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PubMed2024

Lipid-lowering drugs and risk of rapid renal function decline: a mendelian randomization study.

BACKGROUND: Chronic kidney disease (CKD) patients face the risk of rapid kidney function decline leading to adverse outcomes like dialysis and mortality. Lipid metabolism might contribute to acute kidney function decline in CKD patients. Here, we utilized the Mendelian Randomization approach to investigate potential causal relationships between drug target-mediated lipid phenotypes and rapid renal function decline. METHODS: In this study, we utilized two methodologies: summarized data-based Mendelian randomization (SMR) and inverse variance-weighted Mendelian randomization (IVW-MR), to approximate exposure to lipid-lowering drugs. This entailed leveraging expression quantitative trait loci (eQTL) for drug target genes and genetic variants proximal to drug target gene regions, which encode proteins associated with low-density lipoprotein (LDL) cholesterol, as identified in genome-wide association studies. The objective was to investigate causal associations with the progression of rapid kidney function decline. RESULTS: The SMR analysis revealed a potential association between high expression of PCSK9 and rapid kidney function decline (OR = 1.11, 95% CI= [1.001-1.23]; p = 0.044). Similarly, IVW-MR analysis demonstrated a negative association between LDL cholesterol mediated by HMGCR and kidney function decline (OR = 0.74, 95% CI = 0.60-0.90; p = 0.003). CONCLUSION: Genetically predicted inhibition of HMGCR is linked with the progression of kidney function decline, while genetically predicted PCSK9 inhibition is negatively associated with kidney function decline. Future research should incorporate clinical trials to validate the relevance of PCSK9 in preventing kidney function decline.

Mendelian Randomization Analysis↗
PubMed2003

Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice.

High-cholesterol diets elicit changes in gene expression via such transcription factors as sterol-regulatory element binding proteins (SREBPs) and liver X receptors (LXRs). We used Affymetrix microarrays to identify genes in mouse liver regulated by dietary cholesterol (0.0% vs. 0.5% cholesterol wt/wt). Three independent experiments were performed, and data were analyzed with Affymetrix Microarray Suite and ANOVA statistical software. There were 69 unique Unigene clusters consistently regulated by dietary cholesterol (37 downregulated and 32 upregulated). The array results were confirmed by quantitative RT-PCR (Q-PCR) for seven of nine downregulated genes and five of six upregulated genes. A time course of dietary cholesterol feeding over 1 week revealed different temporal patterns of gene regulation for these confirmed genes. Six downregulated genes were examined in transgenic mice overexpressing truncated nuclear forms of SREBP-1a and SREBP-2, and all were induced in these mice. A second microarray analysis of mice treated with the LXR agonist TO901317 confirmed that 13 of the 32 cholesterol upregulated genes were also LXR-activated. This array result was confirmed by Q-PCR for three of three genes. In summary, these studies identified and confirmed six novel dietary cholesterol-regulated genes, three putative SREBP target genes (calcium/calmodulin-dependent protein kinase 1D, fatty acid binding protein 5, and proprotein convertase subtilisin/kexin 9), and three putative LXR target genes (a disintegrin and metalloprotease domain 11, apoptosis-inhibitory 6, and F-box-only protein 3).

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↗
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↗
PubMed2025

Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates.

Epigenetic editing is a promising strategy for modifying gene expression while avoiding the permanent alterations and potential genotoxicity of genome-editing technologies. Here we designed optimized epigenetic regulators (EpiRegs) by testing combinations of transcription activator-like effector (TALE)-based and catalytically deactivated Cas9 (dCas9)-based epigenetic modification effectors and fusion protein structures. TALE-based EpiReg (EpiReg-T) achieved a final efficiency of 98% in mice, surpassing the initial dCas9-based efficiency of 64%. We demonstrated the approach in macaques by introducing DNA methylation and histone modifications to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, thereby lowering low-density lipoprotein cholesterol levels. A single dose of EpiReg-T delivered with lipid nanoparticles achieved efficient (>90%) and long-lasting (343 days) silencing of PCSK9 in the liver. Integrative multiomic analyses revealed minimal off-target effects in EpiReg-T-treated monkeys, mice and human-derived cells. EpiReg can be redirected to other genes by reengineering the DNA-binding domain. Our findings represent a step toward the clinical application of epigenetic editing for the treatment of human diseases.

