Abstract
A constantly elevated level of low-density lipoprotein cholesterol (LDL-C) is mainly associated with the development of atherosclerosis. The use of statins as a treatment for reducing plasma LDL-C levels has led, in some cases, to adverse side effects, including a decrease in hepatic LDL receptor (LDLR), the receptor responsible for the uptake of circulating LDL-C. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme responsible for directing the LDLR–LDL-C complex to lysosomal degradation upon transport into cells, preventing the recycling of LDLR to the cell surface. Therefore, PCSK9 may offer a new target for reducing the levels of plasma LDL-C. In this study, we investigated the mechanisms of action of a selected fraction of A. planci on PCSK9 gene expression, as well as the effect of the fraction on the level of LDLR protein and the uptake of LDL-C. Using real-time PCR, it was shown that the selected A. planci fraction reduced the gene expression of PCSK9 in human liver HepG2 cells. Immunocytochemistry analysis demonstrated that the selected A. planci fraction increased the LDLR protein level and LDL-C uptake in HepG2 cells. Promoter mutational and gene expression analyses revealed that PPRE, a binding site for peroxisome proliferator–activated receptor (PPAR), was responsible for mediating the inhibitory effect of the selected fraction on PCSK9 mRNA. In addition, MAP kinase and PKC components of the signal transduction pathway were activated, inducing the action of the selected A. planci fraction in decreasing PCSK9 gene expression. These findings suggest that the selected fraction shows good potential for reducing circulating LDL-C and, thus, may be a good therapeutic intervention to prevent the progression of atherosclerosis.
Highlights
To the best of our knowledge, this was the first study demonstrating the inhibitory effect of an A. planci fraction on Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene expression
The suppression of PCSK9 was strongly correlated with an increase in LDL receptor (LDLR) expression and LDL uptake in the selected fraction-treated cells
The inhibitory action of A. planci was exerted by a reduction in the transcriptional activity of the peroxisome proliferator response element (PPRE) via the binding of PPARα
Summary
Atherosclerosis has emerged as a major public health concern, as it leads to lifethreatening cardiovascular diseases (CVDs) such as myocardial infarction, unstable angina, sudden cardiac death, and stroke. In Westernized society, it has become the underlying cause of approximately 50% of annual mortality due to coronary heart disease [1]. Atherosclerosis is a complex disease that involves many components of the metabolic, immune, and vascular systems. It develops mainly due to a constantly elevated level of low-density lipoprotein cholesterol (LDL-C) in the blood, which enters the intima layer of Pharmaceuticals 2022, 15, 269.
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