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Anthocyanins inhibit high-glucose-induced cholesterol accumulation and inflammation by activating LXR? 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-?-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 (PPAR?) and liver X receptor alpha (LXR?) 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-?1 (TGF?1), as well as NF?B activation. Incubation with the PPAR?-specific inhibitor GW6471 and LXR? shRNA attenuated the anthocyanin-mediated promotion of ABCA1 expression and cholesterol efflux, suggesting that anthocyanins activated PPAR?-LXR?-ABCA1-dependent cholesterol efflux in HK-2 cells. Moreover, the knockout of LXR? abrogated the anti-inflammatory effect of anthocyanins, whereas the PPAR? antagonist GW6471 does not have this effect. Further investigations revealed that LXR? might interfere with anthocyanin-induced decreased ICAM1, MCP1, and TGF?1 expression by reducing the nuclear translocation of NF?B. Collectively, these findings suggest that blocking cholesterol deposition and inhibiting the LXR? pathway-induced inflammatory response might be one of the main mechanisms by which anthocyanins exert their protective effects in DN.

SUBMITTER: Du C

PROVIDER: S-EPMC4567235 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Du Chunyang C Shi Yonghong Y Ren Yunzhuo Y Wu Haijiang H Yao Fang F Wei Jinying J Wu Ming M Hou Yanjuan Y Duan Huijun H

Drug design, development and therapy 20150904

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. I ...[more]

PMID: 26379423

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Project description:BackgroundThe long-term excessive intake of exogenous cholesterol can lead to abnormally elevated blood lipid levels and induce cardiovascular and cerebrovascular diseases. However, the influence and relevance of exogenous cholesterol on plasma cholesterol components were still unclear, and the influence on intestinal lipid metabolism targets needs to be further explored.MethodsIn vivo, the C57BL/6 + NF group and ApoE-/- + NF group mice were fed a normal specific pathogen-free (SPF) diet; the ApoE-/- + HF group mice were fed a high-cholesterol SPF diet. The plasma and jejunum tissue homogenate were obtained for non-targeted lipid metabolomics. The lipid droplets in tissues were observed by transmission electron microscope and oil red O staining. Jejunum tissue morphology was observed by HE staining. The kits were used to detect lipid content in plasma, tissues, intestinal contents, and cells. Western blot, RT-PCR, immunohistochemistry (IHC), and immunofluorescence (IF) were used to observe the key target of lipid metabolism. In vitro, the final concentration of cholesterol was 100 μmol/L in Caco-cells. Oil red O staining, western blot, RT-PCR and immunofluorescence (IF) were used to observe the changes of lipid metabolism. Finally, the influence of liver X receptor alpha (LXRα) on intestinal cholesterol metabolism was clarified by applying the LXRα inhibitor GSK2033 and siRNA targeting LXRα.ResultsThe aortic arch and intestinal villi of the two groups of ApoE-/- mice showed apparent lesions and lipid accumulation, and there were significant changes in a variety of lipids in the plasma and jejunum. Additionally, jejunum LXRα was markedly activated. High cholesterol can significantly activate LXRα in Caco-2 cells. After LXRα was inhibited, the protein level of ATP-binding cassette transporter A1/G5/G8 (ABCA1/G5/G8) decreased, and the quantity and volume of intracellular lipids soared.ConclusionIn a high-cholesterol environment, the intestine promotes the excretion of cholesterol from the cell through the LXRα-ABCA1/G5/G8 pathway, reduces the intestinal intake of a variety of exogenous cholesterol, and reduces the risk of AS.

Dataset Information

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

Publications

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

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