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PubMed2026

The Impact of PCSK9 Inhibitors on Development of Retinal Vascular Occlusions.

PURPOSE: PCSK9 inhibitors (PCSK9i) are a newer class of lipid-lowering drug that may be effective at lowering risk for retinal artery occlusion (RAO) and retinal vein occlusion (RVO). This study aims to investigate the relationship between PCSK9i use and retinal vascular occlusion among patients with hyperlipidemia. DESIGN: Retrospective, comparative clinical cohort study SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Patients with hyperlipidemia, defined as serum low-density lipoprotein level of ≥130 mg/dL and total cholesterol level of ≥220 mg/dL, prescribed a lipid-lowering medication were identified. Patients prescribed a PCSK9i were included in the study group and compared with control patients prescribed any other type of lipid-lowering drug. METHODS: This study was conducted using electronic health record data from health organizations in the United States through the TrinetX platform. Propensity score matching was completed based on relevant patient demographics, comorbidities, and laboratory values. Comparison of main outcomes between the PCSK9i and non-PCSK9i groups was performed using measures of association analysis to determine risk ratio (RR) with 95% CI. MAIN OUTCOME MEASURES: The outcomes measured consisted of occurrence of retinal vascular occlusion, RAO, RVO, central RAO, and central RVO at 3-year, 5-year, and 7-year time points. RESULTS: After propensity score matching, a total of 12,960 patients were included in each cohort. The analysis revealed that the PCSK9i cohort had a significantly lower risk for development of retinal vascular occlusions at multiple points, including 3-year (RR = 0.56, CI = 0.39-0.79), 5-year (RR = 0.50, CI = 0.37-0.67), and 7-year (RR = 0.46, CI 0.35-0.61) time points. This lower risk was also found in the PCSK9i group for an outcome of RVO at 5 years (RR = 0.50, CI = 0.34-0.73) and 7 years (RR = 0.47, CI = 0.33-0.67). For occurrence of RAOs (RR = 0.47, CI = 0.30-0.76) and central RVO (RR = 0.46, CI = 0.29-0.74) separately, the PCSK9i cohort had a lower risk at 7 years. CONCLUSION: These findings suggest that PCSK9i may reduce the risk of retinal vascular occlusion compared with other classes of lipid-lowering medications.

Humans↗
PubMed2026

Current and Future Perspectives of LDL-C Lowering Therapies 2026.

LDL cholesterol (LDL-C) is the central causal factor for atherosclerotic cardiovascular disease (ASCVD), and its reduction is a cornerstone of both primary and secondary prevention. Since the introduction of statins more than three decades ago, LDL-C-lowering therapy has expanded substantially, now encompassing ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeting agents, bempedoic acid, and other emerging modalities. This expanding therapeutic landscape has improved the feasibility of achieving guideline-recommended LDL-C targets, but it has also increased the complexity of clinical decision making. This review provides a contemporary and practical overview of the LDL-C-lowering strategies, beginning with the initial evaluation of patients with elevated LDL-C, including differentiation between primary and secondary causes and the identification of familial hypercholesterolemia (FH). We summarize the current treatment targets for primary and secondary prevention, highlight the optimal selection and use of statins, and discuss the assessment and management of statin intolerance, including the role of the nocebo effect. Non-statin therapies, including ezetimibe, bile acid sequestrants, PCSK9 inhibitors, inclisiran, and bempedoic acid, are reviewed with an emphasis on their mechanisms, efficacy, and clinical positioning. Advanced therapies for severe dyslipidemia, such as lipoprotein apheresis, lomitapide, and evinacumab, are also discussed in this review. Finally, we outline the future directions, including oral PCSK9 inhibitors, next-generation cholesteryl ester transfer protein (CETP) inhibitors, lipoprotein(a)-lowering agents, and genome-editing approaches. Collectively, these developments offer new opportunities to address unmet clinical needs, particularly in patients with FH, statin intolerance, and residual cardiovascular risk. A comprehensive understanding of these therapies is essential for further reducing the burden of ASCVD in the coming decades.

