Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1303593 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Citrin Deficiency (CD) is caused by inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. We discovered that SLC25A13 loss causes accumulation of glycerol-3-phosphate (G3P), which activates carbohydrate response element binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol, and to transcribe key genes of de novo lipogenesis. Mouse and human data establish G3P-ChREBP as a new mechanistic component of the Randle Cycle that contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) and forms part of a system that communicates metabolic states from liver to brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs, and suggest drug candidates for both lean MASLD and support of urea cycle function in CD.
2025-08-08 | GSE304958 | GEO
Project description:Biallelic inactivating mutations of the transcription factor 1 gene (TCF1), encoding hepatocyte nuclear factor 1a (HNF1a), were identified in 50% of hepatocellular adenomas (HCA) phenotypically characterized by a striking steatosis. To understand the molecular basis of this aberrant lipid storage, we performed a microarray transcriptome analysis validated by quantitative RT-PCR, western-blotting and lipid profiling. In mutated HCA, we showed a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle and fatty acid synthesis predicting elevated rates of lipogenesis. Moreover, the strong dowregulation of L-FABP suggests that impaired fatty acid trafficking may also contribute to the fatty phenotype. In addition, transcriptional profile analysis of the observed deregulated genes in non-HNF1a-mutated HCA as well as in non-tumor livers allowed us to define a specific signature of the HNF1a-mutated HCA. In theses tumors, lipid composition was dramatically modified according to the transcriptional deregulations identified in the fatty acid synthetic pathway. Surprisingly, lipogenesis activation did not operate through SREBP-1 and ChREBP that were repressed. We conclude that steatosis in HNF1a-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1a inactivation and that is independent of both SREBP-1 and ChREBP activation. Finally, our findings have potential clinical implications since lipogenesis can be efficiently inhibited by targeted therapies. Keywords: Disease state analysis
2007-05-01 | GSE7473 | GEO
Project description:To identify hepatic genes specifically regulated by fructose-activated ChREBPα. Fgf21 is one of the genes activated by fructose dependent on ChREBP.
2021-01-06 | GSE164321 | GEO
Project description:Activation of thermogenic brown adipose tissue (BAT) and inducible beige adipose tissue (BeAT) is triggered by environmental or metabolic stimuli, including cold ambient temperatures and nutrient stress. Thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase that is enriched in BAT, suppresses acute cold-induced thermogenesis. Here, we demonstrate that Them1 expression was induced in BAT and BeAT by the carbohydrate response element binding protein (ChREBP) in response to chronic cold exposure or to the activation of the integrated stress response (ISR). Under either condition, Them1 suppressed energy expenditure. Consequently, mice lacking Them1 in BAT and BeAT exhibited resistance to obesity and glucose intolerance induced by feeding with a high-fat diet. During chronic cold exposure or ISR activation, Them1 accumulated in the nucleus, where it interacted with ChREBP and reduced the expression of its target genes, including those encoding enzymes that mediate glycolysis and de novo lipogenesis. These findings demonstrate that in response to chronic cold- or nutrient-induced stress, the induction of Them1 by ChREBP limits thermogenesis while coordinately reducing glucose utilization and lipid biosynthesis through its distinct activities in the cytoplasm and nucleus. Targeted inhibition of Them1 may represent a potential therapeutic approach to increase the activity of BAT and BeAT to enhance energy expenditure in the management of obesity-associated metabolic disorders.
2025-02-19 | GSE280981 | GEO
Project description:Biallelic inactivating mutations of the transcription factor 1 gene (TCF1), encoding hepatocyte nuclear factor 1a (HNF1a), were identified in 50% of hepatocellular adenomas (HCA) phenotypically characterized by a striking steatosis. To understand the molecular basis of this aberrant lipid storage, we performed a microarray transcriptome analysis validated by quantitative RT-PCR, western-blotting and lipid profiling. In mutated HCA, we showed a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle and fatty acid synthesis predicting elevated rates of lipogenesis. Moreover, the strong dowregulation of L-FABP suggests that impaired fatty acid trafficking may also contribute to the fatty phenotype. In addition, transcriptional profile analysis of the observed deregulated genes in non-HNF1a-mutated HCA as well as in non-tumor livers allowed us to define a specific signature of the HNF1a-mutated HCA. In theses tumors, lipid composition was dramatically modified according to the transcriptional deregulations identified in the fatty acid synthetic pathway. Surprisingly, lipogenesis activation did not operate through SREBP-1 and ChREBP that were repressed. We conclude that steatosis in HNF1a-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1a inactivation and that is independent of both SREBP-1 and ChREBP activation. Finally, our findings have potential clinical implications since lipogenesis can be efficiently inhibited by targeted therapies. Keywords: Disease state analysis In a first experiment, microarray analyses were applied to 8 HNF1-alpha mutated HCA and their corresponding non-tumor livers using cDNA in-house manufactured arrays following a randomized and blinded unbalanced design. RNA labelling, hybridization and analysis of fluorescence was carried out, as described in [Graudens et al., Genome Biol 2006, 7: R19; PMID: 16542501], considering that uneven numbers of samples were randomly allocated to each of the engineers who were not aware of sample phenotypes. To assess data reproducibility and minimize dye bias effects, each of the samples was measured four times, twice