Protective effects of a polymethoxy flavonoids-rich Citrus aurantium peel extract on liver fibrosis induced by bile duct ligation in mice

Seol-Wa Lim; Dong-Ryung Lee; Bong-Keun Choi; Hong-Suk Kim; Seung Hwan Yang; Joo-Won Suh; Kyung Soo Kim

doi:10.1016/j.apjtm.2016.10.009

Protective effects of a polymethoxy flavonoids-rich Citrus aurantium peel extract on liver fibrosis induced by bile duct ligation in mice

Asian Pac J Trop Med. 2016 Dec;9(12):1158-1164. doi: 10.1016/j.apjtm.2016.10.009. Epub 2016 Nov 9.

Authors

Seol-Wa Lim¹, Dong-Ryung Lee², Bong-Keun Choi², Hong-Suk Kim³, Seung Hwan Yang⁴, Joo-Won Suh⁵, Kyung Soo Kim⁶

Affiliations

¹ Graduate School of Biomedicine & Health Sciences, Catholic University, Seocho-gu, Seoul 06591, South Korea.
² NutraPharm Tech, Giheung-gu, Yongin, Gyeonggi 17013, South Korea.
³ Interdisciplinary Program of Biomodulation, Myongji University, Yongin, Gyeonggi 17058, South Korea.
⁴ Department of Biotechnology, Chonnam National University, Yeosu, Chonnam 59626, South Korea.
⁵ Center for Nutraceutical and Pharmaceutical Materials, Myongji University, Yongin, Gyeonggi 17058, South Korea.
⁶ Graduate School of Biomedicine & Health Sciences, Catholic University, Seocho-gu, Seoul 06591, South Korea. Electronic address: kskim@catholic.ac.kr.

PMID: 27955743
DOI: 10.1016/j.apjtm.2016.10.009

Abstract

Objective: To evaluate the possible protective effect of Citrus aurantium peel extract (CAE) against apoptosis in cholestatic liver fibrosis induced by bile duct ligation in mice.

Methods: Male ICR mice were divided to 5 groups: 1) Control group (Sham-operated mice), 2) Cholestatic liver injury group induced by bile duct ligation (BDL), 3) BDL mice treated with silymarin (200 mg/kg) for 4 weeks, 4) BDL mice treated with 50 mg/kg CAE for 4 weeks, 5) BDL mice treated with 200 mg/kg CAE for 4 weeks. Mice were sacrificed and liver fibrosis was evaluated by serum and hepatic tissue biochemistry tests and liver histopathological examination. Effects of CAE on inflammation and apoptosis gene regulation were investigated through real-time PCR. CAE effect on lipid metabolism related signaling was determined by western blot analysis.

Results: In BDL mice, administration of CAE for 4 weeks markedly attenuated liver fibrosis based on histopathological alteration. Serum and hepatic tissue biochemistry results revealed that CAE (50 and 200 mg/kg) decreased the levels of alanine transaminase, aspartate transaminase, gamma-glutamyl transferase, total bilirubin, nitric oxide, and thiobarbituric acid reactive substances. Real-time PCR and western blot analysis showed that CAE regulated inflammation, apoptosis, and lipid metabolism factors increased by BDL. Interleukin family, tumor necrosis factor α, and related apoptosis factors mRNA levels were increased by BDL treatment. However, these increases were suppressed by CAE administration. In addition, CAE effectively increased phosphorylation of AMP-activated protein kinase, nuclear factor E2-related factor 2, and related cytoprotective proteins.

Conclusions: CAE can efficiently regulate BDL-induced liver injury with antioxidant, anti-inflammatory, and anti-apoptotic activities.

Keywords: Bile duct ligation; Cholestasis; Citrus aurantium peel extract; Hepatic fibrosis; Liver injury.