J Appl Biomed 21:80-90, 2023 | DOI: 10.32725/jab.2023.009

Antioxidant action of xanthine oxidase inhibitor febuxostat protects the liver and blood vasculature in SHRSP5/Dmcr rats

Mai Kakimoto¹, Moe Fujii¹, Ikumi Sato¹, Koki Honma¹, Hinako Nakayama¹, Sora Kirihara¹, Taketo Fukuoka², Shang Ran¹, Satoshi Hirohata³, Kazuya Kitamori⁴, Shusei Yamamoto^{1, 3}, Shogo Watanabe^{3, *}

¹ Okayama University, Graduate School of Health Sciences, Department of Medical Technology, 2-5-1, Shikata-cho, Kita-ku, Okayama-shi, Okayama 700-8558, Japan

² Okayama University, Faculty of Health Sciences, Department of Medical Technology, 2-5-1, Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan

³ Okayama University, Academic Field of Health Science, 2-5-1, Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan

⁴ Kinjo Gakuin University, College of Human Life and Environment, 2-1723, Omori, Moriyama-ku, Nagoya-shi, Aichi, 463-8521, Japan

Background: Xanthine oxidase (XO) generates reactive oxygen species during uric acid production. Therefore, XO inhibitors, which suppress oxidative stress, may effectively treat non-alcoholic steatohepatitis (NASH) and atherosclerosis via uric acid reduction. In this study, we examined the antioxidant effect of the XO inhibitor febuxostat on NASH and atherosclerosis in stroke-prone spontaneously hypertensive 5 (SHRSP5/Dmcr) rats.

Methods: SHRSP5/Dmcr rats were divided into three groups: SHRSP5/Dmcr + high-fat and high-cholesterol (HFC) diet [control group, n = 5], SHRSP5/Dmcr + HFC diet + 10% fructose (40 ml/day) [fructose group, n = 5], and SHRSP5/Dmcr + HFC diet + 10% fructose (40 ml/day) + febuxostat (1.0 mg/kg/day) [febuxostat group, n = 5]. Glucose and insulin resistance, blood biochemistry, histopathological staining, endothelial function, and oxidative stress markers were evaluated.

Results: Febuxostat reduced the plasma uric acid levels. Oxidative stress-related genes were downregulated, whereas antioxidant factor-related genes were upregulated in the febuxostat group compared with those in the fructose group. Febuxostat also ameliorated inflammation, fibrosis, and lipid accumulation in the liver. Mesenteric lipid deposition decreased in the arteries, and aortic endothelial function improved in the febuxostat group.

Conclusions: Overall, the XO inhibitor febuxostat exerted protective effects against NASH and atherosclerosis in SHRSP5/Dmcr rats.

Keywords: Anti-inflammatory; Atherosclerosis; Febuxostat; Non-alcoholic steatohepatitis (NASH); Oxidative stress; Uric acid

Grants and funding:

This work was supported by grants from the Japan Society for the Promotion of Science (Grant Number 15K19178) and a Grant-in-Aid for Scientific Research (C) (Grant Number 18K10993) to S. Watanabe, and Gout Research Foundation of Japan to S. Watanabe.

Conflicts of interest:

The authors declare no conflict of interests directly relevant to the content of this article.

Received: December 15, 2022; Revised: March 13, 2023; Accepted: April 25, 2023; Prepublished online: May 22, 2023; Published: June 27, 2023  Show citation