Atherogenic diet-induced hepatitis is partially dependent on murine TLR4

Pediatric Critical Care Medicine, Baylor College of Medicine, Houston, TX 77030-2600, USA.
Journal of Leukocyte Biology (Impact Factor: 4.29). 07/2008; 83(6):1336-44. DOI: 10.1189/jlb.0607390
Source: PubMed


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.

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    • "Many proinflammatory genes were induced by the atherogenic diet, which is consistent with other reports [54], [55]. It is known that atherogenic diet-induced hepatic inflammation is partially dependent on toll-like receptor 4 (Tlr4) activation [54]. Tlr4 is a cell surface receptor that detects lipopolysaccharide from gram-negative bacteria, and induces signaling cascades that ultimately induce cytokine production as a component of an inflammatory response. "
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    ABSTRACT: Nutritional intake is a fundamental determinant of health. Many studies have correlated excess caloric intake, as well as a high ratio of n-6:n-3 fatty acids, with detrimental health outcomes, such as the metabolic syndrome. In contrast, low-calorie diets have beneficial health effects. Despite these associations, our understanding of the causal relationship between diet and health remains largely elusive. The present study examined the molecular changes elicited by nine diets with varying fat, sugar, cholesterol, omega-3 fatty acids, omega-6 fatty acids, and calories in C57BL/6 male mice. Microarray analyses were conducted on liver samples from three mice per diet and detected 20,449 genes of which 3,734 were responsive to changes in dietary components. Principal component analysis showed that diet restriction correlated the least with the other diets and also affected more genes than any other diet. Interestingly, Gene Set Enrichment Analysis (GSEA) identified gene sets involved in glutathione metabolism, immune response, fatty acid metabolism, cholesterol metabolism, ABC transporters, and oxidative phosphorylation as being highly responsive to changes in diet composition. On the gene level, this study reveals novel findings such as the induction of the drug efflux pump Abcb1a (p-glycoprotein) by diet restriction and an atherogenic diet, as well as the suppression of the rate limiting step of bile acid synthesis, Cyp7a1, by a high fructose diet. This study provides considerable insight into the molecular changes incurred by a variety of diets and furthers our understanding of the causal relationships between diet and health.
    PLoS ONE 02/2014; 9(2):e88584. DOI:10.1371/journal.pone.0088584 · 3.23 Impact Factor
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    • "Most studies of the effects of diets in apoE−/− mice have focused tightly on development and progression of atherosclerotic plaques. However, the HC diet used here and in many other studies also induces inflammatory responses in the liver [25]–[28], raising the possibility that liver damage might result in elevated plasma levels of arginase I and thus reduce circulating arginine levels. Thus, plasma arginase activities were determined for three independent experiments in which C57BL6 and apoE−/− mice were fed standard, HF or HC diets for 2 months as described in Methods. "
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    ABSTRACT: Increased catabolism of arginine by arginase is increasingly viewed as an important pathophysiological factor in cardiovascular disease, including atherosclerosis induced by high cholesterol diets. Whereas previous studies have focused primarily on effects of high cholesterol diets on arginase expression and arginine metabolism in specific blood vessels, there is no information regarding the impact of lipid diets on arginase activity or arginine bioavailability at a systemic level. We, therefore, evaluated the effects of high fat (HF) and high fat-high cholesterol (HC) diets on arginase activity in plasma and tissues and on global arginine bioavailability (defined as the ratio of plasma arginine to ornithine + citrulline) in apoE(-/-) and wild-type C57BL/6J mice. HC and HF diets led to reduced global arginine bioavailability in both strains. The HC diet resulted in significantly elevated plasma arginase in both strains, but the HF diet increased plasma arginase only in apoE(-/-) mice. Elevated plasma arginase activity correlated closely with increased alanine aminotransferase levels, indicating that liver damage was primarily responsible for elevated plasma arginase. The HC diet, which promotes atherogenesis, also resulted in increased arginase activity and expression of the type II isozyme of arginase in multiple tissues of apoE(-/-) mice only. These results raise the possibility that systemic changes in arginase activity and global arginine bioavailability may be contributing factors in the initiation and/or progression of cardiovascular disease.
    PLoS ONE 12/2010; 5(12):e15253. DOI:10.1371/journal.pone.0015253 · 3.23 Impact Factor
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    • "Atherogenic diets including a Western style diet, high cholesterol or high fat diet have been shown to promote renal interstitial inflammatory disease (Eddy, 1996) and hepatic steatosis (Desai et al., 2008) as well as exacerbate the inflammatory response of the ischemic myocardium (Yaoita et al., 2005). In the brain, a high fat diet increased oxidative stress in the hippocampus (Wu et al., 2004) and cortex (Zhang et al., 2005). "
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    ABSTRACT: While the effects of a proatherogenic diet have been widely studied in the context of systemic inflammation, much less is known about its effects on central or brain inflammation and its modulation with age. In this study, we examined the effect of a high cholesterol/choline diet in adult and older acyclic females to assess its impact on systemic and central inflammatory markers. Moreover, since the loss of ovarian hormones at menopause may predispose women to increased production of pro-inflammatory cytokines, we also tested the impact of estrogen replacement to adult and older females in diet-induced inflammation. Ovariectomized adult female rats and older (reproductive senescent) female rats were replaced with estrogen or a control pellet and maintained thereafter on a diet containing either 4% cholesterol/1% choline or control chow for 10 weeks. Interleukin 1beta (IL-1beta) expression in the liver was used as a marker of systemic inflammation, while a panel of cytokine/chemokines were used to examine the effects of diet on the hippocampus. IL-1beta expression was elevated in the liver of adult and reproductive senescent females fed with the high cholesterol diet, although this was restricted to groups that were ovariectomized and not replaced with estrogen. Estrogen-treated animals of both ages did not have elevated IL-1beta levels when fed the high cholesterol diet. Diet-induced changes in cytokine/chemokine expression in the hippocampus however were critically age dependent and restricted to the reproductive senescent females. In this group, the high cholesterol diet led to an increase in interleukin (IL)-4, IL-6, IL-12p70, IL-13, RANTES (Regulated on Activation, Normal T Expressed and Secreted) and VEGF (vascular endothelial growth factor). Moreover, estrogen treatment to reproductive senescent females suppressed diet-induced expression of specific cytokines (RANTES, VEGF, IL-6) and attenuated the expression of others (IL-4, IL-12p70, and IL-13). These data indicate that a proatherogenic diet presents a significant risk for central inflammation in older females that are deprived of estrogen treatment.
    Journal of neuroimmunology 06/2010; 223(1-2):31-8. DOI:10.1016/j.jneuroim.2010.03.024 · 2.47 Impact Factor
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