Animals↗
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↗
PubMed2026

Association of PCSK9 and CCL22 gene polymorphisms with myocardial infarction in a South Indian population.

Myocardial infarction (MI) remains a major global cause of morbidity and mortality, with a particularly high burden among individuals with type 2 diabetes mellitus (T2DM). Host genetic factors play a significant role in modulating individual susceptibility to MI by influencing lipid metabolism and immune-mediated inflammatory pathways. The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a key regulator of cholesterol homeostasis, while C-C motif chemokine ligand 22 (CCL22) is involved in immune cell recruitment and vascular inflammation. In this study, we investigated the association of PCSK9 rs505151 and rs11591147 and CCL22 rs4359426 polymorphisms with MI risk in a South Indian population. This case-control study included 400 participants categorized into controls (n&#x2009;=&#x2009;100), MI (n&#x2009;=&#x2009;100), T2DM (n&#x2009;=&#x2009;100), and MI with T2DM (n&#x2009;=&#x2009;100). Significant differences in clinical and biochemical parameters, including lipid indices and cardiometabolic risk markers, were observed between groups (p&#x2009;<&#x2009;0.05). Genetic analysis revealed a significant association between the PCSK9 rs505151 variant and MI susceptibility across allelic and genotypic distributions, with significant effects under dominant and recessive inheritance models. Multivariable logistic regression confirmed that the rs505151 risk genotype was independently associated with MI after adjustment for age, sex, body mass index, and smoking status. In contrast, PCSK9 rs11591147 was rare and showed no significant association. The CCL22 rs4359426 polymorphism showed limited evidence of association with MI, with a significant effect observed only under the dominant inheritance model. Furthermore, combined analysis using a genetic risk score suggested that cumulative genetic burden involving PCSK9 and CCL22 variants was associated with an increased risk of MI. Overall, our findings suggest that genetic variation in lipid-regulatory and immune-related pathways may contribute to MI susceptibility in South Indians. Further studies are warranted to validate these associations and clarify their biological and clinical relevance.

Humans↗
PubMed2006

Expression and localization of PCSK9 in rat hepatic cells.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), recently cloned in several laboratories, including ours, causes a third form of autosomal dominant hypercholesterolemia. Its mechanism of action remains unclear. We studied the expression and subcellular localization of PCSK9 in fetal and adult rat tissues associated with cholesterol homeostasis using quantitative reverse transcriptase--PCR, Western blot analysis, subcellular fractionation, and confocal immunofluorescent microscopy. PCSK9 mRNA is most abundant in yolk sac and fetal liver, but the highest expression of the protein was found in differentiated hepatoma FAO-1 cell line, which also shows the highest expression of LDLR. In FAO-1 cells PCSK9 expression is downregulated by cholesterol and 25-hydroxycholesterol and upregulated in the absence of sterols following the same pattern of expression as HMG-CoA reductase, synthase, and LDLR. Subcellular fractionation, combined with Western blotting, showed that PCSK9 is localized in the ER and intermediate vesicular compartment of the cell but not in Golgi cisternae. The mature enzyme is secreted from the liver and hepatoma cells. Double labeling with antibodies to PCSK9 and LDLR or clathrin revealed some colocalization of PCSK9 with clathrin-coated vesicles and LDLR. In conclusion, our results show that PCSK9 is processed in the ER, and the mature convertase is secreted in the plasma.

Animals↗
PubMed2004

NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.

