Adenovirus‑mediated overexpression of bone morphogenetic protein‑9 promotes methionine choline deficiency‑induced non‑alcoholic steatohepatitis in non‑obese mice

Mol Med Rep. 2019 Sep;20(3):2743-2753. doi: 10.3892/mmr.2019.10508. Epub 2019 Jul 19.


Liver inflammation and macrophage infiltration are critical steps in the progression of non‑alcoholic fatty liver to the development of non‑alcoholic steatohepatitis. Bone morphogenetic protein‑9 is a cytokine involved in the regulation of chemokines and lipogenesis. However, the function of bone morphogenetic protein‑9 in non‑alcoholic steatohepatitis is still unknown. The present study hypothesized that bone morphogenetic protein‑9 may contribute to steatohepatitis in mice fed a methionine choline deficiency diet (MCD). C57BL/6 mice overexpressing bone morphogenetic protein‑9 and control mice were fed the MCD diet for 4 weeks. Liver tissue and serum samples were obtained for subsequent measurements. Bone morphogenetic protein‑9 overexpression exacerbated steatohepatitis in mice on the MCD diet, as indicated by liver histopathology, increased serum alanine aminotransferase activity, aspartate transaminase activity, hepatic inflammatory gene expression and M1 macrophage recruitment. Although bone morphogenetic protein‑9 overexpression did not affect the expression of pro‑fibrogenic genes, including Collagen I (α)1 or matrix metalloproteinase (MMP) 9, it did upregulate the expression of transforming growth factor‑β and plasminogen activator inhibitor 1, and downregulated the expression of MMP2. The above results indicate that bone morphogenetic protein‑9 exerts a pro‑inflammatory role in MCD diet‑induced non‑alcoholic steatohepatitis.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Choline Deficiency / complications
  • Growth Differentiation Factor 2 / genetics*
  • Liver / metabolism
  • Liver / pathology*
  • Male
  • Methionine / deficiency
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / pathology
  • RNA, Messenger / genetics
  • Up-Regulation


  • Growth Differentiation Factor 2
  • RNA, Messenger
  • Methionine