Complement alternative pathway activation in human nonalcoholic steatohepatitis

F.M.E. Segers, F.J. Verdam, C. de Jonge, B.T.C. Boonen, A. Driessen, R. Shiri-Sverdlov, N.D. Bouvy, J. Greve, W.A. Buurman, S.S. Rensen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The innate immune system plays a major role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Recently we reported complement activation in human NASH. However, it remained unclear whether the alternative pathway of complement, which amplifies C3 activation and which is frequently associated with pathological complement activation leading to disease, was involved. Here, alternative pathway components were investigated in liver biopsies of obese subjects with healthy livers (n = 10) or with NASH (n = 12) using quantitative PCR, Western blotting, and immunofluorescence staining. Properdin accumulated in areas where neutrophils surrounded steatotic hepatocytes, and colocalized with the C3 activation product C3c. C3 activation status as expressed by the C3c/native C3 ratio was 2.6-fold higher (p<0.01) in subjects with NASH despite reduced native C3 concentrations (0.94+/-0.12 vs. 0.57+/-0.09; p<0.01). Hepatic properdin levels positively correlated with levels of C3c (rs = 0.69; p<0.05) and C3c/C3 activation ratio (rs = 0.59; p<0.05). C3c, C3 activation status (C3c/C3 ratio) and properdin levels increased with higher lobular inflammation scores as determined according to the Kleiner classification (C3c: p<0.01, C3c/C3 ratio: p<0.05, properdin: p<0.05). Hepatic mRNA expression of factor B and factor D did not differ between subjects with healthy livers and subjects with NASH (factor B: 1.00+/-0.19 vs. 0.71+/-0.07, p = 0.26; factor D: 1.00+/-0.21 vs. 0.66+/-0.14, p = 0.29;). Hepatic mRNA and protein levels of Decay Accelerating Factor tended to be increased in subjects with NASH (mRNA: 1.00+/-0.14 vs. 2.37+/-0.72; p = 0.22; protein: 0.51+/-0.11 vs. 1.97+/-0.67; p = 0.28). In contrast, factor H mRNA was downregulated in patients with NASH (1.00+/-0.09 vs. 0.71+/-0.06; p<0.05) and a similar trend was observed with hepatic protein levels (1.12+/-0.16 vs. 0.78+/-0.07; p = 0.08). Collectively, these data suggest a role for alternative pathway activation in driving hepatic inflammation in NASH. Therefore, alternative pathway factors may be considered attractive targets for treating NASH by inhibiting complement activation.
Original languageEnglish
Article numbere110053
Number of pages9
JournalPLOS ONE
Volume9
Issue number10
DOIs
Publication statusPublished - 9 Oct 2014

Keywords

  • FATTY LIVER-DISEASE
  • VASCULAR ENDOTHELIAL-CELLS
  • DECAY-ACCELERATING FACTOR
  • MEMBRANE-ATTACK COMPLEX
  • NECROSIS-FACTOR-ALPHA
  • INSULIN-RESISTANCE
  • PROPERDIN
  • PROTECTS
  • SYSTEM
  • IMMUNE

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