Effect of cellular stress on retinoid homeostasis in the small intestine.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology(2022)
摘要
Vitamin A is an essential diet-derived nutrient. Retinoids are compounds with Vitamin A activity and are essential for many biological processes, including proper cell function and tissue organization. The main active metabolite of Vitamin A is all-trans retinoic acid (RA), which is critical for nuclear receptor mediated signaling for cell proliferation, differentiation, and apoptosis. Retinoid signaling and RA are essential for intestinal immune homeostasis. Intestinal epithelial cells (IEC) produce high levels of RA, which is crucial for RA-dependent signaling, lineage commitment, and barrier function. Vitamin A deficiency can alter intestinal immune and IEC homeostasis. There are many mechanisms in place to maintain retinoic acid homeostasis, including the expression of the main intracellular chaperone protein cellular retinol binding protein, type 1 (CRBP1). CRBP1 binds to retinol and retinal, protects them from non-specific oxidation, and facilitates their delivery to the appropriate enzymes for RA biosynthesis. CRBP1 has been shown to be decreased in diseases that display dysfunctional proliferation and differentiation, including cancer, inflammatory disorders, fibrosis, and infection. Reduction of CRBP1 directly correlates with reduction in the active metabolite, RA, and restoration of CRBP1 expression has been shown to increase RA levels and positively impact RA-dependent outcomes. Therefore, monitoring CRBP1 and retinoid metabolite levels in response to cellular stress will provide useful information about the effect of CRBP1 loss on retinoid signaling. While previous studies have explored the effect of cellular stress on RA levels, the effect of stress on the entirety of the retinoid signaling pathway is not well understood. The objective of these studies is to systematically determine the effect of cellular stress on retinoid homeostasis. We have established three models of cellular stress, including hypoxia, oxidative stress, and inflammation, in two human intestinal epithelial cells lines, HIEC-6 and Caco-2. To mimic hypoxia, cells are treated with 0-100 μM CoCl for 24 hours. To mimic oxidative stress, cells are treated with 0-100 μM H O for 24 hours. To mimic inflammation, cells are treated with 0-1 μg/mL lipopolysaccharide for 48 hours. These conditions were chosen because there was no effect on cell viability. CRBP1 and RA levels will be measured through targeted mass spectrometry methods developed by our lab. Additionally, expression levels of genes associated with retinoid metabolism will be measured. Our current data shows that RA levels decreased in response to hypoxia, oxidative stress, and inflammation in both HIEC-6 and Caco-2 cells.
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关键词
retinoid homeostasis,small intestine,cellular stress
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