Hepatocyte toll-like receptor 4 deficiency protects against alcohol-induced fatty liver disease
Lin Jia1, Xiuli Chang2, Shuwen Qian3
1Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Objective:
Recent studies have suggested a critical role for toll-like receptor 4 (TLR4) in the development of alcoholic liver disease. As TLR4 is widely expressed throughout the body, it is unclear which TLR4-expressing cell types contribute to alcohol-induced liver damage.
Methods:
We selectively ablated TLR4 in hepatocytes and myeloid cells. Male mice were fed a liquid diet containing either 5% alcohol or pair-fed a control diet for 4 weeks to examine chronic alcohol intake-induced liver damage and inflammation. In addition, mice were administered a single oral gavage of alcohol to investigate acute alcohol drinking-associated liver injury.
Results:
We found that selective hepatocyte TLR4 deletion protected mice from chronic alcohol-induced liver injury and fatty liver. This result was in part due to decreased expression of endogenous lipogenic genes and enhanced expression of genes involved in fatty acid oxidation. In addition, mice lacking hepatocyte TLR4 exhibited reduced mRNA expression of inflammatory genes in white adipose tissue. Furthermore, in an acute alcohol binge model, hepatocyte TLR4 deficient mice had significantly decreased plasma alanine transaminase (ALT) levels and attenuated hepatic triglyceride content compared to their alcohol-gavaged control mice. In contrast, deleting TLR4 in myeloid cells did not affect the development of chronic-alcohol induced fatty liver, despite the finding that mice lacking myeloid cell TLR4 had significantly reduced circulating ALT concentrations.
Conclusions:
These findings suggest that hepatocyte TLR4 plays an important role in regulating alcohol-induced liver damage and fatty liver disease.
Insights
Hepatocyte toll-like receptor 4 (TLR4) deletion protects against alcohol-induced liver injury and fatty liver. This highlights the critical role of liver cells, not immune cells, in alcohol-related liver damage.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Alcoholic liver disease (ALD) is a major health concern.
- Toll-like receptor 4 (TLR4) is implicated in ALD development.
- The specific cell types expressing TLR4 that drive alcohol-induced liver damage remain unclear.
Purpose of the Study:
- To investigate the role of TLR4 in hepatocytes and myeloid cells in alcohol-induced liver damage.
- To determine whether TLR4 in specific cell types contributes to chronic and acute alcohol-induced liver injury.
Main Methods:
- Selective ablation of TLR4 in hepatocytes and myeloid cells in male mice.
- Chronic alcohol feeding (4 weeks) and acute alcohol gavage models were used.
- Liver injury, fatty liver, gene expression, and plasma biomarkers were assessed.
Main Results:
- Hepatocyte-specific TLR4 deletion protected against chronic alcohol-induced liver injury and fatty liver.
- This protection was associated with altered lipogenic and fatty acid oxidation gene expression in hepatocytes.
- Acute alcohol exposure also resulted in less liver injury in hepatocyte TLR4-deficient mice.
- Myeloid cell TLR4 deletion did not prevent chronic fatty liver but reduced acute liver injury markers.
Conclusions:
- Hepatocyte TLR4 is a key mediator of alcohol-induced liver damage and fatty liver disease.
- Targeting TLR4 in hepatocytes may be a therapeutic strategy for ALD.
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