Induction of arachidonate 12‐lipoxygenase (Alox15) alters intestinal lipid homeostasis during iron‐deficiency

Abstract

Gene chip analyses were performed with intestinal mucosa from iron‐deficient and Belgrade (i.e. Dmt1‐deficient) rats. Computational analysis, clustering algorithms and gene ontology analysis revealed enrichment of genes related to lipid metabolism. Most striking was induction of arachidonate 12‐lipoxygenase (Alox15); Alox15 metabolizes polyunsaturated fatty acids (PUFAs) to biologically active lipid mediators. qRT‐PCR studies demonstrated induction of Alox15 throughout the length of the intestine and in the liver of Fe‐deficient (up to 100‐fold) and Belgrade rats. IHC studies showed expression of Alox15 in intestinal and colonic epithelial cells with much stronger expression in the iron‐deficients. We also noted greatly increased PUFA metabolite levels in the iron‐deficient intestine, indicative of lipid peroxidation; the overall pattern of lipid peroxide products was consistent with Alox15 activity. We have thus documented significant regulation of Alox15 by iron in the mammalian small intestine and concomitant alterations in lipid homeostasis. These findings may be of significance as Alox15 may be involved in intestinal epithelial cell differentiation and proliferation. Induction of Alox15 may also have relevance to chronic inflammatory states, such as Inflammatory Bowel Diseases and colon cancer, as these and other pathological conditions are known to result in Anemia of Chronic Disease.