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Published online before print March 11, 2008

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(Journal of Leukocyte Biology. 2008;83:1336-1344.)
© 2008 by Society for Leukocyte Biology

Atherogenic diet-induced hepatitis is partially dependent on murine TLR4

Moreshwar S. Desai^*,, M. Michele Mariscalco^*,, Ahmad Tawil, J. G. Vallejo and C. W. Smith^,1

^* Pediatric Critical Care Medicine,
Section of Leukocyte Biology, Children’s Nutrition Research Center, and
Infectious Diseases and Winters Center For Heart Failure Research, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

¹Correspondence: Section of Leukocyte Biology, Department of Pediatrics, Baylor College of Medicine, 1100 Bates Ave., Suite 6014, Houston, TX 77030-2600, USA. E-mail: cwsmith{at}bcm.tmc.edu

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.

Key Words: cholesterol/cholate diet • inflammation • TLR2 • chemokines