Si-Wu-Tang Alleviates Nonalcoholic Fatty Liver Disease via Blocking TLR4-JNK and Caspase-8-GSDMD Signaling Pathways

Yaxing Zhang,Fenglin Wang,Shuhui Zheng,Yangjing Liao,Ge Zhou,Mingmin Bi,Jiongshan Zhang,Xinchao You,Zifeng Chen,Weibing Guan,Hongzhi Yang,Kangquan Xu

doi:10.1155/2020/8786424

Abstract

Background Nonalcoholic fatty liver disease (NAFLD) has high global prevalence; however, the treatments of NAFLD are limited due to lack of approved drugs. Methods Mice were randomly assigned into three groups: Control group, NAFLD group, NAFLD plus Si-Wu-Tang group. A NAFLD mice model was established by feeding with a methionine- and choline-deficient (MCD) diet for four weeks. Si-Wu-Tang was given orally by gastric gavage at the beginning of 3rd week, and it lasted for two weeks. The treatment effects of Si-Wu-Tang were confirmed by examining the change of body weight, serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels, Oil Red O staining, and hematoxylin and eosin (H&E) staining of the liver samples and accompanied by steatosis grade scores. The expression and activation of the possible signaling proteins involved in the pathogenesis of NAFLD were determined by western blotting. Results Mice fed with four weeks of MCD diet displayed elevated serum levels of ALT and AST, while there was decreased body weight. The hepatic Oil Red O staining and H&E staining showed severe liver steatosis with high steatosis grade scores. All these can be improved by treating with Si-Wu-Tang for two weeks. Mechanistically, the increased hepatic TLR4 expression and its downstream JNK phosphorylation induced by MCD diet were suppressed by Si-Wu-Tang. Moreover, the upregulations of Caspase-8, gasdermin D (GSDMD), and cleaved-GSDMD in liver mediated by MCD diet were all inhibited by Si-Wu-Tang. Conclusions Treatment with Si-Wu-Tang improves MCD diet-induced NAFLD in part via blocking TLR4-JNK and Caspase-8-GSDMD signaling pathways, suggesting that Si-Wu-Tang has potential for clinical application in treating NAFLD.

Highlights

Nonalcoholic fatty liver disease (NAFLD) has high global prevalence; the treatments of NAFLD are limited due to lack of approved drugs
NAFLD encompasses a broad spectrum of conditions, from simple steatosis (referred to as nonalcoholic fatty liver (NAFL)), through nonalcoholic steatohepatitis (NASH), to fibrosis, and cirrhosis and hepatocellular carcinoma (HCC) [4, 5]
TLR4-induced Jun NH2-terminal kinase (JNK) phosphorylation and their downstream Caspase-8 activation contribute to the pathogenesis of NAFLD [37,38,39,40,41,42,43,44,45,46,47,48,49]. erefore, hepatocyte-specific Caspase-8 knockout ameliorates the development of methionine- and choline-deficient (MCD) diet-induced NASH by modulating liver injury and attenuates alcoholic hepatic steatosis in mice [39, 50]

Summary

Background

Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of >5% hepatic steatosis (either by histology or imaging techniques); there must be lack of secondary causes of hepatic fat accumulation, such as significant alcohol consumption, long-term use of a steatogenic medication, or monogenic hereditary disorders [1,2,3]. Erefore, hepatocyte-specific Caspase-8 knockout ameliorates the development of MCD diet-induced NASH by modulating liver injury and attenuates alcoholic hepatic steatosis in mice [39, 50]. Si-Wu-Tang has strong anti-inflammatory and antioxidative effects [12, 13, 17, 56,57,58,59,60]; it can improve carbohydrate and lipid metabolisms in blood deficiency animal models [21, 28, 29] and positively regulate the lipid profile and liver function in healthy adults [12]. We will further investigate whether the novel inflammatory and cell death mechanisms of NAFLD discussed above are involved in its protective effects

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Conclusions