Humans↗
PubMed2025

Cost-effectiveness of alternative cascade screening strategies for familial hypercholesterolemia with realistic cascade screening acceptance rates and use of novel treatment.

BACKGROUND AND AIMS: Cascade screening (CS) for familial hypercholesterolemia (FH) has been found to be cost-effective in many published studies. However, most existing studies (i) ignored or overstated first-degree relative (FDR) participation rate (as 60-100 %), (ii) did not consider novel and expensive therapies, e.g. PCSK9 inhibitors (PCSK9i), and (iii) were conducted outside of Asia. This study, conducted in Singapore, where FDR participation rate is about 25 % among probands who have known pathogenic variants, aims to identify drivers of cost-effectiveness of CS protocols for FH. METHODS: Four CS protocols, which vary in the application of genetic tests, were examined using a hybrid decision tree-Markov model. Sensitivity analyses were conducted to identify drivers of cost-effectiveness. RESULTS: Cascade acceptance rates are key drivers of cost-effectiveness. Other drivers include age of proband, prevalence of FH among probands, health-related quality of life loss with cardiovascular disease, timeliness of starting treatment post-screening, treatment effectiveness, cost of PCSK9i and discount rate for cost and QALY. With cascade acceptance rates observed in Singapore, among various screening protocols examined, probabilities of being cost-effective ranged from 86 % to 95 % when no access to PCSK9i and ranged from 75 % to 98 % when PCSK9i are provided. The most cost-effective protocol differs depending on cascade acceptance rates and whether PCSK9i is provided. CONCLUSION: For better cost-effectiveness of CS for FH, health systems need to look for ways to improve proband's willingness to share contact of their relatives and relatives' willingness to be screened and to lower the cost of novel treatment. Other ways to improve cost-effectiveness include to select age groups for proband screening, improve screening detection rate among probands, and start timely treatment post-screening.

Humans↗
PubMed2026

Machine Learning in Hyperlipidaemia Research: Screening and Experimental Insights into Lipid Metabolism Modulators.

Hyperlipidemia, characterized by elevated blood lipid levels, represents a major global health concern due to its strong association with cardiovascular disease, diabetes, and metabolic syndrome. While current therapies - such as statins, fibrates, bile acid sequestrants, and PCSK9 inhibitors - are effective in controlling hyperlipidemia, they are often associated with adverse effects, potential drug resistance, and suboptimal efficacy in certain patient populations. All of the above underscore the urgent need for safer and more effective therapeutic alternatives. Among the major molecular targets involved in the regulation of lipid metabolism are HMG-CoA reductase, PCSK9, peroxisome proliferator-activated receptors (PPARs), cholesteryl ester transfer protein (CETP), and nuclear receptors, including the liver X receptor (LXR) and farnesoid X receptor (FXR), which are also targets for future antihyperlipidemic drug development. Recent advancements in artificial intelligence (AI) and machine learning (ML) have significantly transformed and accelerated drug discovery by enabling the processing of vast amounts of genomic, proteomic, and chemical data. Furthermore, ML tools such as quantitative structure-activity relationship (QSAR) modelling, deep learning, random forest, and support vector machines (SVM) have proven predictive and effective in identifying novel lipid metabolism modulators, thereby enhancing the efficacy and accuracy of virtual screening. Meanwhile, molecular docking has become an integral part of structure-based drug design (SBDD), and software such as AutoDock, Glide, and GOLD have proven effective in generating accurate ligand-target docking models. Molecular docking, together with ML-based approaches, enables the identification of potent and selective drug candidates. Overall, the combination of ML and molecular docking offers an efficient and accurate platform for antihyperlipidemic drug discovery, helping to overcome the limitations of currently available therapeutic strategies.

HMG-CoA reductase↗
PubMed2005

Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.

