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1.
Lipids Health Dis ; 23(1): 163, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38831433

ABSTRACT

OBJECTIVE: High low-density-lipoprotein (LDL) cholesterol has been associated with an increased risk of coronary artery diseases (CAD) including acute myocardial infarction (AMI). However, whether lipids lowering drug treatment is causally associated with decreased risk of AMI remains largely unknown. We used Mendelian randomization (MR) to evaluate the influence of genetic variation affecting the function of lipid-lowering drug targets on AMI. METHODS: Single-nucleotide polymorphisms (SNPs) associated with lipids as instruments were extracted from the Global Lipids Genetics Consortium (GLGC). The genome-wide association study (GWAS) data for AMI were obtained from UK Biobank. Two sample MR analysis was used to study the associations between high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) with AMI (n = 3,927). Genetic variants associated with LDL cholesterol at or near drug target gene were used to mimic drug effects on the AMI events in drug target MR. RESULTS: Genetically predicted higher LDL-C (per one SD increase in LDL-C of 38.67 mg/dL, OR 1.006, 95% CI 1.004-1.007) and TG (per one SD increase in TG of 90.72 mg/dL, 1.004, 1.002-1.006) was associated with increased risk of AMI, but decreased risk for higher HDL-C (per one SD increase in HDL-C of 15.51 mg/dL, 0.997, 0.995-0.999) in univariable MR. Association remained significant for LDL-C, but attenuated toward the null for HDL-C and TG in multivariable MR. Genetically proxied lower LDL-C with genetic variants at or near the PCSK9 region (drug target of evolocumab) and NPC1L1 (drug target of ezetimibe) were associated with decreased risk of AMI (0.997, 0.994-0.999 and 0.986, 0.975-0.998, respectively), whereas genetic variants at HMGCR region (drug target of statin) showed marginal association with AMI (0.995, 0.990-1.000). After excluding drug target-related SNPs, LDL-C related SNPs outside the drug target region remained a causal effect on AMI (0.994, 0.993-0.996). CONCLUSIONS: The findings suggest that genetically predicted LDL-C may play a predominant role in the development of AMI. The drug MR results imply that ezetimibe and evolocumab may decrease the risk of AMI due to their LDL-C lowering effect, and there are other non-drug related lipid lowering pathways that may be causally linked to AMI.


Subject(s)
Cholesterol, HDL , Cholesterol, LDL , Genome-Wide Association Study , Mendelian Randomization Analysis , Myocardial Infarction , Polymorphism, Single Nucleotide , Triglycerides , Humans , Myocardial Infarction/genetics , Myocardial Infarction/drug therapy , Cholesterol, LDL/blood , Triglycerides/blood , Male , Female , Cholesterol, HDL/blood , Middle Aged , Membrane Proteins/genetics , Membrane Transport Proteins/genetics , Proprotein Convertase 9/genetics , Hypolipidemic Agents/therapeutic use , Hydroxymethylglutaryl CoA Reductases/genetics , Aged
2.
BMC Cancer ; 24(1): 602, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38760735

ABSTRACT

BACKGROUND: Melanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject of ongoing debate in both in vitro and clinical studies. METHOD: This study aims to evaluate the causal relationship between various lipid-lowering drug targets, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins), Proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and the outcomes of cutaneous melanoma. To mimic the effects of lipid-lowering drugs, we utilized two genetic tools: analysis of polymorphisms affecting the expression levels of drug target genes, and genetic variations linked to low-density lipoprotein cholesterol levels and drug target genes. These variations were sourced from genome-wide association studies (GWAS). We applied Summary-data-based Mendelian Randomization (SMR) and Inverse Variance Weighted Mendelian Randomization (IVW-MR) to gauge the effectiveness of these drugs. RESULTS: Our findings, with SMR results showing an odds ratio (OR) of 1.44 (95% CI: 1.08-1.92; P = 0.011) and IVW-MR results indicating an OR of 1.56 (95% CI: 1.10-2.23; P = 0.013), demonstrate a positive correlation between PCSK9 expression and increased risk of CM. However, no such correlations were observed in other analyses. CONCLUSION: The study concludes that PCSK9 plays a significant role in the development of CM, and its inhibition is linked to a reduced risk of the disease.