with Cy3 and twice with Cy5. To ensure robustness and flexibility in data analysis, a reference design was used with a universal reference sample (Stratagene, USA) serving as a baseline for the comparisons of tumor samples. Hybridizations were performed onto an 11K human array (11K_VJF-ARRAY, GPL3282), which provides a genome-wide coverage of functional pathways. Raw data were obtained using the ArrayVisionM-bM-^DM-" 7.0 software (Imaging Research Inc., USA); the resulting 3.2x106 hybridization data points collected from 32 arrays were stored in a MIAME-compliant database and pre-processed for normalization and filtering as described in [Graudens et al., Genome Biol 2006, 7: R19; PMID: 16542501]. In a second experiment, HG-U133A Affymetrix GeneChipTM arrays were used to compare the expression profiles of 5 HNF1-alpha mutated HCA and 4 non related non-tumor livers. RNA labelling, hybridization and analysis were carried out following the manufacturerM-bM-^@M-^Ys instructions(Affymetrix, Santa Clara, CA). Raw data were obtained by using Microarray Suite 5.0 (MAS5) software, embedded in the Affymetrix GeneChip Operating Software (Santa Clara, USA); the resulting raw numerical data (CEL files) - available as supplementary files - collected from 9 Affymetrix GeneChips were pre-processed for normalization and filtering as described in [Rebouissou et al., J Biol Chem 2007, in press; PMID: 17379603]. A platform-dependant statistical comparison was performed considering HNF1 alpha-mutated HCA versus non tumor liver tissues, using multiple testing procedures to evaluate statistical significance for differentially expressed genes, as described in [Graudens et al., Genome Biol 2006, 7: R19; PMID: 16542501] and in the supplemental experimental procedures in [Rebouissou et al., J Biol Chem 2007, in press; PMID: 17379603]. Thus, a combined cross-platform analysis was done considering the UGCluster Identifiants as a common primary key (Unigene Build184-June05). Additional information on the procedures is provided in the supplemental experimental procedures in [Rebouissou et al., J Biol Chem 2007, in press; PMID: 17379603].
2007-05-01 | E-GEOD-7473 | biostudies-arrayexpress
Project description:ChREBP-mediated control of Them1 expression coordinates thermogenesis with glycolysis and lipogenesis
| PRJNA1181773 | ENA
Project description:Epidemiologic and animal studies implicate overconsumption of fructose in the development of non-alcoholic fatty liver disease, but the molecular mechanisms underlying fructose-induced chronic liver diseases remains largely unknown. We present evidence supporting the essential function of the lipogenic transcription factor ChREBP in mediating adaptation response to fructose and protecting against fructose-induced hepatotoxicity. High-fructose diet (HFrD) activates hepatic lipogenesis via a ChREBP-dependent manner in wildtype mice, while inducing steatohepatitis in Chrebp-KO mice. In Chrebp-KO mouse livers, HFrD reduces levels of molecular chaperones and activates the CHOP-dependent unfolded protein response, whereas administration of chemical chaperone or Chop shRNA rescues liver injury. Gene expression profiling revealed elevated expression of cholesterol biosynthesis genes in Chrebp-KO livers after HFrD, in parallel with increased abundance of nuclear SREBP2. genes expression were compared between livers of wildtype mice fed 70%-fructose-diet v.s. regular chow, and between livers of Chrebp-/- mice v.s. wildtype mice fed 70%-fructose-diet.
2017-03-21 | GSE96820 | GEO
Project description:Cancer-associated cachexia (CAC) is a multifactorial, metabolic wasting syndrome that coincides with cancer malignancies of multiple entities. CAC is characterized by progressive loss of muscle mass and adipose tissue and diminishes therapy responsiveness. Here, we show that the expression of FGF21 is induced in livers of tumor-bearing mice with CAC. FGF21 deficiency promotes weight loss, exacerbates adipose tissue wasting and increases systemic inflammation, pointing towards a protective role of FGF21 in CAC. In line, IL6-mediated STAT3 activation induces FGF21 expression in hepatocytes as well as adipocytes. FGF21 promotes anabolic signaling cascades, increases cellular glucose uptake in response to IL6 exposure and counteracts cytokine-mediated glycerol release, thereby opposing adipose tissue loss in CAC. Eventually, we find that FGF21 is increased in cancer patients with clinical CAC. Together, we reveal a protective role for FGF21 in experimental CAC and identify the protein as a potential biomarker in clinical cachexia.
2025-03-06 | GSE291252 | GEO
Project description:Intramuscular fat (IMF) content is one of the key factors affecting meat quality. Carbohydrate response element binding protein (ChREBP) can promote glucose metabolism and fat synthesis by activating the expression of glycolysis and lipogenesis-related genes, but its function and regulatory mechanism in IMF are still unclear. This study evaluated the correlation between TG content and ChREBP expression level in muscles of different species to reveal the relationship between ChREBP and IMF. RNA-seq analysis showed that overexpressing ChREBP in C2C12 cells can significantly up-regulate fatty acid synthesis pathways, while significantly down-regulate the expression levels of muscle development pathways and related genes. In vivo, we found that overexpression of ChREBP or activation by fructose significantly increased the triglyceride content of the tibialis anterior muscle (TA) and the IMF content of yellow feather chicken leg and breast muscle in mice. And lipidomics data also found that feeding fructose can change the lipid composition of yellow feather broiler breast muscle and improve the flavor substances. This study demonstrated that ChREBP is a key gene regulating IMF deposition, providing a new target for genetic selection and nutritional regulation of IMF content.
2024-08-08 | GSE228899 | GEO
Project description:This project investigated proline hydroxylation of ChREBP. Proline hydroxylation was investigated in flag-IP enriched protein extracts from ChREBP-flag overexpressing HEK293 cells (A) and in ChREBP-IP enriched mouse liver protein (male, C57BL6/J) (B).
2020-10-19 | PXD019137 | Pride