Megalin and Cubilin

This exploration of the literature started with a Dr Nicholas Gonzalez – Enzymes and Cancer YouTube video. Dr Gonzalez discussed the history of use of pancreatic enzymes and specialized diets to treat cancer. A 2002 Rothman review [1] was cited at the end of his talk. The Rothman good was good for a few references supporting intestinal re absorption of pancreatic enzymes. Goetz (1978) compared the mucosal to serosal flux of inulin and amylase in rabbit ileum mounted in a modified Ussing chamber. [2] The rate of amylase transfer was 2–3 orders of magnitude greater than that for inulin. [2] Absorption was dependent on the tissue getting oxygen. [2] According to the abstract of a 1968 study, human ileal mucosal scrapings incubated with highly purified typsin and chymotrysin. Both were found to bind the mucosal scrapings. [3]

Yes, there are epithelial transporters for proteins…

“By efficient uptake of virtually all filtered proteins, potentially biologically active substances are cleared from the ultrafiltrate, and consequently later segments are not exposed to these substances. The multiligand endocytic receptors megalin and cubilin have been identified as essential receptors in this process, each binding a variety of filtered proteins.” [4] This review covers receptor mediated endocytosis of renal filtratrate by megalin and cubilin. Megalin is being ignored in this post because it does not seem not be abundantly expressed in the GI tract. It is worth noting that megalin mediates absorption of amylase. [4] This is what ProteinAtlas has to say about cubilin: Cubilin acts as a receptor for intrinsic factor vitamine B12 complexes. Cubulin plays a role in lipoprotein, vitamin, and iron uptake. Cubilin acts with megalin to mediate endocytosis of high-density lipoproteins, GC, hemoglobin, albumin, transferrin, and SCGB1A1. Ligand binding requires calcium.

Cubilin serves s a transporter in the embryonic yolk sac. May play an important role in the development of the peri-implantation embryo through internalization of APOA1 and cholesterol. Binds to LGALS3 at the maternal-fetal interface.

While it has not been proven that cubilin can mediate receptor endocytosis of pancreatic enzymes, the diversity of other protein substrates lends a tremendous amount of credence that overloading the GI tract with pancreatic enzymes might result in more ending up in the blood.

References

1. Rothman S, Liebow C, Isenman L. (2002)Conservation of digestive enzymes. Physiol Rev. 2002 Jan;82(1):1-18. free article
2. Goetze H, Rothman SS (1978) Amylase transport across ileal epithelium in vitro.Biochim Biophys Acta5121978214220
3. Goldberg DM, Campbell R, Roy ADBinding of human trypsin and chymotrypsin by human intestinal mucosa.Biochim Biophys Acta1671968613619
4. Nielsen R, Christensen EI, Birn H. (2016) Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease. Kidney Int. 2016 Jan;89(1):58-67. free article