HuR promotes triglyceride synthesis and intestinal fat absorption
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PROVIDER: PRJNA1061476 | ENA |
REPOSITORIES: ENA
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Project description:HuR promotes triglyceride synthesis and intestinal fat absorption
| PRJNA1093368 | ENA
Project description:Triacylglyceride (TAG) synthesis in the small intestine determines the absorption of dietary fat, but the mechanisms underlying are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) promotes TAG synthesis in the small intestine. HuR associates with the 3’UTR of Dgat2 mRNA and the introns 1 of Mgat2 pre-mRNA. Association of HuR with Dgat2 3’UTR stabilizes Dgat2 mRNA, while association of HuR with intron 1 of Mgat2 pre-mRNA promotes the processing of Mgat2 pre-mRNA. Intestinal epithelium-specific HuR knockout reduces the expression of DGAT2 and MGAT2, thereby reducing the dietary fat absorption through TAG synthesis and mitigating high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and obesity. Our findings highlight a critical role of HuR in promoting dietary fat absorption.
2024-01-10 | GSE252591 | GEO
Project description:Triacylglyceride (TAG) synthesis in the small intestine determines the absorption of dietary fat, but the mechanisms underlying are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) promotes TAG synthesis in the small intestine. HuR associates with the 3’UTR of Dgat2 mRNA and the introns 1 of Mgat2 pre-mRNA. Association of HuR with Dgat2 3’UTR stabilizes Dgat2 mRNA, while association of HuR with intron 1 of Mgat2 pre-mRNA promotes the processing of Mgat2 pre-mRNA. Intestinal epithelium-specific HuR knockout reduces the expression of DGAT2 and MGAT2, thereby reducing the dietary fat absorption through TAG synthesis and mitigating high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and obesity. Our findings highlight a critical role of HuR in promoting dietary fat absorption.
2024-04-03 | GSE262777 | GEO
Project description:Human antigen R (HuR) is a member of the Hu family of RNA-binding proteins and is involved in many physiological processes. To investigate the role of adipose HuR, we generate adipose-specific HuR knockout (HuRAKO) mice. As compared with control mice, HuRAKO mice show obesity when induced with a high-fat diet, along with insulin resistance, glucose intolerance, hypercholesterolemia and increased inflammation in adipose tissue. The obesity of HuRAKO mice is attributed to adipocyte hypertrophy in white adipose tissue due to decreased expression of adipose triglyceride lipase (ATGL), a critical lipase involved in lipolysis. HuR positively regulates ATGL expression by promoting the mRNA stability and translation of ATGL. Consistently, the expression of HuR in adipose tissue is reduced in obese humans, which is associated with reduced ATGL expression. This study suggests that adipose HuR may be a critical regulator of ATGL expression and lipolysis and thereby controls obesity and metabolic syndrome.
2019-04-23 | GSE130147 | GEO
Project description:Maintenance of circadian alignment between an organism and its environment is essential to ensure metabolic homeostasis. Synchrony is achieved by cell autonomous circadian clocks. Despite a growing appreciation of the integral relation between clocks and metabolism, little is known regarding the direct influence of a peripheral clock on cellular responses to fatty acids. To address this important issue, we utilized a genetic model of disrupted clock function specifically in cardiomyocytes in vivo (termed cardiomyocyte clock mutant (CCM)). CCM mice exhibited altered myocardial response to chronic high fat feeding at the levels of the transcriptome and lipidome as well as metabolic fluxes, providing evidence that the cardiomyocyte clock regulates myocardial triglyceride metabolism. Time-of-day-dependent oscillations in myocardial triglyceride levels, net triglyceride synthesis, and lipolysis were markedly attenuated in CCM hearts. Analysis of key proteins influencing triglyceride turnover suggest that the cardiomyocyte clock inactivates hormone-sensitive lipase during the active/awake phase both at transcriptional and post-translational (via AMP-activated protein kinase) levels. Consistent with increased net triglyceride synthesis during the end of the active/awake phase, high fat feeding at this time resulted in marked cardiac steatosis. These data provide evidence for direct regulation of triglyceride turnover by a peripheral clock and reveal a potential mechanistic explanation for accelerated metabolic pathologies after prevalent circadian misalignment in Western society.
