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

Abstract

BackgroundThe 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 (PPARα), which is abundantly expressed in enterocytes. In this study we examined the effects of acute nutritional activation of PPARα 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 PPARα-null mice. Treatment with the synthetic PPARα agonist WY14643 served as reference.ResultsWe identified 74 barrier genes that were PPARα-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 PPARα 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.ConclusionWe identified intestinal barrier genes that were PPARα-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 PPARα as an important factor controlling this key function, and underscores the importance of PPARα for nutrient-mediated gene regulation in intestine.

Kidney Function, Cholesterol Absorption and Remnant Lipoprotein Accumulation in Patients with Diabetes Mellitus

“…Although no precise mechanisms have been established, there are possible explanations. First, the Niemann-Pick C1-like 1 (NPC1L1) gene is reported to be downregulated by the activation of PPARα by its agonists, such as WY14643, eicosapentaenoic acid and docosahexaenoic acid 25) . Since the PPARα gene expression is decreased 26) and the n-3 polyunsaturated fatty acid profile is unfavorably altered 27) in patients with renal failure, intestinal cholesterol absorption via NPC1L1 could be increased in subjects with a decreased renal function.…”

DHA attenuates postprandial hyperlipidemia via activating PPARα in intestinal epithelial cells

“…Although it has been shown that PPAR ␣ activation in intestinal epithelial cells reduces postprandial hyperlipidemia, it was unknown whether postprandial hyperlipidemia is also improved by dietary lipids, which generally show lower PPAR ␣ activation than synthesized PPAR ␣ agonists ( 34,35 ). Previous studies have indicated that DHA increases mRNA expression levels of FA oxidation-related genes in intestinal epithelial cells ( 36,37 ) and that PUFAs including DHA enhance FA oxidation in hepatocytes ( 38 ). The present others have recently demonstrated that PPAR ␣ agonists improve postprandial hyperlipidemia through increasing FA oxidation in intestinal epithelial cells ( 15,16 ).…”

Study of the effects of dietary polyunsaturated fatty acids: Molecular mechanisms involved in intestinal inflammation

“…Transcription factors play an important role in IBD (Heimerl et al, 2006;Sanderson et al, 2008), for example NFB in regulating production and activation of pro-inflammatory cytokines (Mitsuyama et al, 2001). Nuclear receptors, a family of ligand-activated transcription factors, are most relevant in mediating the effect of nutrients and their metabolites on gene transcription (De Vogel-van den Bosch, 2008) and can directly or indirectly regulate genes of lipid metabolism and inflammatory signalling (Schmitz and Ecker, 2008). Nuclear receptors that regulate PUFA-induced gene expression include peroxisome proliferatoractivated receptors (PPAR, NR1C), liver X receptor (LXR, NR1H), retinoid X receptor (RXR, NR2B), hepatocyte nuclear factor 4 (HNF4), farnesoid X receptor (FXR, NR1H) and pregnane X receptor (PXR, NR1I) (Heimerl et al, 2006;Salter and Tarling, 2007;Sanderson et al, 2008).…”

“…for particular diseases or physiological states) of organisms with a sequenced genome, allowing investigators to establish gene networks and identify new genes involved in the investigated trait. Gene expression profiling, or transcriptomics, is widely used in both biomedical (Subramanian et al, 2005) and nutrition (Müller and Kersten, 2003) research to characterize molecular-pathway and network data in a variety of tissues in laboratory animals (Langmann et al, 2004;Rivera et al, 2006;Dommels et al, 2007) and in response to dietary treatments to predict a phenotypic outcome (De Vogel-van den Bosch et al, 2008;Nones et al, 2008;Sanderson et al, 2008).…”