PCSK9 encodes proprotein convertase subtilisin/kexin type 9a (PCSK9), a member of the proteinase K subfamily of subtilases. Missense mutations in PCSK9 cause an autosomal dominant form of hypercholesterolemia in humans, likely due to a gain-of-function mechanism because overexpression of either WT or mutant PCSK9 reduces hepatic LDL receptor protein (LDLR) in mice. Here, we show that livers of knockout mice lacking PCSK9 manifest increased LDLR protein but not mRNA. Increased LDLR protein led to increased clearance of circulating lipoproteins and decreased plasma cholesterol levels (46 mg/dl in Pcsk9(-/-) mice versus 96 mg/dl in WT mice). Statins, a class of drugs that inhibit cholesterol synthesis, increase expression of sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor that activates both the Ldlr and Pcsk9 genes. Statin administration to Pcsk9(-/-) mice produced an exaggerated increase in LDLRs in liver and enhanced LDL clearance from plasma. These data demonstrate that PCSK9 regulates the amount of LDLR protein in liver and suggest that inhibitors of PCSK9 may act synergistically with statins to enhance LDLRs and reduce plasma cholesterol.

Animal Feed↗
PubMed2026

Comparative safety of lipid-lowering drugs alone or in combination: insights from a systematic review and network meta-analysis.

BACKGROUND AND AIMS: Although the safety profile of lipid-lowering therapies (LLTs) is known, there are no comprehensive comparative assessments. We aimed to compare the risk of muscle-related events, diabetes, liver dysfunction, and cognitive disorders among LLTs through a network meta-analysis. METHODS AND RESULTS: Databases were searched from inception to May 2025. Eligible studies included adult patients, using statins, ezetimibe, PCSK9 monoclonal antibodies (PCSK9mAbs), inclisiran, bempedoic acid, or their combinations as intervention, reporting the information about any of the selected adverse events, a total sample size of ≥200 subjects, and had ≥1 month of intervention. Pooled estimates were assessed by fixed effects model within a frequentist setting. Pooled relative risks (RR) and their 95% confidence interval were estimated. A total of 303,397 subjects from 153 RCTs were included. Bempedoic acid ranked the lowest risk of myalgia (vs PCSK9mAbs, RR 0.80 [0.69, 0.93]). PCSK9mAbs were associated with lower incidence of creatine kinase (CK) elevation, diabetes, and liver dysfunction comparing to statins (statins vs PCSK9mAbs, RR 1.44 [1.14, 1.81], RR 1.13 [1.05, 1.22], and RR 1.38 [1.17, 1.62], respectively). In terms of muscle-related events and cognitive disorders, no significant risk differences were found among treatments and their combinations. CONCLUSIONS: PCSK9mAbs appear to have a more favourable safety profile regarding the risk of CK elevation, diabetes, and liver dysfunction. Bempedoic acid seem to be a better choice for subjects with high risk of myalgia. This information can be valuable when selecting therapy for specific patient subgroups at higher risk of certain adverse events.

Humans↗
PubMed2006

Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c.

Familial autosomal dominant hypercholesterolemia is associated with high risk for cardiovascular accidents and is related to mutations in the low density lipoprotein receptor or its ligand apolipoprotein B (apoB). Mutations in a third gene, proprotein convertase subtilisin kexin 9 (PCSK9), were recently associated to this disease. PCSK9 acts as a natural inhibitor of the low density lipoprotein receptor pathway, and both genes are regulated by depletion of cholesterol cell content and statins, via sterol regulatory element-binding protein (SREBP). Here we investigated the regulation of PCSK9 gene expression during nutritional changes. We showed that PCSK9 mRNA quantity is decreased by 73% in mice after 24 h of fasting, leading to a 2-fold decrease in protein level. In contrast PCSK9 expression was restored upon high carbohydrate refeeding. PCSK9 mRNA increased by 4-5-fold in presence of insulin in rodent primary hepatocytes, whereas glucose had no effect. Moreover, insulin up-regulated hepatic PCSK9 expression in vivo during a hyperinsulinemic-euglycemic clamp in mice. Adenoviral mediated overexpression of a dominant or negative form of SREBP-1c confirmed the implication of this transcription factor in insulin-mediated stimulation of PCSK9 expression. Liver X receptor agonist T0901317 also regulated PCSK9 expression via this same pathway (a 2-fold increase in PCSK9 mRNA of primary hepatocytes cultured for 24 h in presence of 1 microm T0901317). As our last investigation, we isolated PCSK9 proximal promoter and verified the functionality of a SREBP-1c responsive element located from 335 bp to 355 bp upstream of the ATG. Together, these results show that PCSK9 expression is regulated by nutritional status and insulinemia.

