RNAseq of livers of mice fed high fat high sugar diet and either untreated or treated with curcumin liposomes or calcitriol liposomes. Mus musculus

Non-alcoholic fatty liver disease (NAFLD) is a common complication of obesity, where insulin resistance and hepatocyte fat deposition may progress to steatohepatitis (NASH) and fibrosis/ cirrhosis. NASH has no approved treatment. Consequent upon hepatic fat deposition, NF-κB activation in hepatic myeloid cells mediates inflammation and NASH progression. We delivered micro-doses of liposome-encapsulated lipophilic NF-κB inhibitors, curcumin or 1,25-dihydroxy-vitamin D3 (calcitriol), to the pro-fibrogenic inflammatory liver macrophages and dendritic cells (DCs) in diet-induced NASH. After i.v. administration, liver was the primary organ targeted. MHC class-II+ hepatic DCs taking up liposomes in mice and human were F4/80+ and CD14+ respectively, were lipid-laden and expressed pro-inflammatory genes. Curcumin or calcitriol liposomes suppressed hepatic inflammation, fibrosis and fat accumulation, and reduced insulin resistance associated with suppression of immune activation, cell cycle and collagen deposition pathways in vivo. Thus, hepatic inflammatory DCs passively targeted with liposomes encapsulating lipophilic NF-κB inhibitors are beneficial in NASH. Overall design: Female C57BL/6 mice were fed with high fat high sugar diet for 14 weeks to induce nonalcoholic steatohepatitis. Groups of mice were intravenously injected with either curcumin liposomes or calcitriol liposomes at week 12 and week 13. 2 weeks post initial treatment transcriptome profiling was determined on whole livers.