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

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Abstract

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.

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Abbreviations

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

LPS:

Lipopolysaccharide

LXR:

Liver X receptor

ND:

Normal diet

HF:

High-fat diet

TNF-α:

Tumor necrosis factor-alpha

iNOS:

Inducible nitric oxide synthase

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

IL:

Interleukin

SREBP-1c:

Sterol regulatory element binding protein 1c

ChREBP:

Carbohydrate response element-binding protein

MDM:

Bone marrow-derived macrophages

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Acknowledgments

This work was supported by the Awards from the National Natural Science Foundation of China (#30770963, #30972751, XM), Shanghai Pujiang Program and Program for Innovative Research Team of Shanghai Municipal Education Commission (XM).

Conflict of interest

The authors have declared that no competing interests exist.

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Authors and Affiliations

  1. Department of Gastroenterology, Shanghai Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University School of Medicine, 145 Shandong Middle Road, Shanghai, 200001, China

    Yuan Liu, Xiaofeng Han, Zhaolian Bian, Yanshen Peng, Zhengrui You, Qixia Wang, Xiaoyu Chen, Dekai Qiu & Xiong Ma

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  1. Yuan Liu
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  2. Xiaofeng Han
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Correspondence to Xiong Ma.

Additional information

Yuan Liu, Xiaofeng Han, and Zhaolian Bian contributed equally to this paper.

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Liu, Y., Han, X., Bian, Z. et al. Activation of Liver X Receptors Attenuates Endotoxin-Induced Liver Injury in Mice with Nonalcoholic Fatty Liver Disease. Dig Dis Sci 57, 390–398 (2012). https://doi.org/10.1007/s10620-011-1902-9

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  • DOI: https://doi.org/10.1007/s10620-011-1902-9

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