Sweroside Prevents Non-Alcoholic Steatohepatitis by Suppressing Activation of the NLRP3 Inflammasome.

Gabsik Yang,Sin-Hee Han,Yong-Yeon Cho,Sung Wook Kim,Joo Young Lee,Hye Suk Lee,Han Chang Kang,Joo Hyeon Jang,Jae-Ki Jang,Kyung-Ho Ma

doi:10.3390/ijms21082790

Abstract

Non-alcoholic steatohepatitis (NASH), a type of non-alcoholic fatty liver disease, is characterized as steatosis and inflammation in the liver. NLRP3 inflammasome activation is associated with NASH pathology. We hypothesized that suppressing the NLRP3 inflammasome could be effective in preventing NASH. We searched substances that could inhibit the activation of the NLRP3 inflammasome and identified sweroside as an NLRP3 inhibitor. We investigated whether sweroside can be applied to prevent the pathological symptoms associated with NASH in a methionine–choline-deficient (MCD) diet-induced NASH mouse model. The activation of the NLRP3 inflammasome was determined by detecting the production of caspase-1 and IL-1β from pro-caspase-1 and pro-IL-1β in primary mouse macrophages and mouse liver. In a NASH model, mice were fed an MCD diet for two weeks with daily intraperitoneal injections of sweroside. Sweroside effectively inhibited NLRP3 inflammasome activation in primary macrophages as shown by a decrease in IL-1β and caspase-1 production. In a MCD diet-induced NASH mouse model, intraperitoneal injection of sweroside significantly reduced serum aspartate transaminase and alanine transaminase levels, hepatic immune cell infiltration, hepatic triglyceride accumulation, and liver fibrosis. The improvement of NASH symptoms by sweroside was accompanied with its inhibitory effects on the hepatic NLRP3 inflammasome as hepatic IL-1β and caspase-1 were decreased. Furthermore, sweroside blocked de novo synthesis of mitochondrial DNA in the liver, contributing to suppression of the NLRP3 inflammasome. These results suggest that targeting the NLRP3 inflammasome with sweroside could be beneficially employed to improve NASH symptoms.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a condition with excess fat deposited in the liver without heavy alcohol drinking
To investigate whether sweroside (Figure 1A) inhibited the activation of the NLRP3 inflammasome, the extracellular secretion of mature IL-1β was determined in mouse bone marrow-derived primary macrophages (BMDMs) as a hallmark of NLRP3 inflammasome activation
Sweroside suppressed nigericin- or monosodium uric acid (MSU)-induced degradation of pro-caspase-1 to caspase-1 (p20) in BMDMs (Figure 1E). These results show that sweroside suppresses the activation of the NLRP3 inflammasome induced by various agonists in primary macrophages

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a condition with excess fat deposited in the liver without heavy alcohol drinking. NAFLD is well known to be associated with metabolic diseases such as obesity, type 2 diabetes, hyperlipidemia, hypertension, and insulin resistance [2,3]. NASH induced by a methionine–choline-deficient (MCD) diet is associated with caspase-1 activation in the liver [10]. Mice deficient in NLRP3 or its essential components, ASC or caspase-1, are protected from fatty liver disease caused by the atherogenic and MCD diet [8]. These findings indicate that the activation of the NLRP3 inflammasome is involved in triggering liver inflammation in NASH. We seek to identify substances that could inhibit the activation of the NLRP3 inflammasome and investigate whether the NLRP3 inhibitors can be applied to prevent the pathological symptoms associated with NASH

Methods

Results

Conclusion