Activation of Liver X Receptors Attenuates Endotoxin-Induced Liver Injury in Mice with Nonalcoholic Fatty Liver Disease

Abstract

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. 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. 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. Activation of LXRs attenuates LPS-induced liver injury in murine NAFLD through inhibiting the pro-inflammatory activity of macrophages.