Berberine-cinnamic acid co-crystal effect in ameliorating hyperlipidemia might be regulated through the PI3K/AKT/mTOR/SREBP-1 signaling pathway

》》文章原文链接：Berberine-cinnamic acid co-crystal effect in ameliorating hyperlipidemia might be regulated through the PI3K/AKT/mTOR/SREBP-1 signaling pathway

》》Journal：Federation of European Biochemical Societies Open Bio

》》相关产品：Recilisib (SJ-MX5040A)、LY294002 (SJ-MX0083)、Protease Inhibitor Cocktail (EDTA-Free,100× in DMSO) (SJ-MK0001) 和 Phosphatase Inhibitor Cocktail (Ⅰ+Ⅱ管，100×) (SJ-MK0002)

》》产品引用描述：

》》Abstract：

Hyperlipidemia is a common chronic disease characterized by elevated levels of lipids in the blood. There is some evidence that suggests that berberine (BBR) might be beneficial for the treatment of hyperlipidemia. However, its low intestinal bioavailability limits its potential therapeutic action. In the present study, we explored the effect and the underlying mechanism of berberine-cinnamic acid co-crystal (BBR-CA), which is self-assembled from CA and BBR and displays a high intestinal bioavailability. In mice, BBR-CA showed the ability to decrease body weight gain and hepatic lipid accumulation in animals fed a high-fat diet. To further characterize the molecular basis of this effect, we established a hyperlipidemia cell model by treating human hepatocellular carcinoma cells (HepG2) with free fatty acids. Similarly to our in vivo experiments, lipid accumulation in free fatty acids-induced HepG2 cells was also reduced by BBR-CA. We hypothesized that BBR-CA might act through the regulation of sterol regulatory element-binding proteins-1 (SREBP-1), a key factor regulating lipid synthesis, and, indeed, SREBP-1 protein expression was inhibited by BBR-CA treatment, resulting in the decreased expression of its downstream proteins stearoyl-CoA desaturase 1 and acetyl-CoA carboxylase. Furthermore, the phosphorylation of phosphatidylinositol 3-kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) was inhibited by BBR-CA, contributing to decreased active SREBP-1 in the nucleus, and was reversed and enhanced by the PI3K agonist recilisib and inhibitor LY294002, respectively. Taken together, our results suggest that BBR-CA could function by modulating the PI3K/AKT/mTOR signaling pathway, resulting in decreased nuclear expression of SREBP-1, as well as reduced expression of stearoyl-CoA desaturase 1 and acetyl-CoA carboxylase, thus alleviating hyperlipidemia. Further experimental validation is required to confirm these results.

》》部分实验数据展示：

Fig. 5. The effects of BBR-CA on the expression of SREBP-1 in the nucleus (nSREBP-1) and its upstream proteins in HepG2 cells.

(D) Western blotting detects the protein expression of p-PI3K/PI3K, p-AKT/AKT and p-mTOR/mTOR in HepG2 cells.

Fig. 6. The effects of PI3K agonist and inhibitor on BBR-CA-reduced lipid synthesis in HepG2 cells. (A) Oil Red O staining of HepG2 cells treated with different drugs; scale bar = 50 lm. (B) The lipid content of FFA-induced HepG2 cells treated with different drugs detected by OD510 value (n = 6, where n represents the number of cell samples, and all the cells in each well plate constitute one cell sample). (C) Western blot detects the protein expression of p-PI3K/PI3K, p-AKT/AKT and p-mTOR/mTOR in HepG2 cells treated with different drugs. (D–F) Quantification of the p-PI3K/PI3K, p-AKT/AKT and p-mTOR/mTOR bands from (C) (n = 3, where n represents the number of cell samples, and all the cells in each well plate constitute one cell sample).