Intestinal vitamin D receptor determines cell fate via apoptosis and autophagy
Rong Lu, Yongguo Zhang, Yinglin Xia, Jun Sun*
Medicine, University of Illinois at Chicago, IL 60612, USA
Vitamin D receptor (VDR) deficiency leads to abnormal Paneth cells and impaired autophagy function. We have demonstrated that human vdr gene is a key host factor to shape gut microbiome (Wang, et al., Nature Genetics 2016). Further, we have shown that intestinal epithelial VDR conditional knockout (VDRΔIEC) leads to dysbiosis (imbalanced microbiome) through suppressing ATG16L1 (Wu, et al., Gut 2015). Apoptosis and autophagy are dynamic processes that determine the fate of cells in intestine. Here, we will elucidate the mechanisms of the intestinal epithelial VDR regulation of autophagy and apoptosis. We used in vivo VDRlox and VDR∆IEC mice and ex vivo organoids generated from small intestine and colon tissues. We found that the pro-apoptotic protein Bax was enhanced, whereas ATG16L1 and Beclin-1 were decreased in the intestines of VDRΔIEC mice. Apoptosis induced by Bax reduced autophagy by enhancing the caspase-mediated cleavage of Beclin-1. VDR deficiency induced more apoptotic cells and significantly increased cell death in VDR∆IEC. Bacterial endotoxin levels were high in the serum from VDR∆IEC mice. In the VDR+/+ organoids, vitamin D treatment increased VDR and ATG16L1 protein expression levels, which activated autophagic responses. However, VDR∆IEC organoids did not respond to vitamin D treatment. The growth of VDR∆IEC organoids was significantly slower than that of VDR+/+ organoids. The expression levels of Beclin-1 and lysozyme were decreased in VDR∆IEC organoids. Intestinal epithelial VDR regulates autophagy/apoptosis through ATG16L1 and Beclin-1. Our studies provide fundamental insights into the tissue-specific function of VDR in modulating cell fate. As such, intestinal VDR may represent a useful therapeutic target in a diverse range of human diseases (e.g. chronic inflammation and infection).
References: 1. Dapeng Jin, et al. Lack of Vitamin D Receptor Causes Dysbiosis and Changes the Functions of the Murine Intestinal Microbiome. Clinical Therapeutics. 2015, 37(5): 996-1009 2. Shaoping Wu, et al. Intestinal vitamin D receptor deletion leads to defective autophagy. Gut, 2015 Jul;64(7):1082-94. 3. Jun Wang, et al. Genome wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nature Genetics. 48,1396–1406(2016).
Funding: NIH/NIDDKR01 DK105118 and DOD CDMRP BC160450P1