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.
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The authors declare that they have no conflict of interest.
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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