Mechanisms of lipid malabsorption in Cystic Fibrosis: the impact of essential fatty acids deficiency

Peretti, Noël; Marcil, Valérie; Drouin, Éric; Lévy, Émile

doi:10.1186/1743-7075-2-11

Cited by 62 publications

(27 citation statements)

References 260 publications

(278 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our findings have, at least, contributed to exclude CFTR as a causative factor for defective mucosal uptake and intracellular transport of long-chain FA as well as impaired intra-enterocyte handling of lipids. Of interest, our previous studies reported the significant contribution of the permanent essential FA deficiency to CF malabsorption by interfering with intra-enterocyte lipid transport [15] , [57] .…”

Section: Discussionmentioning

confidence: 99%

CFTR Depletion Results in Changes in Fatty Acid Composition and Promotes Lipogenesis in Intestinal Caco 2/15 Cells

et al. 2010

View full text Add to dashboard Cite

BackgroundAbnormal fatty acid composition (FA) in plasma and tissue lipids frequently occurs in homozygous and even in heterozygous carriers of cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The mechanism(s) underlying these abnormalities remained, however, poorly understood despite the potentially CFTR contributing role.Methodology/Principal FindingsThe aim of the present study was to investigate the impact of CFTR depletion on FA uptake, composition and metabolism using the intestinal Caco-2/15 cell line. shRNA-mediated cftr gene silencing induced qualitative and quantitative modifications in FA composition in differentiated enterocytes as determined by gas-liquid chromatography. With the cftr gene disruption, there was a 1,5 fold increase in the total FA amount, largely attributable to monounsaturated and saturated FA compared to controls. The activity of delta-7 desaturase, estimated by the 16:1(n-7)/16:0, was significantly higher in knockdown cells and consistent with the striking elevation of the n-7 FA family. When incubated with [14C]-oleic acid, CFTR-depleted cells were capable of quick incorporation and export to the medium concomitantly with the high protein expression of L-FABP known to promote intracellular FA trafficking. Accordingly, lipoprotein vehicles (CM, VLDL, LDL and HDL), isolated from CFTR knockdown cells, exhibited higher levels of radiolabeled FA. Moreover, in the presence of [14C]-acetate, knockdown cells exhibited enhanced secretion of newly synthesized phospholipids, triglycerides, cholesteryl esters and free FA, thereby suggesting a stimulation of the lipogenic pathway. Conformably, gene expression of SREBP-1c, a key lipogenic transcription factor, was increased while protein expression of the phosphorylated and inactive form of acetylCoA carboxylase was reduced, confirming lipogenesis induction. Finally, CFTR-depleted cells exhibited lower gene expression of transcription factors (PPARα, LXRα, LXRβ and RXRα).Conclusions/SignificanceCollectively, our results indicate that CFTR depletion may disrupt FA homeostasis in intestinal cells through alterations in FA uptake and transport combined with stimulation of lipogenesis that occurs by an LXR/RXR-independent mechanism. These findings exclude a contributing role of CFTR in CF-associated fat malabsorption.

show abstract

Section: Discussionmentioning

confidence: 99%

CFTR Depletion Results in Changes in Fatty Acid Composition and Promotes Lipogenesis in Intestinal Caco 2/15 Cells

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Nutrient malabsorption, intestinal dysfunction, and malnutrition are among the most important and troubling early manifestations of CF. The malabsorption of fats in CF is largely due to inadequate secretion of the enzyme pancreatic lipase into the intestinal lumen, with contributions from other mechanisms 27 , resulting not only in fatty stools, but also to loss of nutritionally important dietary fat and fat-soluble vitamins. Our results suggest a model wherein excess dietary fat within the CF GI lumen also plays an indirect role in the intestinal inflammation that characterizes childhood CF GI disease by selecting for microbiota that preferentially degrade the SCFAs butyrate and propionate, important molecules for enteric health ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Metagenomic evidence for taxonomic dysbiosis and functional imbalance in the gastrointestinal tracts of children with cystic fibrosis

