Andrographolide Inhibits Intestinal Lipid Secretion via Antagonizing Estrogen-Related Receptor α Activity
LI Li1,2, GAO Jun2, WANG Zihui2,3, ZHANG Minyi2, WU Shangying2, YAO Dongsheng1*, GUAN Min2*
The aim of this study is to investigate the effect and mechanism of AP (andrographolide), an ERRα (estrogen-related receptor α, also called ESRRA) inverse agonist, on lipid secretion of small intestine. Luciferase reporter assay was employed to identify whether AP decreases transcriptional activity of ERRα and its coactivitor PGC1α (peroxisome proliferator-activated receptor coactivator 1α). To determine if AP suppresses the promoter activity and gene expression of ERRα target genes Apob (apolipoprotein B) and Mttp (microsomal triglyceride transfer protein), promoter reporter activity, real-time quantitative PCR and Western blot were used. The intracellular lipid droplet content and TG content were determined by fluorescent staining of lipid droplets and TG (triglyceride) quantification experiments, respectively. Postprandial triglyceride response experiments, oil red O staining of small intestine and TG content determination were performed to study the effect of AP on lipid secretion in the small intestine of mice. The results showed that AP decreased promoter expression and mRNA levels of Apob and Mttp via interfering with transcriptional activity of ERRα/PGC1α. Furthermore, AP increased intracellular lipid droplets, reduced extracellular TG content and blood TG level indicating reduction of lipids secretion in Caco-2 and small intestine. This finding demonstrated that AP, as an ERRα inverse agonist, inhibited intestinal lipid secretion and decreased serum TG levels through downregulating the transcriptional expression of Apob and Mttp.
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