Similar Datasets
Project description:Systematic comparison of multiple models of diabetes / insulin resistance reveals miR-29 as a commonality among them, and further analysis reveals it as a key therapeutic target for insulin resistance.
2019-10-29 | GSE122044 | GEO
Project description:MicroRNAs (miRNAs) are known regulators of lipid homeostasis. We recently demonstrated that miR-29 controls the levels of circulating cholesterol and triglycerides, but the mechanisms remained unknown. In the present study, we demonstrated that systemic delivery of locked nucleic acid inhibitor of miR-29 (LNA29) through subcutaneous injection effectively suppresses hepatic expression of miR-29 and dampens de novo lipogenesis (DNL) in the liver of chow-fed mice. Next, we used mice with liver-specific deletion of Sirtuin 1 (L-Sirt1 KO), a validated target of miR-29, and demonstrated that the LNA29-induced reduction of circulating triglycerides, but not cholesterol, is dependent on hepatic Sirt1. Moreover, lipidomics analysis revealed that LNA29 suppresses hepatic triglyceride levels in a liver-Sirt1 dependent manner. A comparative transcriptomic study of liver tissue from LNA29-treated wild-type/floxed and L-Sirt1 KO mice identified the top candidate lipogenic genes and hepatokines through which LNA29 may confer its effects on triglyceride levels. The transcriptomic analysis also showed that fatty acid oxidation (FAO) genes respond differently to LNA29 depending on the presence of hepatic Sirt1. Overall, this study demonstrates the beneficial effects of LNA29 on DNL and circulating lipid levels. In addition, it provides mechanistic insight that decouples the effect of LNA29 on circulating triglycerides from that of circulating cholesterol.
| S-EPMC6828850 | biostudies-literature
Project description:MiR-29 regulates de novo lipogenesis and controls circulating triglyceride levels in a Sirt1-dependent manner
| PRJNA531687 | ENA
Project description:MiR-29 Regulates de novo Lipogenesis in the Liver and Circulating Triglyceride Levels in a Sirt1-Dependent Manner
| PRJNA503253 | ENA
Project description:Fate and behaviour of neural progenitor cells is tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells, govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multi-enzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors (APs) and reduced progenitor proliferation. Further, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell (ESC)-derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity and progenitor expansion in the developing human forebrain. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor cell polarity and lipid metabolism.
2022-01-14 | PXD026110 | Pride
Project description:ObjectiveMetformin is a first-line pharmacotherapy in the treatment of type 2 diabetes, a condition closely associated with non-alcoholic fatty liver disease (NAFLD). Although metformin promotes weight loss and improves insulin sensitivity, its effect on intrahepatic triglyceride (IHTG) remains unclear. We investigated the effect of metformin on IHTG, hepatic de novo lipogenesis (DNL), and fatty acid (FA) oxidation in vivo in humans.Design and methodsMetabolic investigations, using stable-isotope tracers, were performed in ten insulin-resistant, overweight/obese human participants with NAFLD who were treatment naïve before and after 12 weeks of metformin treatment. The effect of metformin on markers of s.c. adipose tissue FA metabolism and function, along with the plasma metabolome, was investigated.ResultsTwelve weeks of treatment with metformin resulted in a significant reduction in body weight and improved insulin sensitivity, but IHTG content and FA oxidation remained unchanged. Metformin treatment was associated with a significant decrease in VLDL-triglyceride (TG) concentrations and a significant increase in the relative contribution of DNL-derived FAs to VLDL-TG. There were subtle and relatively few changes in s.c. adipose tissue FA metabolism and the plasma metabolome with metformin treatment.ConclusionsWe demonstrate the mechanisms of action of metformin whereby it improves insulin sensitivity and promotes weight loss, without improvement in IHTG; these observations are partly explained through increased hepatic DNL and a lack of change in FA oxidation.
| S-EPMC8859923 | biostudies-literature
Project description:Interindividual variability in the response of plasma triglyceride concentrations (TG) following fish oil consumption has been observed. Our objective was to examine the associations between single-nucleotide polymorphisms (SNPs) within genes encoding proteins involved in de novo lipogenesis and the relative change in plasma TG levels following a fish oil supplementation. Two hundred and eight participants were recruited in the greater Quebec City area. The participants completed a six-week fish oil supplementation (5 g fish oil/day: 1.9-2.2 g eicosapentaenoic acid and 1.1 g docosahexaenoic acid. SNPs within SREBF1, ACLY, and ACACA genes were genotyped using TAQMAN methodology. After correction for multiple comparison, only two SNPs, rs8071753 (ACLY) and rs1714987 (ACACA), were associated with the relative change in plasma TG concentrations (P = 0.004 and P = 0.005, respectively). These two SNPs explained 7.73% of the variance in plasma TG relative change following fish oil consumption. Genotype frequencies of rs8071753 according to the TG response groups (responders versus nonresponders) were different (P = 0.02). We conclude that the presence of certain SNPs within genes, such as ACLY and ACACA, encoding proteins involved in de novo lipogenesis seem to influence the plasma TG response following fish oil consumption.