Animals↗
PubMed2005

Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.

Proprotein convertase subtilisin kexin 9 (PCSK9) is a member of the subtilisin serine protease family with an important role in cholesterol metabolism. PCSK9 expression is regulated by dietary cholesterol in mice and cellular sterol levels in cell culture via the sterol regulatory element binding protein transcription factors, and mutations in PCSK9 are associated with a form of autosomal dominant hypercholesterolemia. Overexpression of PCSK9 in mice leads to increased total and low-density lipoprotein (LDL) cholesterol levels because of a decrease in hepatic LDL receptor (LDLR) protein with normal mRNA levels. To study the mechanism, PCSK9 was overexpressed in human hepatoma cells, HepG2, by adenovirus. Overexpression of PCSK9 in HepG2 cells caused a decrease in whole-cell and cell-surface LDLR levels. PCSK9 overexpression had no effect on LDLR synthesis but caused a dramatic increase in the degradation of the mature LDLR and a lesser increase in the degradation of the precursor LDLR. In contrast, overexpression of a catalytically inactive mutant PCSK9 prevented the degradation of the mature LDLR; whereas increased degradation of the precursor LDLR still occurred. The PCSK9-induced degradation of the LDLR was not affected by inhibitors of the proteasome, lysosomal cysteine proteases, aspartic acid proteases, or metalloproteases. The PCSK9-induced degradation of the LDLR was shown to require transport out of the endoplasmic reticulum. These results indicate that overexpression of PCSK9 induces the degradation of the LDLR by a nonproteasomal mechanism in a post-endoplasmic reticulum compartment.

Animals↗
PubMed2026

PCSK9 as a Key Gene of Metastasis in Lung Adenocarcinoma: A Multi-omics and Experimental Validation Study.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common form of lung cancer. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is abnormally expressed in various tumor tissues and is associated with malignant phenotypes. However, the clinical significance, function, and mechanism of LUAD invasion and metastasis remain unclear. METHODS: We retrospectively enrolled 100 patients with LUAD in this study. Initially, qRT-PCR was performed to detect PCSK9 levels in clinical tissues. Subsequently, bioinformatics analysis of scRNA-seq and The Cancer Genome Atlas Program (TCGA) datasets was performed to predict the role of PCSK9 in tumor cell malignancy and its potential downstream pathways. These predictions were validated experimentally using the CCK-8 assay, TUNEL staining, wound healing, transwell invasion assay, and an in vivo lung metastasis model. Finally, Western blotting and an AKT inhibitor (MK2206) were used to verify the underlying mechanism. RESULTS: PCSK9 was significantly upregulated in LUAD tissues compared to paracancerous tissues and was associated with poorer OS and DFS. Bioinformatics analysis of scRNA-seq data and TCGA analysis predicted that PCSK9 is highly enriched in tumor cells and is involved in EMT, and that the PI3K/AKT pathway plays a significant role in LUAD development. Experiments confirmed that PCSK9 markedly promoted LUAD cell proliferation, migration, and invasion in vitro and lung metastasis in vivo. PCSK9 overexpression significantly upregulated p-AKT, p-PI3K, and p-mTOR levels. Furthermore, the AKT inhibitor, MK2206, reversed the promoting effects of PCSK9. CONCLUSIONS: PCSK9 expression is associated with the prognosis and diagnosis of LUAD. This molecule activates the PI3K/AKT signaling pathway, thereby driving invasion, metastasis, and proliferation in LUAD.

Humans↗
PubMed2005

Inhibitors of proprotein convertases.

