Abstract
Although the anti-inflammatory effect of interleukin-1 (IL-1) receptor antagonist (IL-1Ra) has been described, the contribution of this cytokine to cholesterol metabolism remains unclear. Our aim was to ascertain whether deficiency of IL-1Ra deteriorates cholesterol metabolism upon consumption of an atherogenic diet. IL-1Ra-deficient mice (IL-1Ra(-/-)) showed severe fatty liver and portal fibrosis containing many inflammatory cells following 20 weeks of an atherogenic diet when compared with wild type (WT) mice. Expectedly, the levels of total cholesterol in IL-1Ra(-/-) mice were significantly increased, and the start of lipid accumulation in liver was observed earlier when compared with WT mice. Real-time PCR analysis revealed that IL-1Ra(-/-) mice failed to induce mRNA expression of cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, with concurrent up-regulation of small heterodimer partner 1 mRNA expression. Indeed, IL-1Ra(-/-) mice showed markedly decreased bile acid excretion, which is elevated in WT mice to maintain cholesterol level under atherogenic diet feeding. Therefore, we conclude that the lack of IL-1Ra deteriorates cholesterol homeostasis under atherogenic diet-induced inflammation.
Highlights
When compared with other organs, the liver has one of the largest populations of macrophages, which are key components of the innate immune system
The present study demonstrates that IL-1RaϪ/Ϫ mice develop severe nonalcoholic fatty liver disease (NAFLD) and portal fibrosis with many inflammatory cells following 20 weeks of the atherogenic diet when compared with wild type (WT) mice
We found that mRNA levels of IL-1 and transforming growth factor- were significantly elevated in livers of IL-1RaϪ/Ϫ mice
Summary
When compared with other organs, the liver has one of the largest populations of macrophages, which are key components of the innate immune system. Many recent studies suggest that several proinflammatory cytokines produced by activated Kupffer cells might be involved in the onset of liver disease, including alcoholic and nonalcoholic fatty liver disease (NAFLD)1 [2,3,4]. Atherogenic diets contained high concentrations of cholesterol (5%) and fat (30%) either supplemented with cholic acid (2%) [11] or fed in combination with irradiation treatments [12]. It is well recognized that inflammation or cytokines increase serum lipid levels [16, 17] This increase in serum lipid levels can be considered part of the acute phase response that results in marked changes in the levels of a large number of circulating protein primarily due to alterations in the liver [18].
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