Chemerin Overexpression in the Liver Protects against Inflammation in Experimental Non-Alcoholic Steatohepatitis.

Nichole Mcmullen,Christa Buechler,Susanne Feder,Thomas S Weiss,Astrid Bruckmann,Elisabeth M Haberl,Christopher J Sinal,Marlen Spirk,Lisa Rein-Fischboeck,Rebekka Pohl

doi:10.3390/biomedicines10010132

Nichole Mcmullen, Christa Buechler + Show 8 more

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https://doi.org/10.3390/biomedicines10010132

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Abstract

Non-alcoholic steatohepatitis (NASH) is marked by macrophage infiltration and inflammation. Chemerin is a chemoattractant protein and is abundant in hepatocytes. The aim of this study was to gain insight into the role of hepatocyte-produced prochemerin in NASH. Therefore, mice were infected with adeno-associated virus 8 to direct hepatic overexpression of prochemerin in a methionine–choline deficient dietary model of NASH. At the end of the study, hepatic and serum chemerin were higher in the chemerin-expressing mice. These animals had less hepatic oxidative stress, F4/80 and CC-chemokine ligand 2 (CCL2) protein, and mRNA levels of inflammatory genes than the respective control animals. In order to identify the underlying mechanisms, prochemerin was expressed in hepatocytes and the hepatic stellate cells, LX-2. Here, chemerin had no effect on cell viability, production of inflammatory, or pro-fibrotic factors. Notably, cultivation of human peripheral blood mononuclear cells (PBMCs) in the supernatant of Huh7 cells overexpressing chemerin reduced CCL2, interleukin-6, and osteopontin levels in cell media. CCL2 was also low in RAW264.7 cells exposed to Hepa1–6 cell produced chemerin. In summary, the current study showed that prochemerin overexpression had little effect on hepatocytes and hepatic stellate cells. Of note, hepatocyte-produced chemerin deactivated PBMCs and protected against inflammation in experimental NASH.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver injury with a pathophysiology that is closely linked to obesity and insulin resistance [1,2]
Hepatic chemerin mRNA and protein expression increased in associated virus 8 (AAV8)-muChem-162-infected mice (Figure 1A–C)
The present study demonstrated that hepatic overexpression of prochemerin

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver injury with a pathophysiology that is closely linked to obesity and insulin resistance [1,2]. Hepatic steatosis is relatively common in the Western population and may progress to non-alcoholic steatohepatitis (NASH) [1,3]. Liver inflammation drives hepatic fibrosis, and a blockade of macrophage infiltration prevented activation of hepatic stellate cells and suppressed fibrogenesis [4]. The chemoattractant protein, chemerin, induces chemotaxis in macrophages, dendritic cells, and natural killer cells and is highly expressed in hepatocytes [5,6,7,8,9]. Chemerin is released as inactive prochemerin, and C-terminal proteolysis generates biologically active and inactive variants [10]

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