The potential functional roles of these 24 miRNA were deduced using DIANA-miRPath software, based on miRNA/mRNA interactions. Moreover, seven putative novel miRNA were identified. Using DAVID analysis, it was concluded that the predicted targets of two of these putative novel miRNA are involved in mammary gland morphogenesis. Conclusion/significance: Our study provides an overview of the characteristics of lactating mouse and bovine mammary gland miRNA expression profiles. Moreover, species-conserved miRNA involved in this fundamental biological function were identified. These miRNomes will new be used as references for further studies during which the impact of animal breeding on the miRNA expression will be analysed.
2014-03-24 | GSE53511 | GEO
Project description:To identify genes specifically expressed in lactating mammary glands, the gene expression profiles of luminal and basal cells from different developmental stages were compared.
2015-01-19 | GSE60450 | GEO
Project description:To identify genes specifically expressed in lactating mammary glands, the gene expression profiles of luminal and basal cells from different developmental stages were compared. Comparison of gene expression in luminal and basal cells harvested from the mammary glands of virgin, 18.5 day pregnant and 2 day lactating mice (2 mice per stage).
2015-01-19 | E-GEOD-60450 | biostudies-arrayexpress