Embelin Elevates Endoplasmic Reticulum Calcium Levels and Blocks the Sterol Regulatory Element-Binding Protein 2 Mediated Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Improves the Low-Density Lipoprotein Receptor Mediated Lipid Clearance on Hepatocytes

Abstract

Cardiovascular diseases (CVDs) continue to be one of the leading causes of morbidity and mortality worldwide, with a significant increase in recent years. Atherosclerosis, the pathological basis and prime reason for CVDs is primarily driven by dysregulated lipid metabolism and inflammation. Recently, proprotein convertase subtilisin kexin9 (PCSK9) has been evolved to be highly implicated in the circulatory low-density lipoprotein cholesterol levels by its modulatory effects on the low-density lipoprotein receptor (LDLR) mediated clearance. Even though not economical, the therapies targeting PCSK9 demonstrated appreciable levels of efficiency in managing hyperlipidaemic conditions. Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) is a naturally occurring para-benzoquinone isolated from dried berries of Embelia ribes, which possess several effects in maintaining the cholesterol homeostasis. In this study, we have analysed the role of embelin in sterol regulatory element-binding protein 2 (SREBP2) mediated PCSK9 expression in cultured hepatocytes. The study showed that the embelin treatment attenuates the endoplasmic reticulum (ER) stress-induced reactive oxygen species levels and ER stress markers on cultured hepatocytes. The treatment of embelin modulates the mRNA and protein level expression of SREBP2 and its downstream targets like PCSK9, LDLR, and HMG-CoA reductase (HMGCR). Interestingly the Ca2+ levels and the calcium binding protein of ER were significantly increased with embelin treatment. The work revealed a putative mechanism of embelin in lowering PCSK9 levels by boosting ER Ca2+ levels, thereby blocking SREBP2 nuclear translocation. Further, this reduces LDLR degradation and increases receptor-mediated circulatory lipid clearance. The study summarized the potential clinical applications of embelin in addressing the cardio vascular diseases.