A Lipid-Based Nanocarrier Containing Active Vitamin D₃ Ameliorates NASH in Mice via Direct and Intestine-Mediated Effects on Liver Inflammation

Abstract

The gut–liver axis may be involved in non-alcoholic steatohepatitis (NASH) progression. Pathogen-associated molecular patterns leak through the intestinal barrier to the liver via the portal vein to contribute to NASH development. Active vitamin D₃ (1,25(OH)₂D₃) is a potential therapeutic agent to enhance the intestinal barrier. Active vitamin D₃ also suppresses inflammation and fibrosis in the liver. However, the adverse effects of active vitamin D₃ such as hypercalcemia limit its clinical use. We created a nano-structured lipid carrier (NLC) containing active vitamin D₃ to deliver active vitamin D₃ to the intestine and liver to elicit NASH treatment. We found a suppressive effect of the NLC on the lipopolysaccharide-induced increase in permeability of an epithelial layer in vitro. Using mice in which NASH was induced by a methionine and choline-deficient diet, we discovered that oral application of the NLC ameliorated the permeability increase in the intestinal barrier and attenuated steatosis, inflammation and fibrosis in liver at a safe dose of active vitamin D₃ at which the free form of active vitamin D₃ did not show a therapeutic effect. These data suggest that the NLC is a novel therapeutic agent for NASH.

Graphical Abstract