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Anthocyanins inhibit high-glucose-induced cholesterol accumulation and inflammation by activating LXRα pathway in HK-2 cells

Authors Du C, Shi Y, Ren Y, Wu H, Yao F, Wei J, Wu M, Hou Y, Duan H

Received 9 June 2015

Accepted for publication 28 July 2015

Published 4 September 2015 Volume 2015:9 Pages 5099—5113

DOI https://doi.org/10.2147/DDDT.S90201

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Rekha Dhanwani

Peer reviewer comments 3

Editor who approved publication: Professor Shu-Feng Zhou


Chunyang Du,1,2,* Yonghong Shi,1,2,* Yunzhuo Ren,1,2 Haijiang Wu,1,2 Fang Yao,1,2 Jinying Wei,1,2 Ming Wu,1,2 Yanjuan Hou,1,2 Huijun Duan1,2

1Department of Pathology, Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People’s Republic of China

*These authors contributed equally to this work

Abstract: The dysregulation of cholesterol metabolism and inflammation plays a significant role in the progression of diabetic nephropathy (DN). Anthocyanins are polyphenols widely distributed in food and exert various biological effects including antioxidative, anti-inflammatory, and antihyperlipidemic effects. However, it remains unclear whether anthocyanins are associated with DN, and the mechanisms involved in the reciprocal regulation of inflammation and cholesterol efflux are yet to be elucidated. In this study, we evaluated the regulation of cholesterol metabolism and the anti-inflammatory effects exerted by anthocyanins (cyanidin-3-O-β-glucoside chloride [C3G] or cyanidin chloride [Cy]) and investigated the underlying molecular mechanism of action using high-glucose (HG)-stimulated HK-2 cells. We found that anthocyanins enhanced cholesterol efflux and ABCA1 expression markedly in HK-2 cells. In addition, they increased peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptor alpha (LXRα) expression and decreased the HG-induced expression of the proinflammatory cytokines intercellular adhesion molecule-1 (ICAM1), monocyte chemoattractant protein-1 (MCP1), and transforming growth factor-β1 (TGFβ1), as well as NFκB activation. Incubation with the PPARα-specific inhibitor GW6471 and LXRα shRNA attenuated the anthocyanin-mediated promotion of ABCA1 expression and cholesterol efflux, suggesting that anthocyanins activated PPARα-LXRα-ABCA1-dependent cholesterol efflux in HK-2 cells. Moreover, the knockout of LXRα abrogated the anti-inflammatory effect of anthocyanins, whereas the PPARα antagonist GW6471 does not have this effect. Further investigations revealed that LXRα might interfere with anthocyanin-induced decreased ICAM1, MCP1, and TGFβ1 expression by reducing the nuclear translocation of NFκB. Collectively, these findings suggest that blocking cholesterol deposition and inhibiting the LXRα pathway-induced inflammatory response might be one of the main mechanisms by which anthocyanins exert their protective effects in DN.

Keywords: 3-O-β-glucoside chloride, cyanidin chloride, diabetic nephropathy, inflammation, liver X receptor alpha

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