Z Gastroenterol 2019; 57(01): e49
DOI: 10.1055/s-0038-1677175
3. Metabolism (incl. NAFLD)
Georg Thieme Verlag KG Stuttgart · New York

The role of Formyl Peptide Receptor 1 in the development of non-alcoholic steatohepatitis

M Nati
1   Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine Technische Universität Dresden, Dresden, Germany
,
A Chatzigeorgiou
1   Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine Technische Universität Dresden, Dresden, Germany
,
LS Chen
1   Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine Technische Universität Dresden, Dresden, Germany
,
A Neuwirth
1   Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine Technische Universität Dresden, Dresden, Germany
,
P Subramanian
1   Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine Technische Universität Dresden, Dresden, Germany
,
J Hampe
2   Department of Medicine I, Faculty of Medicine Technische Universität Dresden, Dresden, Germany
,
O Soehnlein
3   Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany
,
T Chavakis
1   Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine Technische Universität Dresden, Dresden, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

 

Non-alcoholic fatty liver disease (NAFLD) affects one in four people worldwide. Despite the enormous clinical and economic burdens, there are currently no approved pharmacological treatments for this pathology. The severe necroinflammatory form of NAFLD, non-alcoholic steatohepatitis (NASH), is one of the leading causes of liver transplantation because of its potential progression to liver cirrhosis and hepatocellular carcinoma. Recent studies have shown that, among NASH histological characteristics, only the fibrosis stage predicts this progression and the disease-specific mortality. The crucial step in hepatic fibrosis development is known to be the transdifferentiation of hepatic stellate cells (HSCs) into fibrogenic myofibroblasts, in response to liver injury; however, the exact underlying mechanisms have not been fully elucidated. Formyl Peptide Receptor 1 (FPR1) is a G-protein coupled receptor known for triggering the innate immune response by sensing necroinflammation and tissue damage. Interestingly, we discovered that FPR1 expression increases during the development of NASH and positively correlates with the expression of liver fibrosis markers, both in mice and in humans. Consistently, when subjected to a model of diet-induced NASH, FPR1-deficient mice displayed significantly blunted HSC activation and hepatic fibrosis as compared to their wild-type littermates. Unexpectedly, FPR1 deficiency protected from liver fibrosis without affecting liver inflammation, damage, and steatosis. By performing bone marrow chimera experiments, we could indeed demonstrate that FPR1 expression in bone marrow-derived immune cells was dispensable for fibrosis development. Congruently, we found that HSCs constitutively express FPR1 and FPR1 expression increases upon in vitro activation and NASH development. Furthermore, treating human and murine HSCs with the FPR1-selective peptide agonist fMLP promoted their activation and collagen deposition in vitro. Importantly, in vivo pharmacological blockade of FPR1 protected from NASH-associated fibrosis in mice. Taken together, we show that the interaction between formylated peptides and FPR1 promotes hepatic fibrosis in an HSC-intrinsic manner, independently of inflammation. Therefore, FPR1 might represent a novel specific target for the treatment of NASH-induced liver fibrosis.