Figure 1. PCSK9 functions with or without presence of berberine. a. PCSK9 mechanism of action. PCSK9 is secreted from the endoplasmic reticulum to the Golgi apparatus and subsequently from the trans-Golgi network into the medium. A secreted form of PCSK9 binds to LDLR on the hepatocyte surface and facilitates degradation of the PCSK9-LDLR-LDL complex (extracellular pathway); PCSK9 directly binds to the newly generated LDLR in the trans-Golgi network, where the PCSK9-LDLR complex is directed to the lysosome (intracellular pathway). b. PCSK9 mechanism of action, in the presence of berberine. Berberine directly facilitates the stabilization of LDLR mRNA. It inhibits hepatocyte nuclear factor 1 alpha (HNF1α) protein, thereby decreasing PCSK9 expression, promoting the expression of LDLR, and limiting its degradation, resulting in more significant clearance of LDL.