Characterization of an in vitro steatosis model for modelling the activated de novo lipogenesis
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ABSTRACT:
PROVIDER: PRJNA933217 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23387178_1.fastq.gz | Fastqsanger.gz | |||
| SRR23387178_2.fastq.gz | Fastqsanger.gz | |||
| SRR23387179_1.fastq.gz | Fastqsanger.gz | |||
| SRR23387179_2.fastq.gz | Fastqsanger.gz | |||
| SRR23387180_1.fastq.gz | Fastqsanger.gz |
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Project description:We establish a novel in vitro steatosis model that induces steatosis based on de novo lipogenesis (DNL) using HepG2 cells without treatment of any fatty acids.To investigate the genetic features of the DNL model, we then performed gene expression profiling analysis using data obtained from RNA-seq.
2023-08-30 | GSE224980 | 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: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:Metabolic dysfunction within the liver is a major cause of human disease worldwide. Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). The underpinning 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) expression was increased in hepatocytes during steatosis and inflammation in humans and mice, and positively correlates with PPARγ-induced lipogenic signalling. Supporting this, PTPRK knockout mice displayed reduced fat accumulation in adipose tissue and liver after exposure to an obesogenic diet. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified specific phosphotyrosine residues in fructose-1,6 bisphosphatase-1 and glycolysis regulation as targets of PTPRK. The changes in glycolysis and de novo lipogenesis revealed PTPRK was a driving force for 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. Through computational modelling, we identified selective PTPRK inhibitors. These 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.
2024-09-26 | GSE247670 | GEO
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: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: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.
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Project description:Non-alcoholic fatty liver disease (NAFLD) is caused by imbalance in lipid metabolism. In this study, we show that the hepatokine Orosomucoid 2 (ORM2) is a key regulator of de novo lipogenesis in the liver. Hepatic and plasma ORM2 levels are markedly decreased in obese murine models and NAFLD patients. Through multiple loss- and gain-of function studies, we demonstrate that ORM2 is essential to maintain hepatic and systemic lipid homeostasis. At the mechanistic level, ORM2 binds to inositol 1, 4, 5-trisphosphate receptor type 2 (ITPR2) to activate AMP-activated protein kinase (AMPK) signaling, thereby inhibiting sterol regulatory element binding protein 1c (SREBP-1c)-mediated lipogenic gene program. Notably, intraperitoneal injections of recombinant ORM2 protein or stabilized ORM2-FC fusion protein markedly improved liver steatosis, steatohepatitis and atherosclerosis in preclinical mouse models, without adverse effects on body weight or food intake. Thus, these findings suggest that ORM2 may serve as a potential target for therapeutic intervention in NAFLD, NASH and related lipid disorders.
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