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Erschienen in:
01.02.2012 | Original Article
Activation of Liver X Receptors Attenuates Endotoxin-Induced Liver Injury in Mice with Nonalcoholic Fatty Liver Disease
Erschienen in: Digestive Diseases and Sciences | Ausgabe 2/2012
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Background/Aims
Nonalcoholic fatty liver disease (NAFLD) is classically associated with insulin resistance and the inflammatory response, especially in the nonalcoholic steatohepatitis phase. The liver X receptors (LXRs) play a critical role in the regulation of cholesterol metabolism and inflammatory processes.
Methods
Wild-type C57BL/6 mice were fed a normal diet (ND) or a high-fat (HF) diet for 8 weeks. Some ND- and HF-fed mice were treated (i.p.) with the LXR agonist T0901317 (30 mg/kg/day) for 7 days. Lipopolysaccharide (LPS, 50 μg/mouse) was then injected intraperitoneally to induce liver injury. The activation of MAPKs, NF-κB and the PI3K pathway was evaluated using Western blot. Bone marrow-derived macrophages (MDMs) were isolated from the femurs of C57BL/6 mice and cultured with or without T0901317 (20 μmol/l). The expression of tumor necrosis factor-alpha (TNF-α) and inducible nitric oxide synthase (iNOS) was evaluated in vitro or in vivo using real-time PCR, immunohistochemistry, or Western blot.
Results
The LXR agonist T0901317 attenuated LPS-induced liver injury in a murine model of NAFLD, reflected by reduced serum alanine aminotransferase and aspartate aminotransferase levels, and reduced liver histology changes. Activation of LXRs reduced TNF-α and iNOS expression through inhibiting JNK and the PI3K signaling pathway. An in vitro study demonstrated that the activation of LXR inhibited the expression of TNF-α and iNOS in the MDMs of mice.
Conclusions
Activation of LXRs attenuates LPS-induced liver injury in murine NAFLD through inhibiting the pro-inflammatory activity of macrophages.