ABSTRACT: Myeloperoxidase (MPO) activity has been associated with the metabolic syndrome, cardiovascular and liver disease. Here, we evaluate the therapeutic potential of MPO inhibition on nonalcoholic steatohepatitis (NASH) and NASH?induced fibrosis, the main determinant of outcomes. MPO plasma levels were elevated in patients with nonalcoholic fatty liver disease (NAFLD) compared with healthy controls. In a second cohort, hepatic MPO messenger RNA expression correlated with higher body mass index and hemoglobin A1c, both being risk factors for NAFLD. We could establish by immunohistochemistry that MPO?positive cells were recruited to the liver in various mouse models of fibrogenic liver injury, including bile duct ligation, carbon tetrachloride (CCl4) treatment, spontaneous liver fibrogenesis in multidrug resistance 2 knockout (MDR2 KO) mice, and NASH?inducing diet. Comparison of MPO?deficient mice and their wild?type littermates exposed to a high?caloric diet revealed that MPO deficiency protects against NASH?related liver injury and fibrosis. In line with this, hepatic gene expression analysis demonstrated a MPO?dependent activation of pathways relevant for wound healing, inflammation, and cell death in NASH. MPO deficiency did not affect NAFLD?independent liver injury and fibrosis in MDR2 KO or CCl4?treated mice. Finally, we treated wild?type mice exposed to NASH?inducing diet with an oral MPO inhibitor. Pharmacological MPO inhibition not only reduced markers of MPO?mediated liver damage, serum alanine aminotransferase levels, and hepatic steatosis, but also significantly decreased NASH?induced liver fibrosis. MPO inhibitor treatment, but not MPO deficiency, significantly altered gut microbiota including a significant expansion of Akkermansia muciniphila. Conclusions: MPO specifically promotes NASH?induced liver fibrosis. Pharmacological MPO inhibition attenuates NASH progression and NASH?induced liver fibrosis in mice and is associated with beneficial changes of intestinal microbiota. Our study shows that in patients, systemic levels of the neutrophil enzyme myeloperoxidase (MPO) correlate with the presence of nonalcoholic steatohepatitis (NASH) and hepatic MPO expression with risk factors of NASH. Using various mouse models, we demonstrate that MPO is essential for NASH progression and consecutive liver fibrosis but not for steatosis?independent liver fibrogenesis. In mice treated with an MPO inhibitor, AZM198, we show that MPO inhibition has the potential to attenuate NASH?induced liver injury and fibrosis, and, moreover, is associated with beneficial changes of intestinal microbiota.