The discovery of autosomal dominant hypercholesterolemic patients with mutations in the PCSK9 gene, encoding the proprotein convertase NARC-1, resulting in the missense mutations suggested a role in low density lipoprotein (LDL) metabolism. We show that the endoplasmic reticulum-localized proNARC-1 to NARC-1 zymogen conversion is Ca2+-independent and that within the zymogen autocatalytic processing site SSVFAQ [downward arrow]SIP Val at P4 and Pro at P3' are critical. The S127R and D374Y mutations result in approximately 50-60% and > or =98% decrease in zymogen processing, respectively. In contrast, the double [D374Y + N157K], F216L, and R218S natural mutants resulted in normal zymogen processing. The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients. The LDLR levels are also reduced in stable HepG2 cells overexpressing NARC-1 or its natural mutant S127R, and this reduction is abrogated in the presence of 5 mm ammonium chloride, suggesting that overexpression of NARC-1 increases the turnover rate of the LDLR. Adenoviral expression of wild type human NARC-1 in mice resulted in a maximal approximately 9-fold increase in circulating LDL cholesterol, while in LDLR-/- mice a delayed approximately 2-fold increase in LDL cholesterol was observed. In conclusion, NARC-1 seems to affect both the level of LDLR and that of circulating apoB-containing lipoproteins in an LDLR-dependent and -independent fashion.

Adenoviridae↗
PubMed2026

Cross-Ancestry Proteogenomic Analyses Identified New Therapeutic Insights for Ischemic Heart Disease.

BACKGROUND: Most drugs target proteins, and proteome-wide genetic analyses in diverse populations could discover potential novel and repurposed targets for improved prevention and treatment of ischemic heart disease (IHD) beyond statin therapy. OBJECTIVES: The purposes of this study were to use cis-acting single nucleotide polymorphisms (cis-pQTLs) identified for plasma proteins in East Asians and Europeans to discover and validate potential drug targets for IHD. METHODS: We measured plasma levels of 9,520 (Olink/SomaScan: 2,923/7,297) proteins in a case-cohort study of IHD (1,976 incident cases and 2,001 subcohort controls) in statin-free individuals in the prospective China Kadoorie Biobank (CKB). Genome-wide association studies identified 2,895 (Olink/SomaScan: 1,301/1,594) cis-pQTLs for these proteins in CKB. Two-sample Mendelian randomization (MR) and colocalization analyses assessed associations of all available cis-pQTLs for these proteins with IHD in East Asians (n = 29,319 cases), with further replication in Europeans (n = 181,522 cases) and comparison with findings in previous MR studies. RESULTS: In CKB observational analyses, a total of 959 (Olink/SomaScan: 426/533) proteins were associated at false discovery rate-corrected P < 0.05 with IHD after adjusting for major IHD risk factors. Two-sample MR analyses provided genetic support for 54 unique (Olink/SomaScan: 36/28) proteins in IHD etiology. Colocalization analyses confirmed shared gene-protein-IHD associations (posterior probability of hypothesis 4 [PPH4] &#x2265;0.8) for 15 unique (Olink/SomaScan: 10/10) proteins, including 8 lipid-related, 3 inflammation-related, 1 blood pressure-related, and 3 alcohol-related proteins in East Asians. In Europeans, MR analyses of 12 non-alcohol-related proteins showed directionally concordant results for 8 proteins, with 5 having strong colocalization evidence of shared gene-protein-IHD associations (PPH4 &#x2265;0.8), including 4 lipid-related (proprotein convertase subtilisin/kexin type 9, LPA, APOE, cadherin-1) and 1 systolic blood pressure-related (fibroblast growth factor 5) protein. However, 4 proteins showed directionally discordant MR results, including 2 lipid-related (APOA5, SORT1) and 1 inflammation-related (transforming growth factor beta 1) proteins with strong colocalization evidence of shared gene-protein-IHD associations (PPH4 &#x2265;0.8). Comparison with previous MR studies revealed little consistency across studies in the number and identity of target proteins for IHD beyond well-established lipid-related (low-density lipoprotein cholesterol, lipoprotein(a), and triglycerides) or inflammation-related (interleukin-6) protein targets. CONCLUSIONS: The findings support a role for lipid-driven chronic inflammation in IHD etiology, and treatment strategies simultaneously targeting multiple lipid and inflammation pathways should be prioritized for further research to improve drug treatment of IHD beyond statin therapy.

