Hepatocyte toll-like receptor 4 deficiency protects against alcohol-induced fatty liver disease.
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.
['Jia|Lin|L|', 'Chang|Xiuli|X|', 'Qian|Shuwen|S|', 'Liu|Chen|C|', 'Lord|Caleb C|CC|', 'Ahmed|Newaz|N|', 'Lee|Charlotte E|CE|', 'Lee|Syann|S|', 'Gautron|Laurent|L|', 'Mitchell|Mack C|MC|', 'Horton|Jay D|JD|', 'Scherer|Philipp E|PE|', 'Elmquist|Joel K|JK|']
D017667:Adipocytes D000410:Alanine Transaminase D000818:Animals D005235:Fatty Liver, Alcoholic D017353:Gene Deletion D022781:Hepatocytes D008297:Male D051379:Mice D022423:Myeloid Cells D051197:Toll-Like Receptor 4 D014280:Triglycerides
Hepatocyte Toll-like receptor 4 Myeloid cell Inflammation Liver injury Alcoholic fatty liver disease