Dataset Information

PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression.

ABSTRACT:

Background

The selective absorption of nutrients and other food constituents in the small intestine is mediated by a group of transport proteins and metabolic enzymes, often collectively called 'intestinal barrier proteins'. An important receptor that mediates the effects of dietary lipids on gene expression is the peroxisome proliferator-activated receptor alpha (PPARalpha), which is abundantly expressed in enterocytes. In this study we examined the effects of acute nutritional activation of PPARalpha on expression of genes encoding intestinal barrier proteins. To this end we used triacylglycerols composed of identical fatty acids in combination with gene expression profiling in wild-type and PPARalpha-null mice. Treatment with the synthetic PPARalpha agonist WY14643 served as reference.

Results

We identified 74 barrier genes that were PPARalpha-dependently regulated 6 hours after activation with WY14643. For eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and oleic acid (OA) these numbers were 46, 41, and 19, respectively. The overlap between EPA-, DHA-, and WY14643-regulated genes was considerable, whereas OA treatment showed limited overlap. Functional implications inferred form our data suggested that nutrient-activated PPARalpha regulated transporters and phase I/II metabolic enzymes were involved in a) fatty acid oxidation, b) cholesterol, glucose, and amino acid transport and metabolism, c) intestinal motility, and d) oxidative stress defense.

Conclusion

We identified intestinal barrier genes that were PPARalpha-dependently regulated after acute activation by fatty acids. This knowledge provides a better understanding of the impact dietary fat has on the barrier function of the gut, identifies PPARalpha as an important factor controlling this key function, and underscores the importance of PPARalpha for nutrient-mediated gene regulation in intestine.

SUBMITTER: de Vogel-van den Bosch HM

PROVIDER: S-EPMC2408604 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression.

de Vogel-van den Bosch Heleen M HM Bünger Meike M de Groot Philip J PJ Bosch-Vermeulen Hanneke H Hooiveld Guido J E J GJ Müller Michael M

BMC genomics 20080519

<h4>Background</h4>The selective absorption of nutrients and other food constituents in the small intestine is mediated by a group of transport proteins and metabolic enzymes, often collectively called 'intestinal barrier proteins'. An important receptor that mediates the effects of dietary lipids on gene expression is the peroxisome proliferator-activated receptor alpha (PPARalpha), which is abundantly expressed in enterocytes. In this study we examined the effects of acute nutritional activati ...[more]

PMID: 18489776

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Project description:Background: The selective absorption of nutrients and other food constituents in the small intestine is mediated by a group of transport proteins and metabolic enzymes, often collectively called âintestinal barrier proteinsâ. An important receptor that mediates the effects of dietary lipids on gene expression is the peroxisome proliferator-activated receptor alpha (PPARÎ±), which is abundantly expressed in enterocytes. In this study we examined the effects of acute nutritional activation of PPARÎ± on expression of genes encoding intestinal barrier proteins. To this end we used triacylglycerols composed of identical fatty acids in combination with gene expression profiling in wild-type and PPARÎ±-null mice. Treatment with the synthetic PPARÎ± agonist WY14643 served as reference. Results: We identified 74 barrier genes that were PPARÎ±-dependently regulated 6 hours after activation with WY14643. For eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and oleic acid (OA) these numbers were 46, 41, and 19, respectively. The overlap between EPA-, DHA-, and WY14643-regulated genes was considerable, whereas OA treatment showed limited overlap. Functional implications inferred form our data suggested that nutrient-activated PPARÎ± regulated transporters and phase I/II metabolic enzymes were involved in a) fatty acid oxidation, b) cholesterol, glucose, and amino acid transport and metabolism, c) intestinal motility, and d) oxidative stress defense. Conclusion: We identified intestinal barrier genes that were PPARÎ±-dependently regulated after acute activation by fatty acids.This knowledge provides a better understanding of the impact dietary fat has on the barrier function of the gut, identifies PPARÎ± as an important factor controlling this key function, and underscores the importance of PPARÎ± for nutrient-mediated gene regulation in intestine. Experiment Overall Design: Pure bred wild-type (129S1/SvImJ) and PPARÎ±-null (129S4/SvJae) mice were treated for 6 hours with the synthetic triacylglycerols triolein [oleic acid (OA, C18:1)], trieicosapentaenoin [eicosapentaenoic acid (EPA, C20:5)] or tridocosahexaenoin [ocosahexaenoic acid (DHA, C22:6)], or the potent PPARÎ± agonist WY14,643. Two weeks before the start of the experiment, mice were put on a modified AIN76A diet, in which corn oil was replaced by olive oil. At the day of the experiment mice were fasted for four hours. At 9 AM mice were dosed by oral gavage with 400 Âµl of a 0.1% WY14643 suspension in 0.5% carboxymethyl cellulose, or 400 Âµl of the synthetic triacylglycerols. Six hours after the gavage the mice were anaesthetized, small intestines were removed, flushed with ice-cold PBS and remaining fat and pancreatic tissue was carefully removed. Total RNA was then isolated. RNA of 4-5 biological replicates was hybridized to Affymetrix 430-2.0 plus arrays. Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.

Project description:BackgroundGut integrity is compromised in abdominal sepsis with increased cellular apoptosis and altered barrier permeability. Intestinal epithelial cells (IEC) form a physiochemical barrier that separates the intestinal lumen from the host's internal milieu and is strongly involved in the mucosal inflammatory response and immune response. Recent research indicates the involvement of the stimulator of interferons genes (STING) pathway in uncontrolled inflammation and gut mucosal immune response.MethodsWe investigated the role of STING signaling in sepsis and intestinal barrier function using intestinal biopsies from human patients with abdominal sepsis and with an established model of abdominal sepsis in mice.FindingsIn human abdominal sepsis, STING expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls, and the degree of STING expression in the human intestinal lamina propria correlated with the intestinal inflammation in septic patients. Moreover, elevated STING expression was associated with high levels of serum intestinal fatty acid binding protein that served as a marker of enterocyte damage. In mice, the intestinal STING signaling pathway was markedly activated following the induction of sepsis induced by cecal ligation perforation (CLP). STING knockout mice showed an alleviated inflammatory response, attenuated gut permeability, and decreased bacterial translocation. Whereas mice treated with a STING agonist (DMXAA) following CLP developed greater intestinal apoptosis and a more severe systemic inflammatory response. We demonstrated that mitochondrial DNA (mtDNA) was released during sepsis, inducing the intestinal inflammatory response through activating the STING pathway. We finally investigated DNase I administration at 5 hours post CLP surgery, showing that it reduced systemic mtDNA and inflammatory cytokines levels, organ damage, and bacterial translocation, suggesting that inhibition of mtDNA-STING signaling pathway protects against CLP-induced intestinal barrier dysfunction.InterpretationOur results indicate that the STING signaling pathway can contribute to lethal sepsis by promoting IEC apoptosis and through disrupting the intestinal barrier. Our findings suggest that regulation of the mtDNA-STING pathway may be a promising therapeutic strategy to promote mucosal healing and protect the intestinal barrier in septic patients. FUND: National Natural Science Foundation of China.

Dataset Information

PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression.

Background

Results

Conclusion

Publications

PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression.

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