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Hepatic FATP5 expression is associated with histological progression and loss of hepatic fat in NAFLD patients

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

Background

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are characterized by the accumulation of excess hepatic fat. However, in the progression from NASH to cirrhosis, hepatic fat is often lost. Our aim was to elucidate the mechanism underlying hepatic fat loss during NASH progression.

Methods

Liver biopsies were performed at The University of Tokyo Hospital between November 2011 and March 2016 on 146 patients with NAFLD and 14 patients with cryptogenic cirrhosis who were not being treated with any diabetes or dyslipidemia drugs. Among them, 70 patients underwent liver biopsy after an overnight fast, and 90 patients were biopsied 5 h after an oral glucose tolerance test. Expression differences in genes encoding several fatty acid metabolism-related factors were examined and correlated with hepatic histological changes based on NAFLD activity scores. Prospective patient follow-up continued until June 2018.

Results

The level of fatty acid transport protein 5 (FATP5), which is associated with free fatty acid intake, was significantly and inversely correlated with features of histological progression, including ballooning and fibrosis. This was confirmed by immunohistochemical analysis. Transcript levels of genes encoding fatty acid metabolism-related proteins were comparable between NASH with severe fibrosis and cryptogenic cirrhosis. Furthermore, a prospective cohort study demonstrated that low FATP5 expression was the most significant risk factor for hepatic fat loss.

Conclusions

Decreased hepatic FATP5 expression in NAFLD is linked to histological progression, and may be associated with hepatic fat loss during NASH progression to cirrhosis.

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Acknowledgements

We thank Ms. Seiko Shinzawa for technical assistance. This work was supported by the Research Program on Hepatitis from the Japan Agency for Medical Research and Development (JP17fk0210304 and JP18fk0210040), and from the Ministry of Education, Culture, Sports, Science and Technology. No additional external funding was received. The funders played no role in the study design, data collection, analysis, decision to publish, or manuscript preparation.

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Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Kenichiro Enooku, Mayuko Kondo, Naoto Fujiwara, Akira Kado, Kazuya Okushin, Hidetaka Fujinaga, Ryo Nakagomi, Tatsuya Minami, Masaya Sato, Koji Uchino, Hayato Nakagawa, Yuji Kondo, Yoshinari Asaoka, Ryosuke Tateishi & Kazuhiko Koike

  2. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Takayoshi Sasako & Takashi Kadowaki

  3. Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Hitoshi Ikeda

  4. Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Kyoji Moriya

  5. Department of Pathology, Kyorin University, Tokyo, Japan

    Junji Shibahara

  6. Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan

    Kohjiro Ueki

  7. Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Takeya Tsutsumi & Hiroshi Yotsuyanagi

  8. Kawakita General Hospital, Tokyo, Japan

    Haruhiko Yoshida

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  1. Kenichiro Enooku
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Correspondence to Kazuhiko Koike.

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Supplementary material 1 (DOCX 13 kb)

535_2019_1633_MOESM2_ESM.pdf

FATP5 and CPT1A mRNA expression in patients with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) In patients with AIH and PBC, FATP5 and CPT1A levels did not show significant decreases compared to patients designated as Matteoni type 1 or 2. (PDF 792 kb)

535_2019_1633_MOESM3_ESM.pdf

Binary images of FATP5 immunostaining in patients A-F. These binary images were obtained from images in Figure 3. (PDF 1390 kb)

535_2019_1633_MOESM4_ESM.pdf

Binary images of CPT1A immunostaining in patients A-F These binary images were obtained from images in Figure 4. (PDF 1541 kb)

535_2019_1633_MOESM5_ESM.pdf

FATP5 and CPT1A expression in binary images We constructed binary images of FATP5 and CPT1A immunostaining in five patients with severe ballooning, five patients without ballooning, and five patients with cirrhosis in both the fasting and glucose-loaded groups. The percentages of the FATP5 and CPT1A reactive areas were measured compared to the total area at 200× magnification. Two fields showing the periportal regions of each patient were successively imaged for histomorphometric evaluation. Mann–Whitney U tests were used to investigate differences, and two-tailed P values < 0.05 were considered statistically significant. (PDF 809 kb)

535_2019_1633_MOESM6_ESM.pdf

Cumulative incidence of hepatic steatosis loss (controlled attenuation parameter [CAP] < 250dB/m) without weight reduction stratified by the FATP5/GAPDH ratio in patients with CAP > 250dB/m at liver biopsy The median follow-up period was 3.69 years (IQR 3.34–4.26 years). (PDF 114 kb)

Relationships between steatosis grades and fibrosis stages. (PDF 105 kb)

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Enooku, K., Tsutsumi, T., Kondo, M. et al. Hepatic FATP5 expression is associated with histological progression and loss of hepatic fat in NAFLD patients. J Gastroenterol 55, 227–243 (2020). https://doi.org/10.1007/s00535-019-01633-2

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  • DOI: https://doi.org/10.1007/s00535-019-01633-2

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