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

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)2 D3) is a potential therapeutic agent to enhance the intes-
tinal 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.
Key words vitamin D3; nanostructured lipid carrier; non-alcoholic steatohepatitis; intestine permeability;
methionine-choline deficient diet