Related Experiment Video
Updated: Mar 26, 2026
An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
Subclinical-Dose Endotoxin Sustains Low-Grade Inflammation and Exacerbates Steatohepatitis in High-Fat Diet-Fed Mice
Honghui Guo1,2, Na Diao1,3, Ruoxi Yuan1
1Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0910, USA.
Abstract:
Subclinical circulating bacterial endotoxin LPS has been implicated as an important cofactor in the development and progression of nonalcoholic steatohepatitis, but the underlying mechanisms remain unclear. In this study, we demonstrated that 4-wk injection with superlow-dose LPS significantly promoted neutrophil infiltration and accelerated nonalcoholic steatohepatitis progression, including exacerbated macrovesicular steatosis, inflammation, and hepatocyte ballooning in high-fat diet-fed apolipoprotein E knockout mice. This effect could sustain for a month after stoppage of LPS injection. LPS also significantly increased numbers of apoptotic nuclei in hepatocytes and expressions of proapoptotic regulators. Moreover, LPS sustained the low-grade activation of p38 MAPK and inhibited the expression of the upstream MAPK phosphatase 7. By applying selective inhibitors, we demonstrated that the activation of p38 MAPKs is required for neutrophil migration induced by superlow-dose LPS in vitro. Together, these data suggest that superlow-dose LPS may sustain the low-grade activation of p38 MAPKs and neutrophil infiltration, leading to the exacerbation of steatohepatitis.
Insights
Subclinical bacterial endotoxin (lipopolysaccharide/LPS) exacerbates nonalcoholic steatohepatitis by promoting neutrophil infiltration and sustained p38 MAPK activation. This effect persists even after LPS exposure ceases, highlighting a potential therapeutic target.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Subclinical bacterial endotoxin, lipopolysaccharide (LPS), is linked to nonalcoholic steatohepatitis (NASH) development.
- The precise mechanisms by which LPS influences NASH progression are not fully understood.
Purpose of the Study:
- To investigate the role of superlow-dose LPS in exacerbating NASH progression.
- To elucidate the underlying molecular mechanisms involving neutrophil infiltration and MAPK signaling.
Main Methods:
- Administration of superlow-dose LPS to high-fat diet-fed apolipoprotein E knockout mice.
- Assessment of liver pathology, including steatosis, inflammation, and hepatocyte ballooning.
- Evaluation of neutrophil infiltration, apoptosis, and p38 MAPK pathway activation.
Main Results:
- Superlow-dose LPS significantly worsened NASH features and promoted neutrophil infiltration.
- LPS-induced effects persisted for one month post-injection and increased hepatocyte apoptosis.
- LPS sustained p38 MAPK activation and inhibited MAPK phosphatase 7, with p38 MAPK activation being crucial for LPS-induced neutrophil migration.
Conclusions:
- Superlow-dose LPS exacerbates NASH by sustaining low-grade p38 MAPK activation and neutrophil infiltration.
- These findings suggest a mechanism linking bacterial endotoxin exposure to chronic liver disease progression.
- Targeting the p38 MAPK pathway may offer a therapeutic strategy for LPS-mediated NASH exacerbation.
