Alterations in intestinal fatty acid metabolism in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) constitutes a severe intestinal disorder in developed countries with increasing incidence worldwide. Upcoming evidence indicates an important role of intestinal epithelial barrier function in the development of IBD. Fatty acids exert nutritional and protective effects on enterocytes, serve as activators of transcription and constitute precursors of inflammatory mediators. The aim of this study was to investigate differential regulation of genes involved in fatty acid uptake and endogenous fatty acid biosynthesis in IBD. Mucosal biopsy specimens from non-affected regions of the intestine were subjected to DNA microarray analysis. Gene array analysis revealed a variety of genes involved in fatty acid uptake and synthesis to be differentially expressed in ileum and colon of selected IBD patients. To verify these results, real-time RT-PCR was performed for selected regulated candidate genes in larger IBD sample numbers. In single biopsy analysis long chain acyl-CoA synthetase (ACSL) 1 and 4 were upregulated in IBD (P<0.05), while a significant decrease in fatty acid synthase expression was found in ileum and colon of ulcerative colitis patients (P<0.001). Expression of the transcription factor liver X receptor (LXR) which was previously shown to induce fatty acid synthase gene expression was not altered on mRNA level in IBD. However, in cell culture experiments using the human intestinal cell line LS174T induction of fatty acid synthase by the LXR ligand T0901317 was inhibited by TNFalpha. Moreover, these experiments indicated a decrease of LXR protein levels by TNFalpha treatment. These data suggest that the decrease of fatty acid synthase expression in ulcerative colitis patients could be at least partially due to a loss of LXR expression and function in the presence of pro-inflammatory cytokines. Observed alterations in expression of genes of fatty acid metabolism may contribute to the pathophysiology of ulcerative colitis.

Spontaneous development of intestinal and colonic atrophy and inflammation in the carnitine-deficient jvs (OCTN2−/−) mice

“…Fatty acids not only exert nutritional effect on the gut but also are protective for enterocytes, serve as activators of transcription, and constitute precursors of inflammatory mediators [40,41]. Fatty acid metabolism related genes are differentially regulated in IBD and are affected by presence of cytokines like TNFα and PPAR-γ ligands in the gut lumen [42].…”

Long-Chain Acyl-Coa Synthetases And Fatty Acid Channeling

“…Although the causality between the change of ACSL isoforms and specific diseases has not been established, these observations indicate that ACSL isoforms are linked to metabolic changes or FA demand under several pathological conditions. For example, in patients with inflammatory bowel disease, the increase of Acsl1 and Acsl4 mRNA in the terminal ileum and colon might provide acyl-CoAs for the synthesis of phospholipids; these can serve as precursors for inflammatory mediators or support membrane integrity of the affected intestine [74].…”

“…Although the causality between the change of ACSL isoforms and specific diseases has not been established, these observations indicate that ACSL isoforms are linked to metabolic changes or FA demand under several pathological conditions. For example, in patients with inflammatory bowel disease, the increase of Acsl1 and Acsl4 mRNA in the terminal ileum and colon might provide acyl-CoAs for the synthesis of phospholipids; these can serve as precursors for inflammatory mediators or support membrane integrity of the affected intestine [74].Despite the presence of other ACSL isoforms in brain, human ACSL4 is associated with depression [75] and mutations in the human Acsl4 gene that decrease 20:4-CoA synthetase activity cause a form of X-linked mental retardation [76][77][78]. The effect of these mutations suggests that ACSL4 is critical for normal brain function, perhaps related to its preference for long-chain polyunsaturated FAs [35], which are enriched in brain phospholipids.…”

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

“…Long chain fatty acids have been known to contribute to enterocyte function and pathology (Heimerl et al, 2006). In particular, long chain n-3 and n-6 PUFA are incorporated into biological membranes and regulate such processes as energy metabolism, eicosanoid production, signal transduction and regulation of gene expression (Mutch et al, 2005;Deckelbaum et al, 2006).…”