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Hepatic vagus nerve regulates Kupffer cell activation via α7 nicotinic acetylcholine receptor in nonalcoholic steatohepatitis

  • Original Article—Liver, Pancreas, and Biliary Tract
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Abstract

Background

Nonalcoholic fatty liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). Kupffer cells play a central role in promoting hepatic inflammation, which leads to the development of NASH. We investigated the anti-inflammatory effect of hepatic vagus-mediated stimulation of the α7 nicotinic acetylcholine receptor (α7nAChR) on Kupffer cells in NASH pathogenesis.

Methods

Wild-type (WT) mice undergoing hepatic vagotomy (HV) were fed a methionine- and choline-deficient (MCD) diet for 1 week. α7nAChR knockout (α7KO) chimeric mice were generated by transplanting α7KO bone marrow cells into irradiated and Kupffer cell-deleted WT recipients. Kupffer cells were isolated from WT mice and treated with α7nAChR agonist under stimulation by lipopolysaccharide and/or palmitic acid.

Results

HV aggravated MCD diet-induced NASH in both steatosis and inflammation. The hepatic inflammatory response, including the upregulation of tumor necrosis factor alpha (TNFα), interleukin (IL)-12, and monocyte chemoattractant protein 1 (MCP-1), was accelerated in HV mice, accompanied by the downregulation of PPARα pathway genes. Kupffer cells were highly activated via the phosphorylation and nuclear translocation of nuclear factor-kappa B (NF-κB) in MCD diet-fed HV mice. The α7nAchR agonist suppressed the inflammatory response of primary Kupffer cells induced by lipopolysaccharide and palmitic acid by attenuating the NF-κB cascade. α7KO chimeric mice fed an MCD diet for 1 week developed advanced NASH with highly activated Kupffer cells. The hepatic expression of TNFα, IL-12, and MCP-1 was upregulated in α7KO chimeric mice, accompanied by abnormal lipid metabolism.

Conclusions

Hepatic vagus activity regulates the inflammatory response of Kupffer cells via α7nAChR in NASH development.

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Abbreviations

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

TLR:

Toll-like receptor

IL:

Interleukin

TNFα:

Tumor necrosis factor alpha

MCP-1:

Monocyte chemoattractant protein 1

α7nAChR:

α7 nicotinic acetylcholine receptor

STAT3:

Signal transducer and activator of transcription 3

NF-κB:

Nuclear factor-kappa B

MCD:

Methionine- and choline-deficient

WT:

Wild type

α7KO:

α7nAChR knockout

HV:

Hepatic vagotomy

CT:

Control

BM:

Bone marrow

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

LPS:

Lipopolysaccharide

PPARα:

Peroxisome proliferator-activated receptor alpha

AOX:

Acyl-CoA oxidase

L-FABP:

Liver-type fatty acid binding protein

SREBF-1c:

Sterol regulatory element binding factor 1c

FAS:

Fatty acid synthase

G6pc:

Glucose 6-phosphatase

PEPCK:

Phosphoenolpyruvate carboxykinase 1

GFP:

Green fluorescent protein

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Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (No. 15K15495), a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 26461909), and a grant from the Ministry of Health, Labor and Welfare of Japan.

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Authors and Affiliations

  1. Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan

    Takahiro Nishio, Kojiro Taura, Keiko Iwaisako, Yukinori Koyama, Kazutaka Tanabe, Gen Yamamoto, Yukihiro Okuda, Yoshinobu Ikeno, Kenji Yoshino, Yosuke Kasai, Masayuki Okuno, Satoru Seo, Etsuro Hatano & Shinji Uemoto

  2. Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Keiko Iwaisako

  3. Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Takaki Sakurai

  4. Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Masataka Asagiri

  5. Department of Surgery, Hyogo College of Medicine, Hyogo, Japan

    Etsuro Hatano

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  1. Takahiro Nishio
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Correspondence to Kojiro Taura.

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Nishio, T., Taura, K., Iwaisako, K. et al. Hepatic vagus nerve regulates Kupffer cell activation via α7 nicotinic acetylcholine receptor in nonalcoholic steatohepatitis. J Gastroenterol 52, 965–976 (2017). https://doi.org/10.1007/s00535-016-1304-z

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