Subject(s)
Genome-Wide Association Study , Hydroxymethylglutaryl CoA Reductases , Melanoma , Mendelian Randomization Analysis , Proprotein Convertase 9 , Skin Neoplasms , Humans , Melanoma/genetics , Melanoma/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/drug therapy , Proprotein Convertase 9/genetics , Hydroxymethylglutaryl CoA Reductases/genetics , Melanoma, Cutaneous Malignant , Antibodies, Monoclonal, Humanized/therapeutic use , Polymorphism, Single Nucleotide , Membrane Transport Proteins/genetics , Membrane Proteins/genetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Ezetimibe/therapeutic use , Hypolipidemic Agents/therapeutic use , Hypolipidemic Agents/pharmacology
3.
BMC Cardiovasc Disord ; 24(1): 289, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38822281

ABSTRACT

LY86, also known as MD1, has been implicated in various pathophysiological processes including inflammation, obesity, insulin resistance, and immunoregulation. However, the role of LY86 in cholesterol metabolism remains incompletely understood. Several studies have reported significant up-regulation of LY86 mRNA in atherosclerosis; nevertheless, the regulatory mechanism by which LY86 is involved in this disease remains unclear. In this study, we aimed to investigate whether LY86 affects ox-LDL-induced lipid accumulation in macrophages. Firstly, we confirmed that LY86 is indeed involved in the process of atherosclerosis and found high expression levels of LY86 in human atherosclerotic plaque tissue. Furthermore, our findings suggest that LY86 may mediate intracellular lipid accumulation induced by ox-LDL through the SREBP2/HMGCR pathway. This mechanism could be associated with increased cholesterol synthesis resulting from enhanced endoplasmic reticulum stress response.


Subject(s)
Atherosclerosis , Endoplasmic Reticulum Stress , Hydroxymethylglutaryl CoA Reductases , Lipoproteins, LDL , Macrophages , Signal Transduction , Sterol Regulatory Element Binding Protein 2 , Up-Regulation , Humans , Lipoproteins, LDL/metabolism , Sterol Regulatory Element Binding Protein 2/metabolism , Sterol Regulatory Element Binding Protein 2/genetics , Macrophages/metabolism , Macrophages/drug effects , Endoplasmic Reticulum Stress/drug effects , Atherosclerosis/metabolism , Atherosclerosis/genetics , Atherosclerosis/pathology , Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl CoA Reductases/genetics , Plaque, Atherosclerotic , THP-1 Cells , Male , Animals , Lipid Metabolism/drug effects , Cholesterol/metabolism
4.
BMC Cancer ; 24(1): 667, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38822303

ABSTRACT

BACKGROUND: The causal impact of lipid-lowering drugs on ovarian cancer (OC) and cervical cancer (CC) has received considerable attention, but its causal relationship is still a subject of debate. Hence, the objective of this study is to evaluate the impact of lipid-lowering medications on the occurrence risk of OC and CC through Mendelian randomization (MR) analysis of drug targets. METHODS: This investigation concentrated on the primary targets of lipid-lowering medications, specifically, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and proprotein convertase kexin 9 (PCSK9). Genetic variations associated with HMGCR and PCSK9 were derived from published genome-wide association study (GWAS) findings to serve as substitutes for HMGCR and PCSK9 inhibitors. Employing a MR approach, an analysis was conducted to scrutinize the impact of inhibitors targeting HMGCR and PCSK9 on the occurrence of OC and CC. Coronary heart disease (CHD) risk was utilized as a positive control, and the primary outcomes encompassed OC and CC. RESULTS: The findings of the study suggest a notable elevation in the risk of OC among patients treated with HMGCR inhibitors (OR [95%CI] = 1.815 [1.316, 2.315], p = 0.019). In contrast, no significant correlation was observed between PCSK9 inhibitors and the occurrence of OC. Additionally, the analysis did not reveal any noteworthy connection between HMGCR inhibitors, PCSK9 inhibitors, and CC. CONCLUSION: HMGCR inhibitors significantly elevate the risk of OC in patients, but their mechanism needs further investigation, and no influence of PCSK9 inhibitors on OC has been observed. There is no significant relationship between HMGCR inhibitors, PCSK9 inhibitors, and CC.


