Antifibrotic Effects of 1,25(OH)₂D₃ on Nonalcoholic Steatohepatitis in Female Mice

Background: Postmenopausal women have a higher risk of nonalcoholic steatohepatitis (NASH) along with an increase in age, and vitamin D deficiency occurs in some patients with NASH. Aim: We performed ovariectomy (OVX) surgery on female mice to mimic menopause, fed them a choline-deficient high-fat (CDHF) diet to induce NASH, and then investigated the effects of treatment with 1,25(OH)₂D₃. Methods: Seven-week-old C57BL/6J female mice were separated into five experimental groups: SHAM, OVX, and OVX + intraperitoneal (i.p.) injection of 1,25(OH)₂D₃ (0.0008, 0.004, and 0.02 μg/kg). All groups were fed a CDHF diet for 8 weeks. Injections took place twice per week throughout the experimental period. Blood samples and liver tissue were collected for analyzing liver histological changes, serum biochemical indicators of hepatic function, and hepatic genes associated with fibrosis. Results: Supplementation of 1,25(OH)₂D₃ in CDHF-diet mice showed decreased serum levels of ALT, AST, indicating the improvement in overall liver function, and suppressed histological NASH regarding fibrosis stage, lobular inflammation, and steatosis compared to the OVX group. Primary fibrotic markers of TGF-β, TIMP-1, α-SMA, and COL1A1 were significantly lower in the 1,25(OH)₂D₃ groups than in the OVX group. Furthermore, down-regulated levels of SMAD2 and SMAD3 were also observed in 1,25(OH)₂D₃ groups. Conclusion: Supplementation of 1,25(OH)₂D₃ may ameliorate liver fibrosis and improve liver function in OVX mice with NASH induced by a CDHF diet, suggesting the therapeutic effects on postmenopause with NASH.