Beneficial Effects of Vitamin D Treatment in an Obese Mouse Model of Non-Alcoholic Steatohepatitis

Background and aims:

25-OH vitamin D3 (VD3) serum levels negatively correlate with obesity and furthermore with the development and progression of non-alcoholic fatty liver disease (NAFLD) in humans. However, the mechanisms linking low VD3 status to disease progression are not completely understood. In this study, we analysed whether VD3 treatment ameliorates non-alcoholic steatohepatitis (NASH) in a mouse model of diet-induced obesity and how this amelioration may be associated with changes of intestinal physiology.

Methods:

To induce obesity, fibrosing NASH and intestinal inflammation, C57BL6/J mice were fed a high-fat/high-sugar diet (HFSD) containing low amounts of VD3 for 16 weeks. The effects of preventive (starting from wk 1) and interventional (starting from wk 12) VD3 treatment were studied on the level of liver histology and hepatic/intestinal gene expression.

Results:

Animals receiving HFSD with low amounts of VD3 became obese and developed histologically-defined NASH and liver fibrosis after 16 weeks of feeding. This phenotype was associated with increased expression of lipogenic, inflammatory and pro-fibrotic target genes in the liver and with increased mRNA levels of pro-inflammatory targets in the intestine. Interestingly, preventive – and to a lesser extend also interventional – treatment with VD3 resulted in improvements of liver histology. These improvements included a significant decrease of steatosis, a trend towards lower NAFLD activity score and a slight non-significant decrease of fibrosis in the preventive treatment group. In line with these changes, preventive VD3 treatment reduced the hepatic expression of certain lipogenic, inflammatory and pro-fibrotic genes. Notably, these beneficial effects of VD3 occurred in conjunction with a reduction of intestinal inflammation on the mRNA level.

Conclusions:

Our data reveal a beneficial impact of dietary VD3 treatment on disease progression in a murine obesity/NASH model. Importantly, our observations suggest that timely initiation of VD3 supplementation (preventive vs. interventional) is a critical determinant of treatment outcome. In the applied animal model, the beneficial effects of VD3 on liver histology occurred in conjunction with reduced inflammation in the gut suggesting a potential relevance of VD3 as therapeutic option in obesity and NASH.