The Medium-Chain Fatty Acid Receptor GPR84 Mediates Myeloid Cell Infiltration Promoting Steatohepatitis and Fibrosis.

Tobias Puengel,Reginald Brys,Kenji F Shoji,Florence Marsais,Steve De Vos,Pavel Strnad,Jana Hundertmark,Tom Luedde,Marielle Auberval,Marlene Kohlhepp,Nurdan Guldiken,Philippe Clément-Lacroix,Philippe Pujuguet,Laurent Saniere,Christian Trautwein,Frank Tacke

doi:10.3390/jcm9041140

Abstract

Medium-chain fatty acids (MCFAs) have been associated with anti-steatotic effects in hepatocytes. Expression of the MCFA receptor GPR84 (G protein-coupled receptor 84) is induced in immune cells under inflammatory conditions and can promote fibrogenesis. We aimed at deciphering the role of GPR84 in the pathogenesis of non-alcoholic steatohepatitis (NASH), exploring its potential as a therapeutic target. GPR84 expression is upregulated in liver from patients with non-alcoholic fatty liver disease (NAFLD), correlating with the histological degree of inflammation and fibrosis. In mouse and human, activated monocytes and neutrophils upregulate GPR84 expression. Chemotaxis of these myeloid cells by GPR84 stimulation is inhibited by two novel, small molecule GPR84 antagonists. Upon acute liver injury in mice, treatment with GPR84 antagonists significantly reduced the hepatic recruitment of neutrophils, monocytes, and monocyte-derived macrophages (MoMF). We, therefore, evaluated the therapeutic inhibition of GPR84 by these two novel antagonists in comparison to selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, in three NASH mouse models. Pharmacological inhibition of GPR84 significantly reduced macrophage accumulation and ameliorated inflammation and fibrosis, to an extent similar to selonsertib. In conclusion, our findings support that GPR84 mediates myeloid cell infiltration in liver injury and is a promising therapeutic target in steatohepatitis and fibrosis.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, making NAFLD and its inflammatory subtype, nonalcoholic steatohepatitis (NASH), a major risk factor for the development of cirrhosis and hepatocellular carcinoma [1,2]
The Medium-chain fatty acids (MCFAs) receptor G protein-coupled receptor 84 (GPR84) is highly expressed in leukocytes, neutrophils and macrophages, and is associated with the inflammatory activation of these myeloid immune cells [21]
With respect to the pathogenesis of NAFLD and NASH, many potential drug targets have been identified over the last years, supporting the hypothesis that combination treatment targeting various signaling pathways at once might be more beneficial than single drug therapies [1,24,25]

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, making NAFLD and its inflammatory subtype, nonalcoholic steatohepatitis (NASH), a major risk factor for the development of cirrhosis and hepatocellular carcinoma [1,2]. As a result of excessive intake of dietary lipids, sugars, and other carbohydrates, NAFLD is characterized by an altered composition of circulating fatty acids, dominated by saturated fatty acids and permanently elevated levels of blood sugar [3]. During acute or chronic liver injury, infiltrating immune cells from the blood circulation, such as monocytes or neutrophils, and tissue resident non-parenchymal cells like Kupffer cells are the key regulators orchestrating the progression of NAFLD and fibrosis [7,8]. These myeloid cells acquire a particular inflammatory phenotype in steatohepatitis, which is (partly) mediated by fatty acids [9]. MCFA was found to reduce lipid accumulation by regulating key lipid-sensing genes in this in vitro model [10]

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