Aged↗
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&#x2010;Cas9↗
PubMed2026

Biological Mechanisms Underlying the Cardiovascular Effects of Branched-Chain Amino Acids: A Proteome-Wide Mendelian Randomization Study.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVES: This study aims to explore these pathways using 2-step proteome-wide Mendelian randomization. METHODS: We examined the associations between genetic proxies for BCAAs and 2922 proteins in the United Kingdom Biobank Pharma Proteomics Project, supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Next, we tested their effects on IHD risk using Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium (122,733 cases and 424,528 controls) and replicated in FinnGen (31,640 cases and 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS: Genetic proxies for BCAAs were associated with 40 proteins. Among these, 6 proteins showed consistent evidence of mediation, including complement C1s subcomponent, coagulation factor II, granulin, proprotein convertase subtilisin/kexin type 9, sex hormone-binding globulin, and V-set and transmembrane domain-containing protein 2-like. These proteins are involved in inflammation, coagulation, lipid metabolism, and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS: This study identified 6 proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. To our knowledge, these findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.

Amino Acids, Branched-Chain↗
PubMed2004

Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.

The clinical phenotype of heterozygous familial hypercholesterolemia (FH) is characterized by increased plasma levels of total cholesterol and low density lipoprotein cholesterol, tendinous xanthomata, and premature symptoms of coronary heart disease. It is inherited as an autosomal dominant disorder with homozygotes having a more severe phenotype than do heterozygotes. FH can result from mutations in the low density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB), and the recently identified proprotein convertase subtilisin/kexin type 9 gene (PCSK9). To date, over 700 variants have been identified in the LDLR gene. With the exception of a small number of founder populations where one or two mutations predominate, most geographically based surveys of FH subjects show a large number of mutations segregating in a given population. Studies of the prevalence of FH would be improved by the use of a consistent and uniformly applied clinical definition. Because FH responds well to drug treatment, early diagnosis to reduce atherosclerosis risk is beneficial. Cascade testing of FH family members is cost effective and merits further research. For screening to be successful, public health and general practitioners need to be aware of the signs and diagnosis of FH and the benefits of early treatment.

Adult↗
PubMed2006

Genetic polymorphisms that predict outcome and need for treatment in cardiovascular disease.

PURPOSE OF REVIEW: Interest in the genetic determinants of complications of cardiovascular disease, and the resultant influence on management, has increased. We have therefore reviewed the literature in the last 12-16 months for studies documenting genetic risk of complications. The focus is on risk of complications or differences in management, rather than only susceptibility to cardiovascular disease itself. RECENT FINDINGS: Polymorphisms in myocyte enhancer factor 2A, a transcription factor, tumor necrosis factor (ligand) superfamily, member 4, the OX40 ligand, and proprotein convertase subtilisin/kexin type 9, which affect low-density lipoprotein levels, have all been associated with an altered risk of coronary artery disease and myocardial infarction. A preliminary study of genotype-specific therapy of the 5-lipoxygenase pathway has shown benefit in the intermediate endpoint of reduction in inflammatory markers in patients at risk of myocardial infarction and stroke. Bleeding and renal complications after coronary artery bypass surgery have also been associated with genetic polymorphisms. A familial study confirms a genetic association with thoracic aortic aneurysms. SUMMARY: A familial risk of cardiovascular disease is well known. The specific genotypes at risk are increasingly being discovered. The science has progressed to the point that genotype-specific interventions are increasingly feasible.

Cardiovascular Diseases↗
PubMed2005

Cord blood lipoproteins and prenatal influences.

