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

Abstract

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. 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. 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 0.02μg/kg). All groups were fed a CDHF diet for 8weeks. 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. 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. 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.