PMID- 26379423 OWN - NLM STAT- MEDLINE DCOM- 20160712 LR - 20210112 IS - 1177-8881 (Electronic) IS - 1177-8881 (Linking) VI - 9 DP - 2015 TI - Anthocyanins inhibit high-glucose-induced cholesterol accumulation and inflammation by activating LXRalpha pathway in HK-2 cells. PG - 5099-113 LID - 10.2147/DDDT.S90201 [doi] AB - 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-beta-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 (PPARalpha) and liver X receptor alpha (LXRalpha) 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-beta1 (TGFbeta1), as well as NFkappaB activation. Incubation with the PPARalpha-specific inhibitor GW6471 and LXRalpha shRNA attenuated the anthocyanin-mediated promotion of ABCA1 expression and cholesterol efflux, suggesting that anthocyanins activated PPARalpha-LXRalpha-ABCA1-dependent cholesterol efflux in HK-2 cells. Moreover, the knockout of LXRalpha abrogated the anti-inflammatory effect of anthocyanins, whereas the PPARalpha antagonist GW6471 does not have this effect. Further investigations revealed that LXRalpha might interfere with anthocyanin-induced decreased ICAM1, MCP1, and TGFbeta1 expression by reducing the nuclear translocation of NFkappaB. Collectively, these findings suggest that blocking cholesterol deposition and inhibiting the LXRalpha pathway-induced inflammatory response might be one of the main mechanisms by which anthocyanins exert their protective effects in DN. FAU - Du, Chunyang AU - Du C AD - Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China. FAU - Shi, Yonghong AU - Shi Y AD - Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China. FAU - Ren, Yunzhuo AU - Ren Y AD - Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China. FAU - Wu, Haijiang AU - Wu H AD - Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China. FAU - Yao, Fang AU - Yao F AD - Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China. FAU - Wei, Jinying AU - Wei J AD - Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China. FAU - Wu, Ming AU - Wu M AD - Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China. FAU - Hou, Yanjuan AU - Hou Y AD - Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China. FAU - Duan, Huijun AU - Duan H AD - Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150904 PL - New Zealand TA - Drug Des Devel Ther JT - Drug design, development and therapy JID - 101475745 RN - 0 (ABCA1 protein, human) RN - 0 (ATP Binding Cassette Transporter 1) RN - 0 (Anthocyanins) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Glucosides) RN - 0 (Inflammation Mediators) RN - 0 (Liver X Receptors) RN - 0 (NR1H3 protein, human) RN - 0 (Orphan Nuclear Receptors) RN - 0 (PPAR alpha) RN - 0 (cyanidin-3-O-beta-glucopyranoside) RN - 7732ZHU564 (cyanidin) RN - 97C5T2UQ7J (Cholesterol) RN - IY9XDZ35W2 (Glucose) SB - IM MH - ATP Binding Cassette Transporter 1/genetics/metabolism MH - Anthocyanins/*pharmacology MH - Anti-Inflammatory Agents/*pharmacology MH - Cell Line MH - Cholesterol/*metabolism MH - Diabetic Nephropathies/*drug therapy/genetics/metabolism MH - Dose-Response Relationship, Drug MH - Gene Expression Regulation MH - Glucose/*metabolism MH - Glucosides/*pharmacology MH - Humans MH - Inflammation Mediators/metabolism MH - Kidney/*drug effects/metabolism MH - Liver X Receptors MH - Nephritis/*drug therapy/genetics/metabolism MH - Orphan Nuclear Receptors/*agonists/genetics/metabolism MH - PPAR alpha/genetics/metabolism MH - RNA Interference MH - Signal Transduction/drug effects MH - Time Factors MH - Transfection PMC - PMC4567235 OTO - NOTNLM OT - 3-O-beta-glucoside chloride OT - cyanidin chloride OT - diabetic nephropathy OT - inflammation OT - liver X receptor alpha EDAT- 2015/09/18 06:00 MHDA- 2016/07/13 06:00 PMCR- 2015/09/04 CRDT- 2015/09/18 06:00 PHST- 2015/09/18 06:00 [entrez] PHST- 2015/09/18 06:00 [pubmed] PHST- 2016/07/13 06:00 [medline] PHST- 2015/09/04 00:00 [pmc-release] AID - dddt-9-5099 [pii] AID - 10.2147/DDDT.S90201 [doi] PST - epublish SO - Drug Des Devel Ther. 2015 Sep 4;9:5099-113. doi: 10.2147/DDDT.S90201. eCollection 2015.