LECT2 as a hepatokine links liver steatosis to inflammation via activating tissue macrophages in NASH

Noboru Takata,Akihiro Kikuchi,Akihiro Seki,Yumie Takeshita,Yasuhiko Yamamoto,Toshinari Takamura,Yukako Matsumoto,Satoshi Yamagoe,Hiroaki Takayama,Yoshio Sakai,Kiyo-Aki Ishii,Tsuguhito Ota,Takeo Tanaka,Mayumi Nagashimada,Kyoko Kamoshita,Shuichi Kaneko

doi:10.1038/s41598-020-80689-0

Noboru Takata, Akihiro Kikuchi + Show 14 more

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https://doi.org/10.1038/s41598-020-80689-0

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Abstract

It remains unclear how hepatic steatosis links to inflammation. Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that senses fat in the liver and is upregulated prior to weight gain. The aim of this study was to investigate the significance of LECT2 in the development of nonalcoholic steatohepatitis (NASH). In human liver biopsy samples, elevated LECT2 mRNA levels were positively correlated with body mass index (BMI) and increased in patients who have steatosis and inflammation in the liver. LECT2 mRNA levels were also positively correlated with the mRNA levels of the inflammatory genes CCR2 and TLR4. In C57BL/6J mice fed with a high-fat diet, mRNA levels of the inflammatory cytokines Tnfa and Nos2 were significantly lower in Lect2 KO mice. In flow cytometry analyses, the number of M1-like macrophages and M1/M2 ratio were significantly lower in Lect2 KO mice than in WT mice. In KUP5, mouse kupffer cell line, LECT2 selectively enhanced the LPS-induced phosphorylation of JNK, but not that of ERK and p38. Consistently, LECT2 enhanced the LPS-induced phosphorylation of MKK4 and TAB2, upstream activators of JNK. Hepatic expression of LECT2 is upregulated in association with the inflammatory signature in human liver tissues. The elevation of LECT2 shifts liver residual macrophage to the M1-like phenotype, and contributes to the development of liver inflammation. These findings shed light on the hepatokine LECT2 as a potential therapeutic target that can dissociate liver steatosis from inflammation.

Highlights

It remains unclear how hepatic steatosis links to inflammation
Leukocyte cell-derived chemotaxin 2 (LECT2) mRNA levels were positively correlated with body mass index (BMI) (r = 0.609, P = 0.001), but not with serum levels of aspartate transferase (AST), alanine transaminase (ALT), and hemoglobin A1c (HbA1c) (Fig. 1A)
We demonstrated that LECT2 is a hepatokine that links obesity to hepatic inflammation via activation of LPS signaling in macrophages (Fig. 4)

Summary

Introduction

It remains unclear how hepatic steatosis links to inflammation. Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that senses fat in the liver and is upregulated prior to weight gain. Hepatic expression of LECT2 is closely associated with body mass index (BMI) in humans and is negatively regulated by the energy depletion-sensing protein adenosine monophosphate-activated protein kinase (AMPK)[6] Both LECT2 gene expression in the liver and LECT2 protein levels in the blood are downregulated in mice that have been fasted for 12 h6. Circulating LECT2 levels in the blood reflects the content of hepatic triglycerides rather than body fat, and predicts the onset of weight cycling in mice[7] These findings indicate that LECT2 is an energy-sensing hepatokine that is upregulated in response to overnutrition. Hwang et al reported that LECT2 induces an atherosclerotic inflammatory reaction via CD209 receptormediated c-Jun N-terminal kinase (JNK) phosphorylation in human endothelial cells[13] Based on these findings, we hypothesized that LECT2 links overnutrition to the development of liver inflammation and the subsequent development of NASH. We tested this hypothesis by investigating the significance of LECT2 gene expression in human liver tissues and the role of LECT2 in liver inflammation and the subsequent development of NASH in a mouse model of inflammation

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