Deficiency of CD147 Attenuated Non-alcoholic Steatohepatitis Progression in an NLRP3-Dependent Manner.

Tian Zhang,Hao Li,Bing Xu,Huijie Bian,Ke Wang,Zhi-Nan Chen

doi:10.3389/fcell.2020.00784

Abstract

Cluster of differentiation 147 (CD147) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. CD147 overexpression has been reported to facilitate the development of hepatocellular carcinoma (HCC) and influence immunologic disorders. Although increased expression of CD147 was reported in non-alcoholic steatohepatitis (NASH), functions of CD147 in NASH have not been evaluated. Firstly, we confirmed that CD147 expression was increased in the liver tissues from methionine-choline-deficient (MCD) diet-induced NASH model mice and NASH patients. Mice with hepatocyte-specific CD147 deletion exhibited attenuated NASH phenotypes, including reduced steatosis, liver injury, hepatocyte apoptosis and inflammatory cytokines IL-1β/IL-18 secretion. Following the administration of the MCD diet, NLRP3 expression was increased gradually along with CD147 expression. Furthermore, CD147 deletion inhibited the NF-κB/NLRP3 signaling pathway in both MCD diet-induced mice and primary hepatocytes. Finally, CypA inhibitor TMN355 attenuated liver steatosis and injury and inhibited NF-κB/NLRP3 signaling pathway. Therefore, our results suggest that CD147 played a vital role in NASH pathogenesis by regulating the inflammatory response, and CypA/CD147 could be attractive therapeutic targets for NASH treatment.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, with an estimated global prevalence of 25–45% (Rinella, 2015)
Inflammation is a common trigger of liver disease and is considered the main driver of liver tissue damage leading to fibrosis and hepatocellular carcinoma (HCC) (Ringelhan et al, 2018)
non-alcoholic steatohepatitis (NASH) has been reported to be frequently associated with inflammation, to our knowledge, the functional importance of Cluster of differentiation 147 (CD147) in NASH and its related mechanism have not been evaluated

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, with an estimated global prevalence of 25–45% (Rinella, 2015). NASH is characterized by hepatic steatosis with inflammation, hepatocyte apoptosis and fibrosis and can progress to more severe stages, such as cirrhosis and hepatocellular carcinoma (HCC) (Younossi et al, 2019). CD147 in Non-alcoholic Steatohepatitis Progression initiates and propagates multiple events, including hepatocyte injury, oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and regulation of inflammation (Friedman et al, 2018). These findings suggest that the proinflammatory response in the liver is closely associated with hepatocellular death and progression from NASH to fibrosis (Schuster et al, 2018). Despite the high prevalence of NASH, its contributing factors remain poorly understood, and no treatment has proven effective

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