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Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis

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

Background

Angiotensin II type 1 receptor blockers (ARBs) have been reported to attenuate hepatic fibrosis in non-alcoholic steatohepatitis (NASH). However, it is uncertain whether ARBs prevent hepatocarcinogenesis in NASH even after hepatic fibrosis has developed.

Methods

Male Wistar rats were fed with a choline-deficient, l-amino acid-defined (CDAA) diet for 24 weeks, and then fed with the CDAA diet with telmisartan (2 mg/kg/day), a novel ARB, or vehicle for another 24 weeks. The liver histology and the expression of genes and proteins related to angiogenesis were investigated.

Results

The 24-week CDAA diet induced liver cirrhosis. The 48-week CDAA diet exacerbated liver cirrhosis, and developed hepatocellular carcinoma (HCC) in 54.6 % of the rats concurrently with increases of hypoxia-inducible factor-1α (HIF-1α) protein and vascular endothelial growth factor (VEGF) mRNA, which are potent angiogenic factors in the liver. Telmisartan inhibited hepatic fibrosis and preneoplastic lesions and prevented the development of HCC along with inducing decreases in HIF-1α protein and VEGF mRNA.

Conclusions

These data indicated that telmisartan may prevent hepatocarcinogenesis through the inhibition of hepatic angiogenesis even after liver cirrhosis has been established.

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Abbreviations

ALT:

Alanine aminotransferase

ARB:

Angiotensin II type 1 receptor blocker

α-SMA:

α-Smooth muscle actin

CDAA:

Choline-deficient l-amino acid-defined

CSAA:

Choline-sufficient, l-amino acid-defined

CTGF:

Connective tissue growth factor

ICAM-1:

Intercellular adhesion molecule-1

GST-P:

The placental form of glutathione-S-transferase

HIF-1α:

Hypoxia-inducible factor-1α

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

PPAR:

Peroxisome proliferator-activated receptor

RAS:

Renin–angiotensin system

ROS:

Reactive oxygen species

TGF-β1:

Transforming growth factor-β1

TNF-α:

Tumor necrosis factor-α

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sport, Science and Technology of Japan (21790687, 23590997, and 23590996) to Y.N., H.N., and M.Y.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Hokkaido, Japan

    Yosui Tamaki, Yuichi Makino, Shiro Yokohama, Mitsuyoshi Okada, Kazunobu Aso & Masakazu Haneda

  2. Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan

    Yukiomi Nakade, Taeko Yamauchi, Hiroyuki Kanamori, Tomohiko Ohashi, Ken Sato, Haruhisa Nakao & Masashi Yoneda

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  1. Yosui Tamaki
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Correspondence to Yukiomi Nakade.

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Tamaki, Y., Nakade, Y., Yamauchi, T. et al. Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis. J Gastroenterol 48, 491–503 (2013). https://doi.org/10.1007/s00535-012-0651-7

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  • DOI: https://doi.org/10.1007/s00535-012-0651-7

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