Characterization of an in vitro steatosis model for modelling the activated de novo lipogenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE224980 | GEO | 2023/08/30
REPOSITORIES: GEO
Similar Datasets
Project description:Characterization of an in vitro steatosis model for modelling the activated de novo lipogenesis
| PRJNA933217 | ENA
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:Background: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Our aims were to investigate whether a sub-set of TAGs were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. </br></br> Results: We conducted direct infusion mass spectrometry of lipids in plasma to study the association between specific triacylglycerols (TAGs) and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study (n=1507), and evaluated clustering of TAGs in the National Survey of Health and Development UK cohort (n=1701). TAGs formed 3 clusters, with those TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons being specifically associated with hepatic steatosis. These TAGs were associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL was measured in hyperphagic ob/ob mice, mice on a Western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs were increased in plasma from patients with biopsy-confirmed steatosis. </br></br> Conclusion: A sub-set of TAGs are associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in Western populations is in part driven by increased DNL following carbohydrate rich meals. </br></br> The protocols and data of the murine study of de novo lipogenesis are included in the study MTBLS614. </br><br/> Linked Studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS614' target='_blank'><span class='label label-success'>MTBLS614</span></a>
2018-03-13 | MTBLS616 | MetaboLights
Project description:RNA-seq analysis of livers from control mice, mice with adult onset, hepatocyte-specific GH receptor (GHR) deficiency, and GHR-deficient mice combined with IGF1 expression or expression of constitutively active ('CA') STAT5b. This dataset is part of a large study showing that adult-onset loss of hepatocyte GHR signaling increases steatosis, associated with enhanced glucokinase activity, de novo lipogenesis (DNL) and pathway selective hepatic insulin resistance.
2023-08-21 | GSE222513 | GEO
Project description:Background: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Our aims were to investigate whether a sub-set of TAGs were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. </br></br> Results: We conducted direct infusion mass spectrometry of lipids in plasma to study the association between specific triacylglycerols (TAGs) and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study (n=1507), and evaluated clustering of TAGs in the National Survey of Health and Development UK cohort (n=1701). TAGs formed 3 clusters, with those TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons being specifically associated with hepatic steatosis. These TAGs were associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL was measured in hyperphagic ob/ob mice, mice on a Western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs were increased in plasma from patients with biopsy-confirmed steatosis. </br></br> Conclusion: A sub-set of TAGs are associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in Western populations is in part driven by increased DNL following carbohydrate rich meals. </br></br> The protocols and data of the human carbohydrate feeding study in healthy volunteers are reported in the study MTBLS616. </br><br/> Linked Studies: <a href='https://www.ebi.ac.uk/metabolights/MTBLS616' target='_blank'><span class='label label-success'>MTBLS616</span></a>
2018-03-12 | MTBLS614 | MetaboLights
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
2012-06-18 | GSE33319 | GEO
Project description:De novo lipogenesis (DNL) has been implicated in the development and progression of hepatic liver steatosis. Hepatic DNL is strongly influenced by dietary macronutrient composition with diets high in carbohydrate increasing DNL and diets high in fat decreasing DNL. The enzymes in the core DNL pathway have been well characterised however less is known about proteins that play accessory or regulatory roles in DNL. In the current study, we associate measured rates of hepatic DNL and liver fat content with abundance of liver proteins from liquid chromatography mass spectrometry in mice to identify known and uncharacterised proteins that may have a role in DNL. Male C57BL/6J mice were fed either a standard chow diet a semi-purified high starch diet or a high fat diet. Both semi-purified diets resulted in increased body weight, fat mass and liver triglyceride content compared to chow-fed mice while hepatic DNL was increased in the high starch fed mice and decreased in the high fat fed mice. Proteomic analysis was carried out on the livers of these mice and proteins were identified that associated with either the rate of DNL or triglyceride content in the liver. There was no overlap between DNL and triglyceride associated proteins. We identify novel proteins associated with DNL that are involved in taurine metabolism, which suggests a link between these pathways. Further analysis identified proteins that are differentially regulated when comparing a non-purified chow diet to either of the semi-purified diets to provide a set of proteins that are regulated by the degree of dietary complexity alone. Finally, we compared the liver proteome between 4 week-fed and 30-week diet-fed mice and found remarkable similarity suggesting that the majority of diet-regulated proteins change early in response to differing dietary components.