| S-EPMC3770099 | biostudies-literature
Project description:Triglyceride (TG) content in chicken muscle tissue signifies intramuscular fat (IMF) content, which is important for improving meat quality. However, the genetic basis of TG deposition in chicken is still unclear. Using 520 chickens from an artificially selected line with significantly increased IMF content and a control line, a genome-wide association study (GWAS) with TG content reports a region of 802 Kb located in chromosome 1. The XP-EHH and gene expression analysis together reveal that the solute carrier family 16 member A7 (SLC16A7) gene is the key candidate gene associated with TG content in chicken muscle tissue. Furthermore, the weighted gene co-expression network analysis (WGCNA) confirmed the regulatory effects of SLC16A7 on promoting TG deposition by de novo lipogenesis (DNL). Functional verification of SLC16A7 in vitro also supports this view, and reveals that this effect mainly occurs in myocytes. Our data highlight a potential IMF deposition pathway by DNL, induced by SLC16A7 in chicken myocytes. These findings will improve the understanding of IMF regulation in chicken and guide the formulation of breeding strategies for high-quality chicken.
| S-EPMC9687483 | biostudies-literature
Project description:Cystic fibrosis (CF) mouse models exhibit exocrine pancreatic function yet do not develop adipose stores to the levels of non-CF mice. CF mice homozygous for the Cftr mutation (F508del) at 3 weeks (post-weaning) and 6 weeks (young adult) of age had markedly less adipose tissue than non-CF mice. Both 3- and 6-week old mice had dietary lipid absorption and fecal lipid excretion comparable to non-CF controls. Fractional hepatic de novo synthesis of palmitate and stearate (de novo lipogenesis, DNL) as determined by deuterium incorporation was reduced in CF mice. At 3 weeks of age, F508del mice had significantly decreased DNL of palmitate and stearate, by 83% and 80%, respectively. By 6 weeks of age, DNL rates in non-CF mice remained unchanged as compared to 3-week old mice, while DNL rates of F508del mice were still reduced, by 33% and 40%, respectively. Adipose tissue fatty acid profiles were comparable in CF and non-CF mice, indicating that adipose differences are quantitative, not qualitative. A correspondingly lower content of deuterium-labeled fatty acids was found in CF adipose tissue, consistent with reduced deposition of newly made hepatic triglycerides and/or decreased adipose tissue lipogenesis. Hepatic transcriptome analysis revealed lower mRNA expression from several genes involved in fatty acid biosynthesis, suggesting down-regulation of several enzymes in fatty acids synthesis as a mechanism for the reduced lipogenesis. These novel data provide a model for altered fat and fatty acid metabolism in CF, independent of malabsorption, and may partly explain the inability of pancreatic enzyme replacement therapy to completely restore normal body mass to CF patients ∆F508 CF mice and its WT littermates (3-weeks old females, C57BL/6J) were examined. RNA extracted from snapped-frozen livers, 4 replicates per genotype.
2012-06-17 | E-GEOD-33319 | biostudies-arrayexpress
Project description:Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identified lysine methyltransferase (KMT)9 as a novel regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types. Mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase (DLAT) at lysine 596. Depletion of KMT9 compromises PDC activity, de novo lipogenesis, and PCa cell proliferation, which can be rescued with exogenous KMT9 targeted to mitochondria. Similarly, comparable defects caused by DLAT depletion can be rescued with exogenous DLAT, but not with a methylation-defective DLAT mutant. Concomitant chemical inhibition of de novo lipogenesis and KMT9 depletion more efficiently impair PCa cell proliferation than either treatment alone. Importantly, KMT9 controls PDC activity, de novo lipogenesis, and tumor growth in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a novel mechanism of PDC regulation and the first example of a histone methyltransferase with nuclear and mitochondrial functions. The exceptional dependency on mitochondrial KMT9 allows to develop novel therapeutic strategies to fight PCa.
2024-12-03 | PXD053942 | Pride