Dataset Information

Berberine Promotes OATP1B1 Expression and Rosuvastatin Uptake by Inducing Nuclear Translocation of FXR and LXR?.

ABSTRACT: Berberine, a quinoline alkaloid, can be used in combination with statins to enhance hypolipidemic effects and reduce the dose and side effects of statins. The hypolipidemic effects of statins in the liver are mainly regulated by organic anion transporting polypeptides (OATPs), and the expression of OATPs is regulated by nuclear receptors. Berberine has been reported to affect nuclear receptors. However, whether berberine affects the uptake of statins by regulating nuclear receptor-mediated expression of OATPs remains to be determined. The aim of this study was to investigate the effects of berberine on the expression of OATP1B1 in HepG2 and explore the underlying mechanism. In HepG2 cells, 10-50 ?M berberine significantly increased the uptake of rosuvastatin by inducing the expression of OATP1B1 mRNA and protein. Dual-Luciferase reporter assay showed that luciferase activity of hFXR and hLXR? activated OATP1B1 promoter was increased by 2.5-50 ?M berberine in a concentration-dependent manner, with half-maximal effective concentration (EC50) of 12.19 ± 0.86 and 32.15 ± 2.32 ?M, respectively. In addition, after silencing FXR or LXR? by small interfering RNA (siRNA), berberine-induced OATP1B1 expression was significantly attenuated. Western blot analysis of FXR and LXR? protein levels in the cytoplasm and nucleus of HepG2 cells after treatment with berberine showed that berberine induced nuclear translocation and activation of FXR and LXR?. In conclusion, berberine-induced nuclear translocation of FXR and LXR? could activate OATP1B1 promoter, resulting in enhanced expression of OATP1B1 and increased uptake of rosuvastatin.

SUBMITTER: Liu M

PROVIDER: S-EPMC7118773 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Berberine Promotes OATP1B1 Expression and Rosuvastatin Uptake by Inducing Nuclear Translocation of FXR and LXRα.

Liu Mingyi M Zhu Dandan D Wen Jinhua J Ding Wei W Huang Shibo S Xia Chunhua C Zhang Hong H Xiong Yuqing Y

Frontiers in pharmacology 20200327

Berberine, a quinoline alkaloid, can be used in combination with statins to enhance hypolipidemic effects and reduce the dose and side effects of statins. The hypolipidemic effects of statins in the liver are mainly regulated by organic anion transporting polypeptides (OATPs), and the expression of OATPs is regulated by nuclear receptors. Berberine has been reported to affect nuclear receptors. However, whether berberine affects the uptake of statins by regulating nuclear receptor-mediated expre ...[more]

PMID: 32292349

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Project description:Macrophages are key immune cells for the initiation and development of atherosclerotic lesions. However, the macrophage regulatory nodes that determine how lesions progress in response to dietary challenges are not fully understood. Liver X receptors (LXRs) are sterol-regulated transcription factors that play a central role in atherosclerosis by integrating cholesterol homeostasis and immunity. LXR pharmacological activation elicits a robust antiatherosclerotic transcriptional program in macrophages that can be affected by LXR? S196 phosphorylation in vitro. To investigate the impact of these transcriptional changes in atherosclerosis development, we have generated mice carrying a Ser-to-Ala mutation in myeloid cells in the LDL receptor (LDLR)-deficient atherosclerotic background (M-S196ALdlr-KO). M-S196ALdlr-KO mice fed a high-fat diet exhibit increased atherosclerotic plaque burden and lesions with smaller necrotic cores and thinner fibrous caps. These diet-induced phenotypic changes are consistent with a reprogramed macrophage transcriptome promoted by LXR?-S196A during atherosclerosis development. Remarkably, expression of several proliferation-promoting factors, including the protooncogene FoxM1 and its targets, is induced by LXR?-S196A. This is consistent with increased proliferation of plaque-resident cells in M-S196ALdlr-KO mice. Moreover, disrupted LXR? phosphorylation increases expression of phagocytic molecules, resulting in increased apoptotic cell removal by macrophages, explaining the reduced necrotic cores. Finally, the macrophage transcriptome promoted by LXR?-S196A under dietary perturbation is markedly distinct from that revealed by LXR ligand activation, highlighting the singularity of this posttranslational modification. Overall, our findings demonstrate that LXR? phosphorylation at S196 is an important determinant of atherosclerotic plaque development through selective changes in gene transcription that affect multiple pathways.

Dataset Information

Berberine Promotes OATP1B1 Expression and Rosuvastatin Uptake by Inducing Nuclear Translocation of FXR and LXR?.

Publications

Berberine Promotes OATP1B1 Expression and Rosuvastatin Uptake by Inducing Nuclear Translocation of FXR and LXRα.

Similar Datasets

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