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Altered de novo lipogenesis contributes to low adipose stores in cystic fibrosis mice.

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE33319 | GEO | 2012/06/18

SECONDARY ACCESSION(S): PRJNA149291

REPOSITORIES: GEO

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Altered de novo lipogenesis contributes to low adipose stores in cystic fibrosis mice.

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

Characterization of an in vitro steatosis model for modelling the activated de novo lipogenesis

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

A bacteria-derived tetramerized protein ameliorates nonalcoholic steatohepatitis (NASH) in mice via binding and relocating acetyl-coA carboxylase

Project description:Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drug targeting the catalytic activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the DNL process, has been approved by FDA. Whether cytosolic ACC1 can be regulated spatially is unknown. Herein, we found that streptavidin, which is a bacterium derived tetrameric protein, forms cytosolic condensates and efficiently induce a spatial re-localization of ACC1 in liver cells, concomitant with inhibited lipid accumulation. Both SA tetrameric structure and multivalent protein interaction are required for condensates formation. Interestingly, the condensates are further characterized as gel-like membraneless organelle (SAGMO) and significantly restrict the cytosolic dispersion of ACC1 and fatty acid synthase (FASN). Notably, AAV mediated delivery of SA partially blocks mice liver DNL and ameliorate NASH without eliciting hypertriglyceridemia. In summary, our study demonstrates that insulating lipogenesis-related proteins by SAGMO might be effective for NASH treatment.

2023-10-25 | GSE245797 | GEO

Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use

Project description:Metabolic diseases are closely linked to aberrant synthesis of endogenous fatty acids in the liver, called de novo lipogenesis (DNL), which is mediated by the enzyme fatty acid synthase (FASN). The composition of complex lipids consists of saturated or monosaturated fatty acids, which can be endogenously produced, and polyunsaturated fatty acids (PUFA), which are strictly dietary. Compositional differences between individuals are insufficiently understood and may influence the onset and progression of metabolic and cardiovascular diseases. Here we show that DNL critically determines the use of dietary PUFA. A patient with a hypofunctional heterozygous de novo Arg2177Cys variant in FASN exhibited an elevated composition of PUFA, which was phenocopied by pharmacological inhibition of FASN with TVB-2640 in patients with nonalcoholic steatohepatitis (NASH). In mice, the incorporation rate of supplemented omega-3 PUFA during an obesogenic diet was increased by genetic or pharmacologic reduction of DNL. Mechanistically, we show that the FASN variant exhibited a cysteine-dependent, non-enzymatic acetylation of FASN, which resulted in hyperubiquitinylation and decreased protein stability. Our study further reveals that PUFA storage is an active, enzymatic process controlled by FASN, diacylglycerol O-acyltransferase 2 (DGAT2) and MFSD2A, a membrane-transport protein, and that combining FASN inhibition and PUFA supplementation exerts additive beneficial metabolic effects. These findings provide evidence that the success of PUFA supplementation may depend on the rate of endogenous DNL and that combined PUFA supplementation and FASN inhibition may be a promising approach targeting metabolic disease.

2023-12-19 | PXD045908 | Pride

Gene expression in CF-vs-non CF human airway epithelial cell samples obtained by nasal brushing.

Project description:A small-scale whole genome microarray study of gene expression in human native nasal epithelial cells from F508del-CFTR homozygous CF patients and non-CF controls. We used the custom designed Affymetrix HsAirwaya520108F Arrays to compare gene expression in 5 CF and 5 non CF nasal epithelial cell samples.

2013-04-10 | GSE40445 | GEO

Expression data from human bronchial epithelial cells

2016-07-01 | GSE70442 | GEO

Expression data from livers of high fat fed rats treated with ACC inhibitor PF-04923503