2010-03-24 | GSE21028 | GEO
Project description:Members of the Estrogen-Related Receptor (ERR) family of nuclear receptors (NR) serve a key role in coordinating triglyceride (TAG) accumulation with juvenile growth and development. In both insects and mammals, loss of ERR activity disrupts (TAG) storage during the post-embryonic growth phase, with loss-of-function mutations in mouseErraandDrosophila melanogaster dERRinducing a lean phenotype. However, the role of insect ERRs in controlling TAG accumulation remains poorly understood, as previous multiomic studies largely relied on whole animal analyses. Here we address this shortcoming by using tissue-specific approaches to determine how dERR regulates lipid metabolism within theDrosophilalarval fat body. We found that dERR autonomously promotes TAG accumulation within fat body cells by regulating expression of genes involved in glycolysis, the pentose phosphate pathway, lipid synthesis, andb-oxidation. As an extension of these results, we not only discovered thatdERRmutant fat bodies exhibit decreased expression of known HNF4 target genes but also found that dHNF4 activity is decreased indERRmutants. Overall, our findings indicate that dERR plays a multifaceted role in the larval fat body to coordinate lipid storage with developmental growth and hint at a conserved mechanism by which ERR and HNF4 homologs coordinately regulate metabolic gene expression
2024-08-02 | GSE273774 | GEO
Project description:Intake and absorption of cholesterol (the latter determined by double labeled cholesterol methodology) were nearly unchanged in mice fed the saturated fat diet, but the fecal excretion of neutral sterols (i.e. cholesterol and its microbial conversion products) was increased compared with control diet(+80%; p<0.01). The saturated fat diet did neither significantly affect biliary cholesterol secretion nor intestinal cholesterol absorption (49% vs. 65% in controls, double labeled water methodology, p>0.1). Thus, the increased fecal neutral sterol excretion was primarily due to increased net transintestinal cholesterol excretion (+89% versus control; p<0.05). Since a major fraction of TICE cholesterol absorption is normally reabsorbed (J Lipid Res 2019 Sep;60(9):1562-1572), the increased fecal cholesterol excretion could be due to more transintestinal excretion of cholesterol into the intestinal lumen and/or to its decreased reabsorption. The saturated fat diet increased jejunal expression of genes involved in cholesterol synthesis (Srebf2 and target genes), but did not affect whole body de novo cholesterol synthesis. Conclusion This proof-of-principle study shows that increasing the saturation of the dietary fat can stimulate fecal cholesterol excretion. Individual components of saturated fat diets are to be explored to address the responsible molecular mechanisms
2021-02-01 | GSE37097 | GEO
Project description:Inhibition of granuloma triglyceride synthesis imparts control of Mycobacterium tuberculosis through curtailed inflammatory responses
| PRJNA743689 | ENA
Project description:Synthesis of milk fat is a complex biochemical process regulated by a series of molecular events. To determine gene expression changes during milk fat synthesis in bovine mammary epithelial cells, we established a cell model with a high capacity for milk fat synthesis using stimulation with acetate and β-hydroxybutyrate. RNA sequencing was used to identify differentially expressed genes (DEGs) between the high-milk-fat and control cells. A total of 625 DEGs (358 upregulated, 267 downregulated) were identified. Among the highly expressed genes, there was enrichment for terms associated with fatty acid synthesis, activation, and triacylglycerol synthesis, consistent with active milk fat synthesis. Kyoto Encyclopedia of Genes and Genomes analysis suggested that DEGs were most enriched in the “lipid metabolism” subcategory of the “metabolism” category, and in the “signal transduction” subcategory of the “environmental information processing” category. Although an in vitro cell model cannot completely simulate in vivo lactation, it eliminates interference from other cell types and from the synthesis of other milk components during transcriptome profile analysis. This work provides a profile of gene expression changes that occur during milk fat synthesis in bovine mammary epithelial cells, which furthers our understanding of the molecular regulation of lipid metabolism.
2019-07-05 | GSE133827 | GEO
Project description:Human antigen R (HuR) protein, a RNA binding protein (RBP), has been reported to regulate essential steps in RNA metabolism and immune response in a variety of cell types, but its function in metabolism remains unclear. This study identifies HuR as a major repressor during adipogenesis. Knockdown and overexpression of HuR in primary adipocyte culture enhances and inhibits adipogenesis in vitro, respectively. Fat-specific knockout of HuR significantly enhances adipogenic gene program in all three major adipose tissues including epidydimal, inguinal white and brown adipose tissue, accompanied with systemic glucose intolerance and insulin resistance. Conversely, transgenic overexpression of HuR in adipose tissue prevents the HFD induced obesity by repressing adipogenesis. Mechanistically, HuR may inhibit adipogenesis by recognizing and modulating the stability of hundreds of adipocyte transcripts, including the mRNA of Insig1, a negative regulator during adipogenesis. Taken together, our work establishes HuR as a novel posttranscriptional regulator of adipogenesis and provides a new insight into how RNA processing contributes to adipocyte development.
2019-09-09 | GSE124278 | GEO