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.
Highlights
In recent decades, the incidence and prevalence of nonalcoholic fatty liver disease (NAFLD) has dramatically increased [1]
Quantification of the immunofluorescent images for MPO+ and properdin+/MPO+ double positive cells showed both significant increases in infiltrated MPO+ neutrophils (51.9066.79% vs. 4.1560.70%; p,0.001) and properdin+/MPO+ double positive cells (29.0464.89% vs. 0.6660.24% of MPO+ cells; p,0.001) in subjects with nonalcoholic steatohepatitis (NASH) compared to healthy controls
We have shown that human NASH is characterized by reduced production but increased hepatic activation of C3, related to alternative pathway activation
Summary
The incidence and prevalence of nonalcoholic fatty liver disease (NAFLD) has dramatically increased [1]. NAFLD can progress from relatively benign hepatic fat accumulation or steatosis to more severe stages characterized by hepatic inflammation, in a condition referred to as nonalcoholic steatohepatitis (NASH). In spite of the high prevalence of NAFLD, its etiology and the mechanisms responsible for progression towards nonalcoholic steatohepatitis (NASH) remain to be fully elucidated [2,3]. Complement activation is classically considered an important antimicrobial defense system. Accumulating evidence associates complement activation with inflammatory conditions such as transplant rejection, neurodegenerative diseases, ischemia/ reperfusion damage, and cancer. Key functions of complement in immune surveillance, homeostasis, and mediation of inflammatory responses have been elucidated. Excessive activation or dysregulation of the complement system may have far-reaching clinical consequences [4]
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