Person:

Softic, Samir

Transport of biologically active molecules across tight epithelial barriers is a major challenge preventing therapeutic peptides from oral drug delivery. Here, we identify a set of synthetic glycosphingolipids that harness the endogenous process of intracellular lipid-sorting to enable mucosal absorption of the incretin hormone GLP-1. Peptide cargoes covalently fused to glycosphingolipids with ceramide domains containing C6:0 or smaller fatty acids were transported with 20-100-fold greater efficiency across epithelial barriers in vitro and in vivo. This was explained by structure-function of the ceramide domain in intracellular sorting and by the affinity of the glycosphingolipid species for insertion into and retention in cell membranes. In mice, GLP-1 fused to short-chain glycosphingolipids was rapidly and systemically absorbed after gastric gavage to affect glucose tolerance with serum bioavailability comparable to intraperitoneal injection of GLP-1 alone. This is unprecedented for mucosal absorption of therapeutic peptides, and defines a technology with many other clinical applications.

Hepatic inflammation is a key pathologic feature of nonalcoholic steatohepatitis (NASH). Natural killer T (NKT) cells and clusters of differentiation (CD)8+ T‐cells are known to play an important role in obesity‐related adipose tissue inflammation. We hypothesized that these same inflammatory phenotypes would be present in progressive NASH. We used a previously established high‐fat high‐carbohydrate (HFHC) murine obesogenic diet model of progressive NASH to investigate the role of NKT cells and CD8+ T‐cells in C57Bl6/J mice. To better understand the impact of these cell populations, CD1d‐deficient and CD8+ T‐cell‐depleted mice were subjected to an HFHC diet for 16 weeks. C57Bl6/J mice fed an HFHC diet had increased body weight, liver triglyceride content, serum alanine aminotransferase levels, and increased NKT‐cell and CD8+ T‐cell infiltration in the liver. In addition, human liver sections from patients with NASH showed increased CD8+ T‐cells. In comparison, CD1d‐deficient and CD8 T‐cell‐depleted mice fed an HFHC diet had a lower hepatic triglyceride content, lower alanine aminotransferase levels, lower activated resident macrophages and infiltrating macrophages, improved nonalcoholic fatty liver disease activity scores, and reduced α‐smooth muscle actin, collagen type 1 alpha 1, and collagen type 1 alpha 2 messenger RNA expression. Further, while CD1d‐deficient mice were protected against weight gain on the HFHC diet, CD8 T‐cell‐depleted mice gained weight on the HFHC diet. Conclusion:: We found that NASH has an immunological signature that includes hepatic infiltrating NKT and CD8+ T‐cells. Depletion of these cells resulted in reduced NASH progression and thus presents novel therapeutic avenues for the treatment of NASH. (Hepatology Communications 2017;1:299–310)