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Absence of invariant natural killer T cells deteriorates liver inflammation and fibrosis in mice fed high-fat diet

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

Background

Invariant natural killer T (iNKT) cells have been suggested to play critical roles in a wide range of immune responses by acting in a proinflammatory or anti-inflammatory manner. Nonalcoholic steatohepatitis (NASH) is a chronic liver disease progressing to advanced cirrhosis and hepatocellular carcinoma. Despite the abundance of iNKT cells in the liver, their role in the pathogenesis of NASH remains obscure. Here, we investigated their role in the development of diet-induced steatosis/steatohepatitis.

Methods

We used BALB/c wild-type mice and Jα18-deficient (KO) mice lacking iNKT cells fed either a normal diet or a high-fat diet (HFD). The liver and blood were collected from these mice to examine liver inflammation, steatosis, and fibrosis at the indicated time points.

Results

KO mice fed the HFD, compared with control mice fed the HFD, exhibited a clearly higher serum alanine aminotransferase level and a greater number of hepatic inflammatory foci, although there was no significant difference in hepatic lipid retention between these groups of mice. The HFD enhanced hepatic messenger RNA expression of inflammatory cytokines and chemokines in KO but not in control mice. The HFD also increased the proportion of hepatic CD4 T cells and CD8 T cells that composed hepatic inflammatory foci in KO mice, but not in the controls. Prolonged feeding with the HFD augmented liver fibrosis in KO but not in control mice.

Conclusions

These findings indicate that iNKT cells play a protective role against liver inflammation progressing to fibrosis, but not against steatosis, enhanced by dietary excess fat, suggesting a key role of these cells in NASH pathogenesis.

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Abbreviations

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

iNKT:

Invariant natural killer T

NK:

Natural killer

TCR:

T cell receptor

Th:

T helper

IFN:

Interferon

IL:

Interleukin

WT:

Wild type

ND:

Normal diet

HFD:

High-fat diet

KO:

Jα18-deficient

ALT:

Alanine aminotransferase

RT-PCR:

Reverse transcription polymerase chain reaction

H&E:

Hematoxylin–eosin

SEM:

Standard error of the mean

TNF:

Tumor necrosis factor

CCL:

Chemokine (C–C motif) ligand

CXCL:

Chemokine (C–X–C motif) ligand

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Acknowledgments

The authors thank Drs. Masaru Taniguchi and Ken-ichiro Seino for providing Jα18-deficient BALB/c mice. This work was supported by a Grant-in-Aid for Scientific Research (to T. Takehara) and Global Centers of Excellence Program (to T. Miyagi) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Takuya Miyagi, Tetsuo Takehara, Akio Uemura, Kumiko Nishio, Satoshi Shimizu, Takahiro Kodama, Hayato Hikita, Wei Li, Akira Sasakawa, Tomohide Tatsumi, Kazuyoshi Ohkawa, Tatsuya Kanto, Naoki Hiramatsu & Norio Hayashi

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  1. Takuya Miyagi
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  2. Tetsuo Takehara
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Correspondence to Norio Hayashi.

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Miyagi, T., Takehara, T., Uemura, A. et al. Absence of invariant natural killer T cells deteriorates liver inflammation and fibrosis in mice fed high-fat diet. J Gastroenterol 45, 1247–1254 (2010). https://doi.org/10.1007/s00535-010-0272-y

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  • DOI: https://doi.org/10.1007/s00535-010-0272-y

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