The discovery of mammalian subtilases, proprotein convertases (PCs) or subtilisin-like proprotein convertases (SPCs), in 1990 was a result of sustained efforts in searching for enzyme/s responsible for maturation of inactive protein precursors. Since then, seven PCs have so far been discovered that cleave at the carboxy-terminal of a basic amino acid characterized by the consensus sequence Arg/Lys/His-X-X/Lys/Arg-Arg downward arrow, where X denotes any amino acid other than Cys. Two additional PC subtypes--called subtilisin kexin isozyme 1 (SKI-1) or site 1 protease (S1P) and neural apoptosis regulated convertase 1 (NARC-1), also known as PCSK9--that cleave at the carboxy terminus of nonbasic amino acids were discovered later. Numerous studies revealed various important functional roles of PCs in health and diseases such as tumorigenesis, diabetes, viral infections, bacterial pathogenesis, atherosclerosis, and neurodegenarative diseases such as Alzheimer's. Owing to these findings, PCs became a promising frontier for treatment of diverse pathologies. Thus modulation of PC activity with designed inhibitors is an attractive proposition not only for intervention of diseases, but also for biochemical characterization of these enzymes. Various physiological and bioengineered proteins as well as small molecules such as peptide, peptidomimetic, and nonpeptide compounds as inhibitors of PCs have been described in the literature. Among the strategies used for design of PC inhibitors, the most successful is the one based on bioengineered serpin proteins, of which the best example is alpha1-PDX, the double mutant variant of alpha1-antitrypsin (from A(355)IPM(358) to R(355)IPR(358)). Others include small peptide inhibitors with C-terminal carboxyl function modified with a potent neucleophile or those containing pseudo or isosteric peptide bond at the scissile site of a suitable peptide substrate. Among nonpeptide PC inhibitors, the number is very limited. So far, these include 20-carbon atoms containing alicyclic diterpenes of andrographolide family and heterocyclic compounds that are ligands of Zn2+ and Cu2+ ions. Overall, these molecules display only a modest enzyme inhibition; however, they may serve as important lead structures for further development of more potent and specific nonpeptide PC inhibitors as potential therapeutic agents. Many PC inhibitors display their functional properties in proliferation, fertilization, tumorigenesis, obesity, embryogenesis, or diabetes via their inhibitory action on PC activities.

Animals↗
PubMed2006

PCSK9: a promising therapeutic target for dyslipidemias?

PCSK9 is the third gene to be implicated in autosomal dominant hypercholesterolemia. The recent discovery of mutations in PCSK9 protein associated with low plasma low-density lipoprotein in humans, the characterization of PCSK9-deficient mice hypersensitive to statins and the severely pathological phenotype of D374Y PCSK9-mutated patients shed a new light on this gene: is it a promising therapeutic target for dyslipidemias?

Animals↗
PubMed2026

Engineered Transformer Base Editor with Enhanced Editing Efficiency.

Canonical cytosine base editors (CBEs) achieve precise C-to-T conversions without inducing DNA double-strand breaks (DSBs), yet their clinical potential remains hampered by substantial off-target (OT) mutations. The recently developed transformer base editor (tBE) significantly reduces both genomic and transcriptomic OT mutations by using a cleavable deoxycytidine deaminase inhibitor (dCDI) domain. However, the modest base editing efficiency limits its broader applications. Here, through rational deaminase engineering and fusion of a uracil DNA glycosylase inhibitor (UGI) domain, we developed the engineered tBE (etBE). The etBE exhibited substantially enhanced editing efficiencies compared with the parental tBE (up to 35.11-fold improvement), while maintaining high editing fidelity and background levels of OT mutations. As a therapeutic proof-of-concept, dual adeno-associated virus (AAV)-mediated delivery of etBE targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-established therapeutic target for cardiovascular diseases, was evaluated in a humanized mouse model. The treatment achieved efficient in vivo base editing (up to 35.13%), resulting in substantial reductions in plasma PCSK9 protein (24%) and low-density lipoprotein cholesterol (LDL-C) levels (33%), while inducing only minimal OT mutations. Collectively, etBE represents a highly efficient and specific base editing platform with enormous potential for both basic research and clinical applications.

CRISPR‐Cas9↗
PubMed2025

Silencing FAF2 mitigates alcohol-induced hepatic steatosis by modulating lipolysis and PCSK9 pathway.

