title: Anthocyanins inhibit high-glucose-induced cholesterol accumulation and inflammation by activating LXRα pathway in HK-2 cells.
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.
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Du
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China.
authors.forename: Yunzhuo
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China.
authors.forename: Haijiang
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yao
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China.
authors.forename: Jinying
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China.
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Pathology, Hebei Medical University, Shijiazhuang, People's Republic of China ; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, People's Republic of China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Duan
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000872:Anthocyanins / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D005960:Glucosides / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D000071518:Liver X Receptors; D009393:Nephritis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000872:Anthocyanins; D000893:Anti-Inflammatory Agents; D005960:Glucosides; D018836:Inflammation Mediators; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; C462279:cyanidin-3-O-beta-glucopyranoside; C017154:cyanidin; D002784:Cholesterol; D005947:Glucose
keywords: 3-O-β-glucoside chloride; cyanidin chloride; diabetic nephropathy; inflammation; liver X receptor alpha