A novel compound 4010B-30 upregulates apolipoprotein A-I gene expression through activation of PPARγ in HepG2 cells. Issue 2 (April 2015)

• Record Type: Journal Article
• Authors: Du, Yu; Wang, Li; Si, Shuyi; Yang, Yuan; Hong, Bin
• Is Part Of: Atherosclerosis. Volume 239:Issue 2(2015)
• Page Start: 589
• Page End: 598
• Publication Date: 2015-04
• Subjects: Apolipoprotein (Apo) A-I -- Cholesterol efflux -- Reverse cholesterol transport (RCT) -- Atherosclerosis -- PPARγ; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2015.02.030
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Objective: Apolipoprotein (Apo) A-I is the major lipoprotein content of HDL and upregulating endogenous ApoA-I expression has been proposed as a desirable approach to raise the functional HDL. In this study we investigated the effect of a novel small molecule 4010B-30 on transcriptional regulation of ApoA-I gene in HepG2 cells, and the influence on the level of ApoA-I expression and function. Then the mechanisms by which 4010B-30 regulated ApoA-I expression was further explored. Methods and results: In human hepatic HepG2 cells, 4010B-30 increased the mRNA level and the protein production of ApoA-I both in cell lysates and media. The 4010B-30-induced ApoA-I containing particles increased cholesterol efflux from RAW264.7 macrophages. 4010B-30 also upregulated ABCA1 expression confirmed by transcriptional activity assay and Western blot analysis in both HepG2 and RAW264.7 cells. Promoter luciferase assay was used to identify the 4010B-30-responsive region which is mapped to the proximal −277 bp region of the ApoA-I promoter. Further study indicated that the regulation of 4010B-30 on ApoA-I transcription or protein expression in HepG2 cells was abrogated with the suppression of PPARγ by its small interfering RNA or a specific inhibitor, GW9662. Conclusions: These findings suggest that the novel small molecular upregulator 4010B-30 increases ApoA-I gene expression, thereby enhances its function of promoting cholesterol efflux, as well as ABCA1 expression in vitro, and activation of PPARγ is required for 4010B-30 to induce hepatic ApoA-I production. Highlights: 4010B-30 is a potential compound upregulating Apolipoprotein (Apo) A-I expression. 4010B-30 increases ApoA-I level in HepG2 cells with physiological activity. 4010B-30 also stimulates ABCA1 but does not affect ApoB production. PPARγ activation is required for the effect of 4010B-30 on ApoA-I expression.