BACKGROUND: Chronic alcohol consumption leads to lipid accumulation, oxidative stress, cellular damage, and inflammation in the liver, collectively referred to as alcohol-associated liver disease (ALD). FAF2/UBXD8/ETEA (Fas-associated factor 2) is a ubiquitin ligase adaptor protein that plays a crucial role in the ubiquitin-mediated degradation of misfolded proteins in the endoplasmic reticulum. A recent genome-wide association study indicated an association between FAF2 and ALD; however, the exact contribution of FAF2 to ALD pathogenesis remains unclear. METHODS: FAF2 was knocked down using AAV-delivered shRNA in C57/BL6 mice. Mice were subjected to a chronic-plus-single binge ethanol feeding (NIAAA) model. Nine hours after gavage, liver, blood, and other organs of interest were collected for gene expression and biochemical analyses. RESULTS: We first observed a significant elevation in hepatic FAF2 protein expression in individuals with ALD and in mice subjected to an ethanol-binge model. Interestingly, knocking down FAF2 in the liver using adeno-associated virus serotype 8-delivered short hairpin RNA conferred a protective effect against alcohol-induced liver steatosis in ethanol-binged mice. Transcriptomic analysis revealed that differentially expressed genes were enriched in multiple lipid metabolism regulation pathways. Further analysis of transcription factors regulating these differentially expressed genes suggested potential regulation by SREBP1. Several SREBP1 target genes, including Fasn, Scd1, Lpin1, and Pcsk9 (proprotein convertase subtilisin/kexin type 9), were dysregulated in the livers of ethanol-fed FAF2 knockdown mice. Additionally, Pcsk9 could be regulated through the FOXO3-SIRT6 pathway in the livers of ethanol-fed FAF2 knockdown mice, leading to increased liver low-density lipoprotein receptor expression and reduced plasma LDL cholesterol levels. Furthermore, FAF2 knockdown in mouse liver enhanced adipose triglyceride lipase lipolytic activity by upregulating the adipose triglyceride lipase activator, comparative gene identification-58, and downregulating the adipose triglyceridelipase transport inhibitor, Elmod2, contributing to the alleviation of liver steatosis. CONCLUSIONS: Our study uncovers a novel mechanism involving FAF2 in the pathogenesis of ALD.

Animals↗
PubMed2006

Proapoptotic effects of NARC 1 (= PCSK9), the gene encoding a novel serine proteinase.

BACKGROUND: NARC 1/PCSK9 encodes a novel serine proteinase known to play a role in cholesterol homeostasis. NARC 1 mRNA expression in cerebellar granule neurons (CGNs) was discovered to be induced following an apoptotic injury. Coregulation of known apoptotic mediators (caspase-3 and death receptor 6) raises the possibility that NARC 1 might be involved in the propagation of apoptotic signaling in neurons. METHODS: CGNs were transfected with EGFP-fusion constructs of wild-type and mutant NARC 1, and a laser scanning cytometry-based method of scoring cell death in transfectants was applied. Use of the poly-caspase inhibitor BAF allowed assessment of the caspase-dependence of the NARC 1 proapoptotic effect. RESULTS: Wild-type NARC 1 was found to have substantial proapoptotic effects that were only partially reversible by BAF. Mutation of the active site serine or deletion of the catalytic domain resulted in a reduced level of cell death, consistent with loss of the BAF-sensitive component of cell death. NH(2)-terminal deletion constructs of NARC 1 had effects similar to wild-type, both in the absence and presence of BAF, whereas expression of COOH-terminal deletion mutants produced a rate of cell death similar to wild-type in the absence of BAF treatment, but which lacked the capacity to be reduced by treatment with BAF. CONCLUSION: The mechanism by which NARC 1-EGFP over-expression induces cell death in cultured CGNs remains unclear. Mutation analysis established a positive correlation between the presence of the Narc 1 active site serine in the transiently expressed protein and induction of the BAF-sensitive component of the cell death phenotype. A caspase-independent component proved sufficiently complex to map discretely within the Narc 1 protein.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia.

