Regulation of Gene Expression by Fatty Acids for IBD

Dietary fat has several essential functions in the human body. First, it functions as a supply of energy and structural components for the cells and second, it functions as a regulator of gene expression, which influences lipid, carbohydrate, and protein metabolism, along with cell growth and differentiation. The effects of fatty acids on gene expression are cell-specific and influenced by structure and metabolism. Fatty acids interact with the genome. They regulate PPAR, and the activity or nuclear abundance like SREBP. Fatty acids bind directly with one another to regulate gene expression.

What’s the role of fatty acids towards disease pathogenesis?

Alternately, fatty acids behave on gene expression through their effects on specific enzyme-mediated pathways, such as cyclooxygenase, lipoxygenase, protein kinase C, or sphingomyelinase signal transduction pathways, or through pathways that require changes in tissue lipid to lipid raft composition which affect G-protein receptor or tyrosine kinase-linked receptor signaling. Additional definition of these fatty acid-regulated pathways can offer insight into the role dietary fat plays in human health as well as the beginning and growth of many chronic diseases, such as coronary artery disease and atherosclerosis, dyslipidemia and inflammation, obesity and diabetes, cancer, major depressive disorders, and schizophrenia. The effects of fatty acids on gene expression, however, have been widely described on inflammatory bowel disease, or IBD.

Fatty Acids and Gene Expression

The effect of fatty acids on gene expression was previously determined to result mainly from changes in tissue phospholipids or eicosanoid production. More recently, the discovery of nuclear receptors; such as peroxisome proliferator-activated receptors, or PPARs, and their regulation by fatty acids, has significantly altered this view. PPARs are ligand activated transcription factors that upon heterodimerization with the retinoic X receptor, or RXR, comprehend PPAR response elements in the promoter regions of different genes, that have an impact on gene transcription. PPARs bind various ligands, including nonsteroidal anti inflammatory medications, or NSAIDS, thiazolidinediones (antidiabetic agents) along with PUFAs and their metabolites. Several subtypes of the receptor are recognized (α,δ,γ) and are expressed in several different cells. PPARγ is extracted from the adrenal gland, with most of its numbers observed in the colon.

PPARγ has been implicated in the regulation of inflammation, and it has become a potential therapeutic goal in treating inflammatory diseases, such as IBD. It has been suggested that people with ulcerative colitis, or UC, have a mucosal deficit in PPARγ that could bring about the development of their own disease. Analysis of the mRNA and proteins within colonic biopsies demonstrated decreased levels of PPARγ in UC patients in comparison with Crohn’s patients or healthy subjects.

Using colon cancer lines, it has been demonstrated that PPAR ligands attenuate cytokine gene expression by inhibiting NF-κB via an IκB determined mechanism. Further research studies imply that PPAR activators inhibit COX2 by interruption with NF-κB. PPARs impair interactions with STAT and other signaling pathways as well as the AP-1 signaling pathway.

Animal studies support using PPAR for autoimmune inflammation. Inflammation decreased by ligands for PPAR. The direction of PPAR and RXR agonists synergistically reduced TNBS-induced colitis, together with improved macroscopic and histologic scores, reductions in TNFα and IL-1β mRNA, and diminished NF-κB DNA binding actions. Though clinical evidence is limited, the results of an open source research study with rosiglitazone, a PPARγ ligand as therapy for UC, demonstrated that 27 percent of patients achieved remission after 12 weeks of therapy. Thus, PPARγ ligands may represent a cure for UC, where double-blind, placebo-controlled, randomized trials have been warranted.

Of substantial curiosity, the capability to regulate PPAR nutritionally has been examined. Dietary PUFA demonstrated an impact during the regulation of transcription factors on gene expression. Fatty acid regulation of PPAR was originally detected by Gottlicher et al.. A choice of fatty acids, like eicosanoids, and metabolites are proven to activate PPAR. Both PPARα and PPARγ bind mono- and polyunsaturated fatty acids. Thus, the anti inflammatory effects of n3 PUFA may entail PPAR and its interruption with NFκB, rather than only changes in eicosanoid synthesis.

Conclusion

Fatty acids regulate gene expression involved in lipid and energy metabolism. Polyunsaturated fatty acids, or PUFA, though not saturated or polyunsaturated FA, suppress the induction of lipogenic genes by inhibiting their expression and processing of SREBP-1c. This impact of PUFA suggests that SREBP-1c may regulate the synthesis of fatty acids to glycerolipids, among others. PPARalpha has a role in the adaptation to fasting by inducing ketogenesis in mitochondria. During fasting, fatty acids are considered as ligands of PPARalpha. Dietary PUFA, except for 18:2 n-6, are extremely prone to induce fatty acid oxidation enzymes through PPARalpha because of specific mechanisms. Signaling functions of PPARalpha pPARalpha is needed for controlling the synthesis of fatty acids. Further research is needed to conclude the full effects of fatty acids in relation to the regulation of transcription factors for gene expression in inflammatory bowel disease, or IBD.

Information referenced from the National Center for Biotechnology Information (NCBI) and the National University of Health Sciences. The scope of our information is limited to chiropractic and spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

By Dr. Alex Jimenez

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