Vitamin D exacerbates steatosis while calcipotriol inhibits inflammation in non-alcoholic fatty liver disease in knockout mice: a comparative study of two forms of vitamin D

The role of vitamin D (VD) in non-alcoholic fatty liver disease (NAFLD) remains controversial, possibly due to the differential effects of various forms of VD. In our study, Sod1 gene knockout (SKO) mice were utilized as lean NAFLD models, which were administered 15 000 IU VD 3 per kg diet, or intraperitoneally injected with the active VD analog calcipotriol for 12 weeks. We found that VD 3 exacerbated hepatic steatosis in SKO mice, with an increase in the levels of Cd36 , Fatp2 , Dgat2 , and CEBPA. However, calcipotriol exerted no significant effect on hepatic steatosis. Calcipotriol inhibited the expression of Il-1a , Il-1b , Il-6 , Adgre1 , and TNF, with a reduction of NFκB phosphorylation in SKO mice. No effect was observed by either VD 3 or calcipotriol on hepatocyte injury and hepatic fibrosis. Co-immunofluorescence stains of CD68, a liver macrophage marker, and VDR showed that calcipotriol reduced CD68 positive cells, and increased the colocalization of VDR with CD68. However, VD 3 elevated hepatocyte VDR expression, with no substantial effect on the colocalization of VDR with CD68. Finally, we found that VD 3 increased the levels of serum 25(OH)D 3 and 24,25(OH) 2 D 3 , whereas calcipotriol decreased both. Both VD 3 and calcipotriol did not disturb serum calcium and phosphate levels. In summary, our study found that VD 3 accentuated hepatic steatosis, while calcipotriol diminished inflammation levels in SKO mice, and the difference might stem from their distinct cellular selectivity in activating VDR. This study provides a reference for the application of VD in the treatment of lean NAFLD. In a lean NAFLD mouse model, vitamin D 3 accentuated hepatic steatosis, while calcipotriol diminished inflammation; the reason may be their selective activation of VDR in hepatocytes and liver macrophages, respectively.