System L Amino Acid Transporter LAT1 is required for Mouse Intestinal Epithelial Homeostasis

The adult mammalian intestinal epithelium is constantly self-renewed via cell proliferation in the crypt. Earlier studies have revealed many genes and pathways important for regulating intestinal epithelial cell proliferation and differentiation to maintain adult epithelial homeostasis. Of interest among them is system L amino acid transporter 1 (LAT1), also known as slc7a5. Slc7a5 can transport thyroid hormone and large, neutral amino acids such as leucine and tryptophan. It can activate mTORC1 to increase cell proliferation by transporting amino acid. We have previously shown that slc7a5 is highly expressed in adult mouse intestinal crypt and that intestinal epithelial cell-specific knockout (^ΔIEC) of slc7a5 (Slc7a5 ^ΔIEC) reduces mTORC1 signaling. Unexpectedly, slc7a5 ^ΔIEC intestinal crypts have increased cell proliferation in the small intestine. There is also a drastic reduction in mature Paneth cells, suggesting a possible indirect effect of slc7a5 on cell proliferation by regulating secretory cell differentiation. Here, we have generated a tamoxifen-inducible intestinal epithelial-specific slc7a5 knockout line (slc7a5 ^ind∆IEC ). We show that inducible knockout of slc7a5 in adult mice also leads to reduced mature Paneth cells and increased cell proliferation in the crypt, revealing that slc7a5 is important for adult intestinal epithelial homeostasis. Kinetically, the reduction of mature Paneth cells occurs before the increase in cell proliferation. Furthermore, in stable intestinal epithelial cell-specific knockout (Slc7a5 ^ΔIEC) animals, a reduction in mature Paneth cells occurs soon after mature Paneth cells are first formed during post-natal development while an increase in crypt cell proliferation occurs later by postnatal day 28 after intestinal maturation is complete. These findings support a mechanism where slc7a5 affects cell proliferation indirectly by regulating Paneth cell differentiation to maintain adult intestinal epithelial homeostasis.