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Letrozole ameliorates liver fibrosis through the inhibition of the CTGF pathway and 17β-hydroxysteroid dehydrogenase 13 expression

  • Original Article―Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

To establish a treatment option for liver fibrosis, the possibility of the drug repurposing theory was investigated, with a focus on the off-target effects of active pharmaceutical ingredients.

Methods

First, several active pharmaceutical ingredients were screened for their effects on the gene expression in the hepatocytes using chimeric mice with humanized hepatocytes. As per the gene expression-based screening assay for 36 medications, we assessed the mechanism of the antifibrotic effect of letrozole, a third-generation aromatase inhibitor, in mouse models of liver fibrosis induced by carbon tetrachloride (CCl4) and a methionine choline-deficient (MCD) diet. We assessed liver histology, serum biochemical markers, and fibrosis-related gene and protein expressions in the hepatocytes.

Results

A gene expression-based screening assay revealed that letrozole had a modifying effect on fibrosis-related gene expression in the hepatocytes, including YAP, CTGF, TGF-β, and CYP26A1. Letrozole was administered to mouse models of CCl4- and MCD-induced liver fibrosis and it ameliorated the liver fibrosis. The mechanisms involved the inhibition of the Yap-Ctgf profibrotic pathway following a decrease in retinoic acid levels in the hepatocytes caused by suppression of the hepatic retinol dehydrogenase, Hsd17b13 and activation of the retinoic acid hydrogenase, Cyp26a1.

Conclusions

Letrozole slowed the progression of liver fibrosis by inhibiting the Yap-Ctgf pathway. The mechanisms involved the modification of the Hsd17b13 and Cyp26a1 expressions led to the suppression of retinoic acid in the hepatocytes, which contributed to the activation of Yap-Ctgf pathway. Because of its off-target effect, letrozole could be repurposed for the treatment of liver fibrosis.

Graphical abstract

The third-generation aromatase inhibitor letrozole ameliorated liver fibrosis by suppressing the Yap-Ctgf pathway by partially modifying the Hsd17b13 and Cyp26a1 expressions, which reduced the retinoic acid level in the hepatocytes. The gene expression analysis using chimeric mice with humanized liver revealed that the mechanisms are letrozole specific and, therefore, may be repurposed for the treatment of liver fibrosis.

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Abbreviations

ALT:

Alanine aminotransferase

Acta2:

Actin alpha 2, α-smooth muscle actin

AI:

Aromatase inhibitor

AST:

Aspartate aminotransferase

BW:

Body weight

CCl4:

Carbon tetrachloride

COL1A1:

Collagen type I alpha 1

CTGF:

Connective tissue growth factor

CYP26A1:

Cytochrome P450 26A1

H&E:

Hematoxylin and eosin

HSC:

Hepatic stellate cell

HSD17B13:

17β-Hydroxysteroid dehydrogenase 13

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

LW:

Liver weight

M2BP:

Mac-2 binding protein

MMP:

Matrix metalloproteinase

MCD:

Methionine choline-deficient

NS:

No statistical significance

RA:

Retinoic acid

RDH:

Retinol dehydrogenase

SERM:

Selective estrogen receptor modulator

SCFA:

Short-chain fatty acid

T-Bil:

Total bilirubin

TC:

Total cholesterol

TGF-β:

Transforming growth factor-β

TG:

Triglycerides

YAP:

Yes-associated protein

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Acknowledgements

The authors would like to thank Takao Tsuchida in the Division of Gastroenterology and Hepatology at the Niigata University for his excellent assistance in histological analyses. The authors would also like to thank Nobuyoshi Fujisawa, Yoshitaka Maeda, Kanako Oda, Shuko Adachi, Toshikuni Sasaoka, and all staff members at the Division of Laboratory Animal Resources in Niigata University. They also thank Enago for the critical reading of the manuscript and English language review. The authors declare that they have no conflict of interest.

Funding

Kamimura K, Sakai N, and Terai S of Niigata University received research funds from Towa Pharmaceutical Co., Ltd., and Nakashima M, Ohyama K, Miyamoto H, Inamine T, and Tokunaga A of Nagasaki University received research funds from Towa Pharmaceutical Co., Ltd.