Manor

Levy

Pope

et al. 2016

Sci Rep

107

160

View full text Add to dashboard Cite

Cystic fibrosis (CF) results in inflammation, malabsorption of fats and other nutrients, and obstruction in the gastrointestinal (GI) tract, yet the mechanisms linking these disease manifestations to microbiome composition remain largely unexplored. Here we used metagenomic analysis to systematically characterize fecal microbiomes of children with and without CF, demonstrating marked CF-associated taxonomic dysbiosis and functional imbalance. We further showed that these taxonomic and functional shifts were especially pronounced in young children with CF and diminished with age. Importantly, the resulting dysbiotic microbiomes had significantly altered capacities for lipid metabolism, including decreased capacity for overall fatty acid biosynthesis and increased capacity for degrading anti-inflammatory short-chain fatty acids. Notably, these functional differences correlated with fecal measures of fat malabsorption and inflammation. Combined, these results suggest that enteric fat abundance selects for pro-inflammatory GI microbiota in young children with CF, offering novel strategies for improving the health of children with CF-associated fat malabsorption.

show abstract

“…Similarly, intestinal epithelial cells from CF patients bearing the F508del-CFTR mutation exhibited an impressive derangement of cellular proteostasis, with OxS [ 61 ]. On the other hand, regarding the formation of intestinal lipoproteins, the literature is very poor and is limited to describing the malabsorption of fats, essentially caused by digestive defects related to pancreatic lipase, bile acids and bicarbonate [ 62 ]. The impact of CFTR deficiency on intra-enterocyte processes has been very little investigated.…”

Section: Discussionmentioning

confidence: 99%

CFTR Deletion Confers Mitochondrial Dysfunction and Disrupts Lipid Homeostasis in Intestinal Epithelial Cells

et al. 2018

View full text Add to dashboard Cite

Background: Cystic Fibrosis (CF) is a genetic disease in which the intestine exhibits oxidative and inflammatory markers. As mitochondria are the central source and the main target of reactive oxygen species, we hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) defect leads to the disruption of cellular lipid homeostasis, which contributes to mitochondrial dysfunction. Methods. Mitochondrial functions and lipid metabolism were investigated in Caco-2/15 cells with CFTR knockout (CFTR-/-) engineered by the zinc finger nuclease technique. Experiments were performed under basal conditions and after the addition of the pro-oxidant iron-ascorbate (Fe/Asc) complex. Results. Mitochondria of intestinal cells with CFTR-/-, spontaneously showed an altered redox homeostasis characterised by a significant decrease in the expression of PPARα and nuclear factor like 2. Consistent with these observations, 8-oxoguanine-DNA glycosylase, responsible for repair of ROS-induced DNA lesion, was weakly expressed in CFTR-/- cells. Moreover, disturbed fatty acid β-oxidation process was evidenced by the reduced expression of CPT1 and acyl-CoA dehydrogenase long-chain in CFTR-/- cells. The decline of mitochondrial cytochrome c and B-cell lymphoma 2 expression pointing to magnified apoptosis. Mitochondrial respiration was also affected as demonstrated by the low expression of respiratory oxidative phosphorylation (OXPHOS) complexes and a high adenosine diphosphate/adenosine triphosphate ratio. In contrast, the FAS and ACC enzymes were markedly increased, thereby indicating lipogenesis stimulation. This was associated with an augmented secretion of lipids, lipoproteins and apolipoproteins in CFTR-/- cells. The addition of Fe/Asc worsened while butylated hydroxy toluene partially improved these processes. Conclusions: CFTR silencing results in lipid homeostasis disruption and mitochondrial dysfunction in intestinal epithelial cells. Further investigation is needed to elucidate the mechanisms underlying the marked abnormalities in response to CFTR deletion.

show abstract

Mechanisms of lipid malabsorption in Cystic Fibrosis: the impact of essential fatty acids deficiency

Cited by 62 publications

References 260 publications

CFTR Depletion Results in Changes in Fatty Acid Composition and Promotes Lipogenesis in Intestinal Caco 2/15 Cells

CFTR Depletion Results in Changes in Fatty Acid Composition and Promotes Lipogenesis in Intestinal Caco 2/15 Cells

Metagenomic evidence for taxonomic dysbiosis and functional imbalance in the gastrointestinal tracts of children with cystic fibrosis

CFTR Deletion Confers Mitochondrial Dysfunction and Disrupts Lipid Homeostasis in Intestinal Epithelial Cells

Contact Info

Product

Resources

About