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

<p>Abstract</p> <p>Background</p> <p>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 (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.</p> <p>Results</p> <p>We 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.</p> <p>Conclusion</p> <p>We 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.</p

The role of the small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J mice

<p>Abstract</p> <p>Background</p> <p>Obesity and insulin resistance are two major risk factors underlying the metabolic syndrome. The development of these metabolic disorders is frequently studied, but mainly in liver, skeletal muscle, and adipose tissue. To gain more insight in the role of the small intestine in development of obesity and insulin resistance, dietary fat-induced differential gene expression was determined along the longitudinal axis of small intestines of C57BL/6J mice.</p> <p>Methods</p> <p>Male C57BL/6J mice were fed a low-fat or a high-fat diet that mimicked the fatty acid composition of a Western-style human diet. After 2, 4 and 8 weeks of diet intervention small intestines were isolated and divided in three equal parts. Differential gene expression was determined in mucosal scrapings using Mouse genome 430 2.0 arrays.</p> <p>Results</p> <p>The high-fat diet significantly increased body weight and decreased oral glucose tolerance, indicating insulin resistance. Microarray analysis showed that dietary fat had the most pronounced effect on differential gene expression in the middle part of the small intestine. By overrepresentation analysis we found that the most modulated biological processes on a high-fat diet were related to lipid metabolism, cell cycle and inflammation. Our results further indicated that the nuclear receptors Ppars, Lxrs and Fxr play an important regulatory role in the response of the small intestine to the high-fat diet. Next to these more local dietary fat effects, a secretome analysis revealed differential gene expression of secreted proteins, such as Il18, Fgf15, Mif, Igfbp3 and Angptl4. Finally, we linked the fat-induced molecular changes in the small intestine to development of obesity and insulin resistance.</p> <p>Conclusion</p> <p>During dietary fat-induced development of obesity and insulin resistance, we found substantial changes in gene expression in the small intestine, indicating modulations of biological processes, especially related to lipid metabolism. Moreover, we found differential expression of potential signaling molecules that can provoke systemic effects in peripheral organs by influencing their metabolic homeostasis. Many of these fat-modulated genes could be linked to obesity and/or insulin resistance. Together, our data provided various leads for a causal role of the small intestine in the etiology of obesity and/or insulin resistance.</p

Induction of lipid oxidation by polyunsaturated fatty acids of marine origin in small intestine of mice fed a high-fat diet

Abstract Background Dietary polyunsaturated fatty acids (PUFA), in particular the long chain marine fatty acids docosahexaenoic (DHA) and eicosapentaenoic (EPA), are linked to many health benefits in humans and in animal models. Little is known of the molecular response to DHA and EPA of the small intestine, and the potential contribution of this organ to the beneficial effects of these fatty acids. Here, we assessed gene expression changes induced by DHA and EPA in the wildtype C57BL/6J murine small intestine using whole genome microarrays and functionally characterized the most prominent biological process. Results The main biological process affected based on gene expression analysis was lipid metabolism. Fatty acid uptake, peroxisomal and mitochondrial beta-oxidation, and omega-oxidation of fatty acids were all increased. Quantitative real time PCR, and -in a second animal experiment- intestinal fatty acid oxidation measurements confirmed significant gene expression differences and showed in a dose-dependent manner significant changes at biological functional level. Furthermore, no major changes in the expression of lipid metabolism genes were observed in the colon. Conclusion We show that marine n-3 fatty acids regulate small intestinal gene expression and increase fatty acid oxidation. Since this organ contributes significantly to whole organism energy use, this effect on the small intestine may well contribute to the beneficial physiological effects of marine PUFAs under conditions that will normally lead to development of obesity, insulin resistance and diabetes.</p

PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression-0

genes for each treatment. A) Overlap between OA, EPA and DHA, B) Overlap between EPA, DHA, and WY14643.<p><b>Copyright information:</b></p><p>Taken from "PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression"</p><p>http://www.biomedcentral.com/1471-2164/9/231</p><p>BMC Genomics 2008;9():231-231.</p><p>Published online 19 May 2008</p><p>PMCID:PMC2408604.</p><p></p

PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression-2

Ed genes in sections isolated along the proximal-distal axis of the small intestine from PPARα-null mice (white, open bars) and wild-type mice (black, closed bars) that were acutely treated (6 hr) with the 4 agonists (n = 4 per group). The small intestine was divided into 10 equal parts; part 1 refers to the most proximal part (duodenum), part 10 refers to the most distal (terminal ileum). Messenger RNA levels were standardized to cyclophilin; part 1 of the PPARα-null mice was arbitrarily set to 1. White bars represent the PPARα-null mice, black bars represent the wild-type mice. Significance of treated WT versus treated KO mice was determined per segment using an unpaired student's -test. * p-value < 0.05. Data are presented as mean ± standard error. A) fatty acid transport protein 4 (Fatp4). B) ATP-binding cassette, sub-family D, member 3 (Abcd3; ALD). C) cytochrome P450, family 2, subfamily c, polypeptide 65 (Cyp2c65). D) cytochrome P450, family 4, subfamily f, polypeptide 16 (Cyp4f16).<p><b>Copyright information:</b></p><p>Taken from "PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression"</p><p>http://www.biomedcentral.com/1471-2164/9/231</p><p>BMC Genomics 2008;9():231-231.</p><p>Published online 19 May 2008</p><p>PMCID:PMC2408604.</p><p></p

PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression-1

Lated along the proximal-distal axis of the small intestine of wild-type mice that received the control diet (white, open bars), or were acutely treated (6 hr) with WY14643 (black, closed bars) (n = 4 per group). Small intestines were divided into 10 equal parts; part 1 refers to the most proximal part (duodenum), part 10 refers to the most distal (terminal ileum). Messenger RNA levels were standardized to cyclophilin; part 1 of the non-treated mice was arbitrarily set to 1. Significance of control versus treated wild-type mice was determined per segment using an unpaired student's -test. * p-value < 0.05. Data are presented as mean ± standard error.<p><b>Copyright information:</b></p><p>Taken from "PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression"</p><p>http://www.biomedcentral.com/1471-2164/9/231</p><p>BMC Genomics 2008;9():231-231.</p><p>Published online 19 May 2008</p><p>PMCID:PMC2408604.</p><p></p

The role of the small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J mice-7

Ly expressed genes with fold changes < -1.5 and > +1.5 in at least one week of diet intervention. Red and green boxes indicate a significant up- and down-regulation, respectively. NC = no change, A = absent.<p><b>Copyright information:</b></p><p>Taken from "The role of the small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J mice"</p><p>http://www.biomedcentral.com/1755-8794/1/14</p><p>BMC Medical Genomics 2008;1():14-14.</p><p>Published online 6 May 2008</p><p>PMCID:PMC2396659.</p><p></p