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Author notes

  1. Norihiro Sakai, Kenya Kamimura and Hirotaka Miyamoto have contributed equally to this work.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, 951-8510, Japan

    Norihiro Sakai, Kenya Kamimura, Masayoshi Ko, Takuro Nagoya, Toru Setsu, Akira Sakamaki, Takeshi Yokoo, Hiroteru Kamimura & Shuji Terai

  2. Department of General Medicine, Niigata University School of Medicine, Niigata, Niigata, 951-8510, Japan

    Kenya Kamimura

  3. Department of Pharmaceutics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, 852-8588, Japan

    Hirotaka Miyamoto & Ayako Tokunaga

  4. Unit of Medical Pharmacy, Department of Pharmacy Practice, Nagasaki University, Nagasaki, Nagasaki, 852-8588, Japan

    Hiroyuki Soki, Mikiro Nakashima & Kaname Ohyama

  5. Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, 852-8588, Japan

    Tatsuo Inamine

  6. Organization for Research Promotion, University of the Ryukyus, Nishihara-Cho, Okinawa, 903-0213, Japan

    Tatsuo Inamine

  7. Scientific Research and Business Development Department, Towa Pharmaceutical Co., Ltd., Kadoma, Osaka, 571-8580, Japan

    Hatsune Enomoto, Kazuki Kousaka & Hidehisa Tachiki

  8. Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Nagasaki, 852-8501, Japan

    Kaname Ohyama

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  1. Norihiro Sakai
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Contributions

NS, KK, HM, and KO contributed to the study conception and design. Material preparation, data collection, and analysis were performed by NS, KK, HM, MK, TN, YN, TS, AS, TY, HK, HS, AT, TI, MN, HE, KK, and HT. The first draft of the manuscript was written by NS, KK, TI, KK, KO, and ST. All authors read and approved the final manuscript.

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Correspondence to Kenya Kamimura.

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Supplementary Information

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Supplementary file1 (DOCX 20 KB) Table 1. Administration of the medicines

535_2022_1929_MOESM2_ESM.tif

Supplementary file2 (TIF 2084 KB) Figure S1. The heat map and gene expression list changed significantly with LET administration. Six chimeric mice with humanized liver were used to test all 36 medicines

535_2022_1929_MOESM3_ESM.tif

Supplementary file3 (TIF 811 KB) Figure S2. (A), (B). Effect of LET on the hepatic steatosis of CCl4- and MCD-treated mice. The scale bar represents 100 µm. (C), (D). The relative gene expressions of Hsd17b13 and Cyp26a1 in the female mice treated with CCl4 and MCD. The values represent mean ± SD (n=5 for each group), * p <0.05, One-way ANOVA followed by Bonferroni’s multiple comparison test

535_2022_1929_MOESM4_ESM.tif

Supplementary file4 (TIF 1872 KB) Figure S3. The heat map and list of chemokine and cytokine gene expressions after 36 medicines were tested on six chimeric mice

535_2022_1929_MOESM5_ESM.tif

Supplementary file5 (TIF 4428 KB) Figure S4. The heat map and list of oxidative stress-related gene expressions after 36 medicines were tested on six chimeric mice

535_2022_1929_MOESM6_ESM.tif

Supplementary file6 (TIF 207 KB) Figure S5. Correlation between liver fibrosis and serum RA, and ATRA in the liver tissue. (A). The relationship between liver fibrosis (%) and serum RA. (B). The relationship between liver fibrosis (%) and ATRA in the liver tissue of the CCl4 model mice. The black circles indicate data from animals. The bold black line shows the trend line, and correlation analyses were performed. ** p <0.01, *** p <0.001, and NS, no statistical significance. r, correlation coefficient

535_2022_1929_MOESM7_ESM.tif

Supplementary file7 (TIF 469 KB) Figure S6. Effect of LET on estradiol in female mice. (A). Urine estradiol. (B). Urine creatinine. (C) Creatinine adjusted urinary estradiol. The values represent mean ± SD (n=5 for each group), N.S., not significant, the Student's t-test was used to evaluate the differences in gene expression between the control and drug-treated groups

535_2022_1929_MOESM8_ESM.tif

Supplementary file8 (TIF 659 KB) Figure S7. The dose-dependent effect of LET on gene expression in PXB cells. Relative gene expressions of CTGF, YAP, ACTA2, TGF-β, and HSD17B13 in PXB cells treated with different doses of LET. The values represent mean ± SD (n=4 for each group), * p <0.05, ** p <0.01. The Student's t-test was used to evaluate the differences in gene expression between the control and drug-treated groups

535_2022_1929_MOESM9_ESM.tif

Supplementary file9 (TIF 385 KB) Figure S8. Effect of LET on gene expression in human hepatic stellate cells. Relative gene expressions of CTGF, YAP, ACTA2, TGF-β, and HSD17B13 in PXB cells treated with LET (1 μg/ml). The values represent mean ± SD (n=8 for each group), NS Not statistically significant. The Student's t-test was used to evaluate the differences in gene expression between the control and drug-treated groups

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Sakai, N., Kamimura, K., Miyamoto, H. et al. Letrozole ameliorates liver fibrosis through the inhibition of the CTGF pathway and 17β-hydroxysteroid dehydrogenase 13 expression. J Gastroenterol 58, 53–68 (2023). https://doi.org/10.1007/s00535-022-01929-w

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