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

## TL;DR

A new form of berberine, called BBR-CA, may help treat high cholesterol by blocking a key pathway involved in fat production.

## Contribution

The study identifies a novel mechanism by which BBR-CA reduces lipid levels through the PI3K/AKT/mTOR/SREBP-1 pathway.

## Key findings

- BBR-CA reduced body weight and liver fat in mice on a high-fat diet.
- BBR-CA inhibited SREBP-1 and its downstream proteins SCD1 and ACC in HepG2 cells.
- Phosphorylation of PI3K, AKT, and mTOR was suppressed by BBR-CA, affecting SREBP-1 activation.

## 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.

Berberine–cinnamic acid co‐crystal (BBR‐CA) inhibits the phosphorylation of the phosphatidylinositol 3‐kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, suppressing the transfer of pre‐sterol regulatory element‐binding proteins‐1 (SREBP‐1) from the endoplasmic reticulum to the nucleus. This results in a decrease in the expression level of nSREBP‐1 within the nucleus, and further affects the functions of downstream lipases such as stearoyl‐CoA desaturase 1 (SCD1) and acetyl‐CoA carboxylase (ACC), thereby influencing lipid synthesis.