Atherogenic diet-induced hepatitis is partially dependent on murine TLR4

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.

Cattle bile but not bear bile or pig bile induces lipid profile changes and fatty liver injury in mice: mediation by cholic acid

“…Thus, CE rather than TAG can be assumed to be a predominant pathogenic factor for the formation of fatty liver in our experimental models. Furthermore, similar pathological responses have been shown in the mice fed diets supplemented with CA and high levels of fats (Desai et al, 2008;Jeong et al, 2005), in which lipid-accumulation-mediated inflammatory responses were suggested to play an important role. Therefore, to better understand the pathogenesis of CA-induced fatty liver injury in the mice, we should further investigate the mechanism by which MUFA-containing CE accumulated in the liver contribute to the onset of inflammatory events in the liver.…”

Mild Hypercholesterolemia Blunts the Proinflammatory and Prothrombotic Effects of Hypertension on the Cerebral Microcirculation

“…This observation is inconsistent with previous reports from our laboratory 7 and by others. 25 While an explanation for the inconsistency is not readily apparent, it may result from the presence or absence of cholate in the cholesterol-enriched diet used in the different studies. Dietary cholate has been previously shown to induce inflammation and to potentiate the inflammation induced by a high fat diet.…”

Cholate-Containing High-Fat Diet Induces the Formation of Multinucleated Giant Cells in Atherosclerotic Plaques of Apolipoprotein E−/− Mice

“…Enhanced expression of TLRs has been described in apoEϪ/Ϫ mice and in human carotid atherosclerotic plaques. 24 Recently, it has been shown that a cholate-containing HFD induces an early inflammatory response that is mediated through TLR4 25 and that high-fat meals induce low-grade endotoxemia in humans and mice. 12,26 An increased serum concentration of IL-4 might be a factor that directly initiates MGC formation because this cytokine is required for the formation of FBMGCs in vivo and in vitro.…”