Research Article: Fc gamma RIIb expression levels in human liver sinusoidal endothelial cells during progression of non-alcoholic fatty liver disease

Date Published: January 29, 2019

Publisher: Public Library of Science

Author(s): Tomoko Ishikawa, Hiroshi Yokoyama, Tomokazu Matsuura, Yoko Fujiwara, Yu Wang.


Liver sinusoidal endothelial cells (LSECs) play a pivotal role in hepatic function and homeostasis. LSEC dysfunction has been recognized to be closely involved in various liver diseases, including non-alcoholic steatohepatitis (NASH), but not much is known about the fate of the scavenger receptors in LSECs during NASH. Fc gamma receptor IIb (FcγRIIb), known as a scavenger receptor, contributes to receptor-mediated endocytosis and immune complexes clearance. In this study, to elucidate the fate of FcγRIIb in the progression of non-alcoholic fatty liver disease (NAFLD), we examined FcγRIIb levels in NAFLD biopsy specimens by immunohistochemistry, and investigated their correlation with the exacerbation of biological indexes and clinicopathological scores of NASH. The FcγRIIb expression levels indicated significant negative correlations with serum levels of blood lipids (triglyceride, total cholesterol, high-density lipoprotein-cholesterol), type 4 collagen and hyaluronic acid, which are involved in hepatic lipid metabolism disorder, fibrosis, and inflammation, respectively. However, there was no significant difference of FcγRIIb expression levels among the pathological grades of NAFLD. During NAFLD progression, inflammation and fibrosis may influence the expression of FcγRIIb and their scavenger functions to maintain hepatic homeostasis.

Partial Text

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is categorized into non-alcoholic fatty liver (NAFL), with simple fatty liver, and non-alcoholic steatohepatitis (NASH), with inflammation and fibrosis. NAFL is a benign disease, but NASH can lead to severe chronic hepatic diseases, such as advanced fibrosis [1], cirrhosis [2], and hepatocellular carcinoma (HCC) [3, 4]. In 1998, a two-hit model [5] was proposed as a mechanism of NASH pathogenesis. The first hit is fat accumulation in the liver parenchyma caused by obesity and insulin resistance, and subsequent second hits are several cellular stresses including oxidative stress, mitochondrial dysfunction, and apoptosis stress. In recent years, a multiple parallel-hit hypothesis [6] has been attracting a lot of attention. Namely, the multiple factors (e.g., inflammation from gut-derived endotoxin or adipocytokines, endoplasmic reticulum stress, and innate immunity) may act in parallel and lead to the progression of steatosis, hepatocellular ballooning, inflammation, and fibrosis. There are many cases in which patients are not obese or diabeti, and they are asymptomatic until they reach a severe period of NAFLD. So it is necessary to elucidate the details of clinical phenotypes in the early stages of NASH.

In this study, we determined the expression levels of FcγRIIb, which is a scavenger receptor on the LSEC, in human NAFL and NASH biopsy specimens, and elucidated their correlations with individual biological indexes and pathological grades. The FcγRIIb expression levels indicated significant negative correlations with serum TG, TC, HDL-C, VICol, and hyaluronan concentrations, respectively.

In summary, the present study contributes to support the notion that the changes in LSEC phenotype are one of crucial events in human NASH progression. Our results suggest that progression of inflammation, hepatic fibrosis, and hepatic lipid metabolism disorder during NASH may influence the expression and scavenger functions of FcγRIIb in LSECs.




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