PURPOSE OF REVIEW: Blood lipoprotein profiles in early life are known to be related to and predictive of those in adulthood, but little is known about their determinants. Genetic and environmental influences affect cord blood lipoproteins, but how this occurs and the relative contribution of these influences to the overall profile in healthy newborns remains uncertain. RECENT FINDINGS: This review discusses findings from a range of earlier and more recent studies, and summarizes the key influences on cord blood lipoproteins. In particular, we review the potential contribution of maternal blood total cholesterol levels during pregnancy and the increased maternal transmission in newborns of mothers with diabetes. SUMMARY: In cord blood, cholesterol levels are lower than in adults and the relative proportion present in HDL as opposed to LDL is much higher. The currently available evidence suggests that several factors influence the composition of cord blood lipoproteins. Although inheritance of major monogenic disorders can affect cord lipids in general, the genetic contribution appears to be minimal, although effects of the proprotein convertase subtilisin/kexine type 9 gene (PCSK9) need fuller exploration in this regard in certain ethnic groups. Evidence is summarized that maternal lipoprotein levels, particularly those due to diet or induced by pregnancy, influence cord lipid levels. Placental insufficiency and other conditions affecting fetal growth and the mode of delivery may also influence cord lipoprotein concentrations. How maternal glucose tolerance during pregnancy affects cord blood lipoproteins remains unclear. In view of increasing evidence that cardiovascular risk may have prenatal antecedents, this would seem to be an important area for further investigation.

Cholesterol↗
PubMed2006

Thematic review series: patient-oriented research. What we have learned about VLDL and LDL metabolism from human kinetics studies.

Lipoprotein metabolism is the result of a complex network of many individual components. Abnormal lipoprotein concentrations can result from changes in the production, conversion, or catabolism of lipoprotein particles. Studies in hypolipoproteinemia and hyperlipoproteinemia have elucidated the processes that control VLDL secretion as well as VLDL and LDL catabolism. Here, we review the current knowledge regarding apolipoprotein B (apoB) metabolism, focusing on selected clinically relevant conditions. In hypobetalipoproteinemia attributable to truncations in apoB, the rate of secretion is closely linked to the length of apoB. On the other hand, in patients with the metabolic syndrome, it appears that substrate, in the form of free fatty acids, coupled to the state of insulin resistance can induce hypersecretion of VLDL-apoB. Studies in patients with familial hypercholesterolemia, familial defective apoB, and mutant forms of proprotein convertase subtilisin/kexin type 9 show that mutations in the LDL receptor, the ligand for the receptor, or an intracellular chaperone for the receptor are the most important determinants in regulating LDL catabolism. This review also demonstrates the variance of results within similar, or even the same, phenotypic conditions. This underscores the sensitivity of metabolic studies to methodological aspects and thus the importance of the inclusion of adequate controls in studies.

Apolipoproteins B↗
PubMed1997

Pro-protein convertase gene expression in human breast cancer.

As a first step towards elucidating the role that pro-protein convertases play in the growth regulation of breast cancer, we studied the gene expression of 6 known human convertase members (PC1/PC3, PC2, furin/PACE, PACE4, PC5/PC6 and PC7/LPC) in human breast cancer tumors and cell lines. PC1, furin, PACE4 and PC7 mRNAs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) amplification in all 7 human breast cancer cell lines and 30 breast tumor tissues tested. PC5 expression was detected in 2/30 tumor tissues. PC2 mRNA, however, was not detected. In situ hybridization localized furin mRNA to the tumor cells; adjacent fibrous stroma and blood vessel elements were negative for furin gene expression. Thirty breast tumors with varying quantities of estrogen and progesterone receptors were assayed for furin, PACE4 and PC1 mRNAs by quantitative RT-PCR, and 22 tumors were assayed for PC7 mRNA. An apparent association was observed only between PACE4 and estrogen receptors. No statistically significant correlation was found between the levels of steroid receptors and the expression of human furin, PCI and PC7 genes. Convertase mRNA levels appeared similar in both the estrogen-responsive and -unresponsive breast cancer cell lines. Also, proprotein convertase mRNAs were not detected in 9 histologically normal human breast tissues. These results suggest that elevated expression of some members of the pro-protein convertase gene family is a characteristic of human breast cancer, an event which may be important for human breast tumorigenesis.

Breast Neoplasms↗