OBJECTIVE: Neural apoptosis-regulated convertase (NARC)-1 is the newest member of the proprotein convertase family implicated in the cleavage of a variety of protein precursors. The NARC-1 gene, PCSK9, has been identified recently as the third locus implicated in autosomal dominant hypercholesterolemia (ADH). The 2 other known genes implicated in ADH encode the low-density lipoprotein receptor and apolipoprotein B. As an approach toward the elucidation of the physiological role(s) of NARC-1, we studied its transcriptional regulation. METHODS AND RESULTS: Using quantitative RT-PCR, we assessed NARC-1 regulation under conditions known to regulate genes involved in cholesterol metabolism in HepG2 cells and in human primary hepatocytes. We found that NARC-1 expression was strongly induced by statins in a dose-dependent manner and that this induction was efficiently reversed by mevalonate. NARC-1 mRNA level was increased by cholesterol depletion but insensitive to liver X receptor activation. Human, mouse, and rat PCSK9 promoters contain 2 typical conserved motifs for cholesterol regulation: a sterol regulatory element (SRE) and an Sp1 site. CONCLUSIONS: PCSK9 regulation is typical of that of the genes implicated in lipoprotein metabolism. In vivo, PCSK9 is probably a target of SRE-binding protein (SREBP)-2.

Alitretinoin↗
PubMed2006

Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy.

OBJECTIVE: The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene encodes a proprotein convertase that causes degradation of cell surface low-density lipoprotein receptors (LDLRs). Mutations in the PCSK9 gene that disrupt the normal function of PCSK9 could therefore result in increased number of LDLRs and hypocholesterolemia. Also, the cholesterol-lowering effect of statins could be increased in subjects carrying mutations in the PCSK9 gene. METHODS AND RESULTS: We have screened 38 unrelated hypocholesterolemic subjects as well as 25 unrelated familial hypercholesterolemia (FH) heterozygotes who responded particularly well to statin therapy for mutations in the 12 exons of the PCSK9 gene by DNA sequencing. Six of the 38 (15.8%) hypocholesterolemic subjects were heterozygous for 1 of the 3 mutations R46L, G106R, or R237W in the PCSK9 gene. In the group of 25 FH heterozygotes who responded particularly well to statin therapy, 3 (8.8%) were heterozygous for mutations R46L or N157K in the PCSK9 gene. None of 441 hypercholesterolemic subjects without mutations in the LDLR gene or in the apolipoprotein B-100 gene possessed any of the 4 mutations. CONCLUSIONS: The 4 missense mutations R46L, G106R, N157K, and R237W are associated with hypocholesterolemia and possibly increased response to statin therapy.

Adult↗
PubMed2006

Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.

We investigated the effect of statins and statins plus ezetimibe in 65 FH heterozygotes carrying LDLR-defective or LDLR-negative mutations as well as the effect of ezetimibe monotherapy in 50 hypercholesterolemic (HCH) patients intolerant to statins. PCSK9 and NPC1L1 genes were analysed to assess the role of genetic variants in response to therapy. In FH patients combined therapy reduced LDL-C by 57%, irrespective of the type of LDLR mutation. The additional decrease of plasma LDL-C induced by ezetimibe showed wide inter-individual variability (from -39% to -4.7%) and was negatively correlated with percent LDL-C decrease due to statin alone (r=-0.713, P<0.001). The variable response to statins was not due to PCSK9 gene variants associated with statin hyper-sensitivity. The highest response to ezetimibe was observed in a carrier of R174H substitution in NPC1L1, which had been found to be associated with high cholesterol absorption. In HCH patients, ezetimibe monotherapy induced a variable decrease of plasma LDL-C (from -47.7% to -13.4%). To investigate this variability, we sequenced NPC1L1 gene in patients with the highest and the lowest response to ezetimibe. This analysis showed a higher prevalence of the G allele of the c.816 C>G polymorphism (L272L) in hyper-responders, an observation confirmed also in FH patients hyper-responders to ezetimibe. In both FH and HCH patients, the G allele carriers tended to have a higher LDL-C reduction in response to ezetimibe. These observations suggest that in FH heterozygotes LDL-C reduction following combined therapy reflects a complex interplay between hepatic synthesis and intestinal absorption of cholesterol.

Adult↗