PCSK9 as a Target for Development of a New Generation of Hypolipidemic Drugs

PCSK9 has now become an important target to create new classes of lipid-lowering drugs. The prevention of its interaction with LDL receptors allows an increase in the number of these receptors on the surface of the cell membrane of hepatocytes, which leads to an increase in the uptake of cholesterol-rich atherogenic LDL from the bloodstream. The PCSK9 antagonists described in this review belong to different classes of compounds, may have a low molecular weight or belong to macromolecular structures, and also demonstrate different mechanisms of action. The mechanisms of action include preventing the effective binding of PCSK9 to LDLR, stimulating the degradation of PCSK9, and even blocking its transcription or transport to the plasma membrane/cell surface. Although several types of antihyperlipidemic drugs have been introduced on the market and are actively used in clinical practice, they are not without disadvantages, such as well-known side effects (statins) or high costs (monoclonal antibodies). Thus, there is still a need for effective cholesterol-lowering drugs with minimal side effects, preferably orally bioavailable. Low-molecular-weight PCSK9 inhibitors could be a worthy alternative for this purpose.

Proprotein Convertase Subtilisin/Kexin Type 9 Gene Variants in Familial Hypercholesterolemia: A Systematic Review and Meta-Analysis

Proprotein Convertase Subtilisin Kexin type 9 (PCSK9), comprises 12 exons, encoded for an enzyme which plays a critical role in the regulation of circulating low density lipoprotein. The gain-of-function (GOF) mutations aggravate the degradation of LDL receptors, resulting in familial hypercholesterolemia (FH), while loss-of-function (LOF) mutations lead to higher levels of the LDL receptors, lower the levels of LDL cholesterol, and preventing from cardiovascular diseases. It is noted that, previous publications related to the mutations of PCSK9 were not always unification. Therefore, this study aims to present the spectrum and distribution of PCSK9 gene mutations by a meta-analysis. A systematic literature analysis was conducted based on previous studies published by using different keywords. The weighted average frequency of PCSK9 mutation was calculated and accessed by MedCalc®. A total of 32 cohort studies, that included 19,725 familial hypercholesterolemia blood samples, were enrolled in the current study. The analysis results indicated that, based on the random-effect model, the weighted prevalence of PCSK9 mutation was 5.67% (95%CI = 3.68–8.05, p < 0.0001). The prevalence of PCSK9 GOF mutations was 3.57% (95%CI = 1.76–5.97, p < 0.0001) and PCSK9 LOF mutations was 6.05% (95%CI = 3.35–9.47, p < 0.0001). Additionally, the first and the second exon were identified as the hot spot of mutation occurred in PCSK9. Both GOF and LOF mutations have a higher proportion in Asia and Africa compared with other regions. The GOF PCSK9 p.(Glu32Lys) and LOF PCSK9 p.(Leu21dup/tri) were dominant in the Asia region with the proportion as 6.58% (95%CI = 5.77–7.47, p = 0.62) and 16.20% (95%CI = 6.91–28.44, p = 0.0022), respectively. This systematic analysis provided scientific evidence to suggest the mutation of PCSK9 was related to the metabolism of lipoprotein and atherosclerotic cardiovascular disease.

Profile of circulating MicroRNAs in low density lipoprotein uptake: literature review

Objective: Delineate a profile of circulating miRNA that interfere with the uptake of c-LDL through the regulation of LDL, APOB-100 and PCSK9 genes that can be used as biomarkers for prognosis and treatment of atherosclerosis. Bibliography review: The atherosclerosis, a chronic and inflammatory disease that occurs when there are high levels of LDL on plasma. This important risk factor for development of cardiovascular disease is the main cause of death worldwide. The miRNAs have recently emerged as potential biomarkers and therapeutic target for lipid metabolism disorders. In this review, we will provide profile of circulating miRNAs that have demonstrated being regulators of PCSK9, LDL and APOB100 genes. Recent work has identified the miR-148, miR-128, miR-27a/b, miR-185, miR-301, miR-130 as important regulators of this pathway because they decrease supply of LDL receptors through interaction with PCSK9. Final considerations: We conclude that, when overexpressed, miR-148a, mir128 and miR-27a/b, miR-122 and miR-34 are related to decrease in LDL, facilitating occurrence of atherosclerosis. Detection of miRNAs profile could be used in the future as a biomarker for disturbs linked to c-LDL uptake and in future anti-miRNAs therapies may be used in the treatment of atherosclerosis.

PCSK9: A Key Target for the Treatment of Cardiovascular Disease (CVD)

Proprotein convertase subtilisin/kexin type 9 (PCSK9), as a vital modulator of low-densitylipoprotein cholesterol (LDL-C) , is raised in hepatocytes and released into plasma where it bindsto LDL receptors (LDLR), leading to their cleavage. PCSK9 adheres to the epidermal growthfactor-like repeat A (EGF-A) domain of the LDLR which is confirmed by crystallography. LDLRexpression is adjusted at the transcriptional level through sterol regulatory element bindingprotein 2 (SREBP-2) and at the post translational stages, specifically through PCSK9, and theinducible degrader of the LDLR PCSK9 inhibition is an appealing new method for reducing theconcentration of LDL-C. In this review the role of PCSK9 in lipid homeostasis was elucidated, theeffect of PCSK9 on atherosclerosis was highlighted, and contemporary therapeutic techniquesthat focused on PCSK9 were summarized. Several restoration methods to inhibit PCSK9 havebeen proposed which concentrate on both extracellular and intracellular PCSK9, and theyinclude blockage of PCSK9 production by using gene silencing agents and blockage of it’sbinding to LDLR through antibodies and inhibition of PCSK9 autocatalytic processes by tinymolecule inhibitors.

Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine

Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid constituent of the inner layer of the plasma membrane (PM). In PTDSS1-deficient cells where PS is low, LDL cholesterol leaves lysosomes but fails to reach the ER, instead accumulating in the PM. The addition of PS restores cholesterol transport to the ER. We conclude that LDL cholesterol normally moves from lysosomes to the PM. When the PM cholesterol exceeds a threshold, excess cholesterol moves to the ER in a process requiring PS. In the ER, excess cholesterol acts to reduce cholesterol uptake, preventing toxic cholesterol accumulation. These studies reveal that one lipid—PS—controls the movement of another lipid—cholesterol—between cell membranes. We relate these findings to recent evidence indicating that PM-to-ER cholesterol transport is mediated by GRAMD1/Aster proteins that bind PS and cholesterol.