Carnosic acid alleviates hyperlipidemia and insulin resistance by promoting the degradation of SREBPs via the 26S proteasome

Carnosic acid (CA), from rosemary, a food additive used for long history in western countries, reduces triglyceride, cholesterol and glucose levels. However, the detailed mechanisms contributing to these effects remain unclear. Here we investigate the potential mechanism of how CA regulates lipid metabolism. Using reporter cell lines, we found CA inhibited SREBPs activity, using radioactive isotope labeling, we found CA impeded de novo lipid synthesis, using gene silencing and inhibitors, we investigated the possible mechanism of how CA affects SREBPs stability. In hepatocytes, CA reduces the nuclear abundance of SREBPs and downregulates their target genes, thereby inhibiting the de novo biosynthesis of both fatty acids and cholesterol. Furthermore, in western type diet-induced obese mice, CA alleviates hyperlipidemia, fatty liver and insulin resistance by suppressing SREBPs target gene expression in the liver. Our results indicate that CA promotes the degradation of mature form of SREBPs via the 26S proteasome. To our knowledge, this study is the first to describe a small molecule that strongly reduces mature SREBPs.