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United States Department of Agriculture

Agricultural Research Service

Title: Atherogenic diet-induced hepatitis is partially dependent on murine TLR4

Authors
item Desai, Moreshwar - BAYLOR COLLEGE OF MED
item Mariscalco, Michele - BAYLOR COLLEGE OF MED
item Tawil, Ahmad - BAYLOR COLLEGE OF MED
item Vallejo, J - BAYLOR COLLEGE OF MED
item Smith, C Wayne

Submitted to: Journal of Leukocyte Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 5, 2008
Publication Date: June 20, 2008
Citation: Desai M.S., Mariscalco, M.M., Tawil, A., Vallejo, J.G., Smith, C.W. 2008. Atherogenic diet-induced hepatitis is partially dependent on murine TLR4. Journal of Leukocyte Biology. 83:1336-1344.

Interpretive Summary: This paper uses an animal model of diet-induced inflammation in the liver that causes liver injury. The purpose of the investigation is to determine if TLR-4 is important to diet-induced liver injury. TLR-4 is the scientific designation of a molecule on the surface of many cells in the body. This molecule functions as a receptor for certain molecules released from the cell walls of some bacteria, especially those found in the intestinal track. When TLR-4 binds to bacterial molecules it is capable of causing inflammation that helps to prevent the bacteria from causing infection. However, if bacterial molecules are released into the blood, TLR-4 may cause inflammation that is harmful to the body (for example, cause liver injury). This paper shows that diet-induced liver inflammation is significantly reduced in mice that lack TLR-4. Further studies will be necessary to determine if this is due to release of bacterial molecules from the intestinal track into the blood, or due to the ability of TLR-4 to bind some molecules present in the high fat diet.

Technical Abstract: Diets high in cholesterol and cholate such as the Paigen diet have been used to study atherogenesis, lithogenesis, and proinflammatory microvascular changes induced by nutritional hypercholesterolemia. Although these diets lead to chronic hepatic inflammation and fibrosis, the early inflammatory changes have been poorly characterized. TLR4, a known receptor for LPS, is also a receptor for a variety of endogenous ligands and has been implicated in atheroma formation. Here, we specifically examined the early inflammatory response of the liver to the atherogenic (ATH) diet and the possible contribution of TLR4. Animals fed the high-cholesterol/cholate diet for 3 weeks developed a significant, predominantly mononuclear leukocyte infiltration in the liver, hepatic steatosis, elevated hepatic expression of MCP-1, RANTES, and MIP-2, and increased serum levels of liver enzymes. In TLR4-deleted animals, there was a 30% attenuation in the serum alanine transaminase levels and a 50% reduction in the leukocyte infiltration with a fourfold reduction in chemokine expression. In contrast, hepatic steatosis did not differ from wild-type controls. TLR2 deletion had no effect on diet-induced hepatitis but increased the amount of steatosis. We conclude that the early inflammatory liver injury but not hepatic lipid loading induced by the ATH diet in mice is mediated in part by TLR4.

Last Modified: 7/30/2014
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