2024-10-30 | PXD054323 | Pride
Project description:In non-alcoholic fatty liver disease (NAFLD) caused by ectopic lipid accumulation, lipotoxicity is a crucial molecular risk factor. Mechanisms to eliminate lipid overflow can prevent the liver from functional complications. This may involve increased secretion of lipids or metabolic adaptation to ß-oxidation in lipid-degrading organelles such as mitochondria and peroxisomes. In addition to dietary factors, increased plasma fatty acid levels may be due to increased triglyceride synthesis, lipolysis, as well as de novo lipid synthesis (DNL) in the liver. In the present study, we investigated the impact of fatty liver caused by elevated DNL, in a transgenic mouse model with liver-specific overexpression of human sterol regulatory element-binding protein-1c (alb-SREBP-1c), on hepatic gene expression, on plasma lipids and especially on the proteome of peroxisomes by omics analyses, and we interpreted the results with knowledge-based analyses. In summary, the increased hepatic DNL is accompanied by marginal gene expression changes but massive changes in peroxisomal proteome. Furthermore, plasma phosphatidylcholine (PC) as well as lysoPC species were altered. Based on these observations, it can be speculated that the plasticity of organelles and their functionality may be directly affected by lipid overflow.
2019-10-15 | GSE132298 | GEO
Project description:Fat accumulation, de novo lipogenesis, and glycolysis are key contributors to hepatocyte reprogramming and the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms affected by steatosis and inflammation in the obese states remain unknown. Here we report that obesity leads to dysregulated expression of protein-tyrosine phosphatases (PTPs) in the liver. Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) was increased in hepatocytes by steatosis and inflammation in humans and mice, and positively correlates with PPARγ-induced lipogenic signalling. Mechanistically, PTPRK-PPARγ upregulation by fat accumulation is dependent upon Notch signalling in mouse primary hepatocytes. PTPRK knockout mice have reduced fat accumulation in adipose tissue and liver after exposure to an obesogenic diet. Phosphoproteomic analysis in isolated hepatocytes and hepatic metabolomics identified specific phosphotyrosine residues in fructose-1,6 bisphosphatase-1 and glycolysis regulation as targets of PTPRK. These changes in glycolysis and de novo lipogenesis revealed PTPRK-dependent metabolic reprogramming in hepatocytes. Moreover, hepatoma cell lines showed reduced colony-forming ability after PTPRK silencing in vitro, and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis in vivo. Computational modelling identified potential PTPRK inhibitors, which selectively reduced PTPRK activity. The compounds decreased glycolytic rates in hepatoma cell lines, PPARγ expression in primary hepatocytes and steatosis in obese mice. In conclusion, our study defines a novel mechanism for the development of MASLD, revealing a key role of PTPRK on hepatic glycolysis regulation with implications in lipid metabolism, and liver tumour development. We propose PTPRK as a potential target for metabolic liver dysfunction, and the identified inhibitors may represent promising candidates for therapy in obesity-associated liver diseases.
2024-10-21 | PXD046506 | Pride
Project description:Through a series of epidemiological analyses, flux analyses, and genetic interventions, we identified amino acid as a primary carbon source in hepatic de novo lipogenesis (DNL), and revealed the vital role of dietary protein in non-alcoholic fatty liver disease (NAFLD). To evaluate whether this finding can be applied to treat hepatic steatosis, we implemented protein restriction in obese mice. A short-term low-protein diet (5% kcal protein intake) not only reduced food intake and body weight gain of mice but also ameliorated hepatic lipid accumulation and liver damage. Here, we conducted RNA sequencing for liver samples from these mice and demonstrated a global downregulation of lipogenic genes. Together, this study uncovers a significant role of amino acids in hepatic DNL, and suggests a previously unappreciated target for NAFLD.
2024-08-12 | GSE264493 | GEO