Exogenous Administration of Low-Dose Lipopolysaccharide Potentiates Liver Fibrosis in a Choline-Deficient l-Amino-Acid-Defined Diet-Induced Murine Steatohepatitis Model

Keisuke Nakanishi,Kenichiro Seki,Soichiro Saikawa,Kei Moriya,Kosuke Kaji,Masanori Furukawa,Tadashi Namisaki,Hitoshi Yoshiji,Mitsuteru Kitade,Shinya Sato,Naotaka Shimozato,Takuya Kubo,Hideto Kawaratani

doi:10.3390/ijms20112724

Keisuke Nakanishi, Kenichiro Seki + Show 11 more

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https://doi.org/10.3390/ijms20112724

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Various rodent models have been proposed for basic research; however, the pathogenesis of human nonalcoholic steatohepatitis (NASH) is difficult to closely mimic. Lipopolysaccharide (LPS) has been reported to play a pivotal role in fibrosis development during NASH progression via activation of toll-like receptor 4 (TLR4) signaling. This study aimed to clarify the impact of low-dose LPS challenge on NASH pathological progression and to establish a novel murine NASH model. C57BL/6J mice were fed a choline-deficient l-amino-acid-defined (CDAA) diet to induce NASH, and low-dose LPS (0.5 mg/kg) was intraperitoneally injected thrice a week. CDAA-fed mice showed hepatic CD14 overexpression, and low-dose LPS challenge enhanced TLR4/NF-κB signaling activation in the liver of CDAA-fed mice. LPS challenge potentiated CDAA-diet-mediated insulin resistance, hepatic steatosis with upregulated lipogenic genes, and F4/80-positive macrophage infiltration with increased proinflammatory cytokines. It is noteworthy that LPS administration extensively boosted pericellular fibrosis with the activation of hepatic stellate cells in CDAA-fed mice. Exogenous LPS administration exacerbated pericellular fibrosis in CDAA-mediated steatohepatitis in mice. These findings suggest a key role for LPS/TLR4 signaling in NASH progression, and the authors therefore propose this as a suitable model to mimic human NASH.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is defined as ectopic lipid accumulation in the liver without other secondary causes such as chronic viral hepatitis, excessive alcohol consumption, autoimmune hepatitis, or congenital hepatic disorders [1,2]
NAFLD patients often develop nonalcoholic steatohepatitis (NASH), which is histologically characterized by the presence of hepatic inflammation and may potentially progress to fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC) [3,4]
NASH is a currently growing cause of liver cirrhosis and HCC in developed countries, and a recent longitudinal study in NASH patients showed that the fibrosis stage is uniquely associated with long-term overall mortality, liver transplantation, and liver-related events [5,6]

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Introduction

Nonalcoholic fatty liver disease (NAFLD) is defined as ectopic lipid accumulation in the liver without other secondary causes such as chronic viral hepatitis, excessive alcohol consumption, autoimmune hepatitis, or congenital hepatic disorders [1,2]. The effect of choline deficiency on NASH development is well established, corroborated by the fact that a choline-deficient l-amino-acid-defined (CDAA) diet is frequently utilized in murine NASH models [7,8,9]. These CDAA-fed rodents are available as NASH experimental models, they are not entirely inadequate for mimicking NASH, as some important characteristics are missing. CDAA-fed mice exhibiting obesity and IR develop limited liver fibrosis [11]. This defect is inconvenient for NASH fibrogenesis basic research and evidences the need for a further improved CDAA-fed mouse model

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