Project description:Fundamental alterations in lipid metabolism including increased rates of de novo lipogenesis (DNL), reduced fatty acid oxidation (FAOX) and ectopic lipid accumulation in skeletal muscle and liver are characteristic of type 2 diabetes mellitus (T2DM) and have been hypothesized to directly contribute to the molecular pathogenesis of the disease. Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, the rate limiting substrate for DML and key regulator of FAOX. ACC inhibitors have the potential to pharmacologically rebalance these metabolic alterations. In the present study, PF-04923503, a potent dual ACC1/ACC2 inhibitor with properties optimized for in vivo studies, suppressed levels of malonyl-CoA in primary hepatocytes, rat skeletal muscle ex vivo, as well as rat liver and skeletal muscle in vivo. This impact on malonyl-CoA was directly correlated (r2>0.9) with reduced hepatic DNL and inversely correlated with incresed rates of FAOX (r2>0.9). The pharmacological eccfect of PF-04923503 persisted with chronic treatment. High-fat fed rats treated with PF-04923503 for six weeks showed dose-dependent reductions in skeletal muscle and liver lipid accumulation. These changes correlated directly with markers for improved insulin sensitization. However, liver gene expression indicates that pharmacological inhibition results in compensation by up-regualtion of genes involved with DNL. These results suggest that pharmacological inhibition of ACC may have utility to help rebalance metabolic abnormalities in T2DM and improve insulin sensitivity. Differential gene expression was assessed by Affymetrix microarray experiments for 15 liver samples across 3 pharmacological treatment groups (vehicle control 0.5% methylcellulose had 5 samples, PF-04923503 10mpk had 5 samples, PF-04923503 30mpk had 5 samples)

2011-06-30 | E-GEOD-28058 | biostudies-arrayexpress

Expression data from human bronchial epithelial cells

Project description:The F508del mutation, the most frequent in cystic fibrosis (CF), impairs the maturation of the CFTR chloride channel. The F508del defect can be partially overcome at low temperature (27 Â°C) or with pharmacological correctors. The rescue elicited by low temperature may involve a direct stabilization of mutant CFTR protein and/or a change in cell transcriptome that creates a more favorable proteostasis environment. To assess the effect of low temperature on gene expression we investigated the transcriptome of bronchial epithelial cells derived from CF with F508del mutation. Cells were kept under control conditions or incubated at 27 Â°C. Microarray data indicate that hypothermia induces a profound and global change in gene expression that may be in part responsible for rescue of F508del-CFTR. Bronchial epithelial cells from cystic fibrosis patients homozygotes for F508del mutation were isolated. Cells differentiated as epithelial monolayers on porous membranes (Snapwell inserts) were incubated for 24 hours at 27 Â°C or kept under control conditions. Rescue of mutant CFTR channel by low temperature was checked by measuring transepithelial chloride currents with the Ussing chamber technique. Total RNA was extracted from treated and control cells to assess changes in gene expression with microarrays.

2016-07-01 | E-GEOD-70442 | biostudies-arrayexpress

Nucleoside-Diphosphate Kinase 1 and 2 are master regulators of a liver protective response to high fat diet [RNA-seq]

Project description:Fatty acid homeostasis is critical for normal cellular physiology and leads to severe diseases when deregulated. Here we report Nucleoside-Diphosphate Kinase 1 and 2 (NME1/2) as major cellular co-enzyme A (CoA) and acetyl-CoA binding proteins and negative regulators of de novo lipogenesis (DNL). Structural studies demonstrate that Nme1 recognizes CoA through its nucleotide moiety, which competes for binding with ADP/ATP. By using a Nme2 ko mouse model, we observe that NME2 is required for the gene transcriptional response to a high fat diet (HFD) in liver cells, leading to a repression of lipogenesis and the activation of a protective gene response. Nme2 ko mice submitted to a HFD challenge are unable to repress key lipogenic genes, resulting in an excessive triglyceride synthesis and liver steatosis. Mechanistically, the NME2-dependent down-regulation of DNL in response to HFD changes the balance for the use of acetyl-CoA between the competing paths of acetylation and DNL, thereby increasing TSS-targeted histone acetylation and gene activation. A structure-guided generation of a NME1 mutant, with intact NDK activity, but unable to bind CoA, directly demonstrates the functional impact of acetyl-CoA/CoA binding by NME1/2 in repressing DNL. Taken together, these findings highlight a yet unknow protective liver response to HFD, regulated by multi-ligand binding proteins which act as direct sensors for the cellular levels of NDP/NTP and CoA/acetyl-CoA.

2023-08-01 | GSE198686 | GEO