Subject(s)
Genome-Wide Association Study , Hydroxymethylglutaryl CoA Reductases , Mendelian Randomization Analysis , Ovarian Neoplasms , Proprotein Convertase 9 , Uterine Cervical Neoplasms , Humans , Female , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/drug therapy , Hydroxymethylglutaryl CoA Reductases/genetics , Ovarian Neoplasms/genetics , Ovarian Neoplasms/drug therapy , Proprotein Convertase 9/genetics , Hypolipidemic Agents/therapeutic use , Hypolipidemic Agents/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Polymorphism, Single Nucleotide
5.
Sci Rep ; 14(1): 12094, 2024 05 27.
Article in English | MEDLINE | ID: mdl-38802400

ABSTRACT

Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95% CI 1.30-1.84, P = 6.87 × 10-7). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine.


Subject(s)
Genome-Wide Association Study , Hydroxymethylglutaryl CoA Reductases , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Mendelian Randomization Analysis , Migraine Disorders , Polymorphism, Single Nucleotide , Humans , Hydroxymethylglutaryl CoA Reductases/genetics , Hydroxymethylglutaryl CoA Reductases/metabolism , Migraine Disorders/genetics , Migraine Disorders/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Quantitative Trait Loci , Genetic Predisposition to Disease
6.
Medicine (Baltimore) ; 103(18): e38010, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38701318

ABSTRACT

Accumulating evidences have indicated that lipid-lowering drugs have effect for the treatment of cancers. However, causal associations between lipid-lowering drugs and the risk of cancers are still unclear. In our study, we utilized single nucleotide polymorphisms of proprotein convertase subtilis kexin 9 (PCSK9) inhibitors and 3-hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors and performed a drug target Mendelian randomization to explore the causal association between lipid-lowering drugs and the risk of cancers. Five regression methods were carried out, including inverse variance weighted (IVW) method, MR Egger, weighted median, simple mode and weighted mode methods, of which IVW method was considered as the main analysis. Our outcome dataset contained the risk of breast cancer (BC), colorectal cancer, endometrial cancer, gastric cancer (GC), hepatocellular carcinoma (HCC), lung cancer, esophageal cancer, prostate cancer (PC), and skin cancer (SC). Our results demonstrated that PCSK9 inhibitors were significant associated with a decreased effect of GC [IVW: OR = 0.482, 95% CI: 0.264-0.879, P = .017]. Besides, genetic inhibitions of HMGCR were significant correlated with an increased effect of BC [IVW: OR = 1.421, 95% CI: 1.056-1.911, P = .020], PC [IVW: OR = 1.617, 95% CI: 1.234-2.120, P = .0005] and SC [IVW: OR = 1.266, 95% CI: 1.022-1.569, P = .031]. For GC [IVW: OR = 0.559, 95% CI: 0.382-0.820, P = .0029] and HCC [IVW: OR = 0.241, 95% CI: 0.085-0.686, P = .0077], HMGCR inhibitors had a protective risk. Our method suggested that PCSK9 inhibitors were significant associated with a protective effect of GC. Genetic inhibitions of HMGCR were significant correlated with an increased effect of BC, PC and SC. Meanwhile, HMGCR inhibitors had a protective risk of GC and HCC. Subsequent studies still needed to assess potential effects between lipid-lowering drugs and the risk of cancers with clinical trials.


Subject(s)
Hydroxymethylglutaryl CoA Reductases , Mendelian Randomization Analysis , Neoplasms , Polymorphism, Single Nucleotide , Proprotein Convertase 9 , Humans , Neoplasms/genetics , Neoplasms/epidemiology , Hydroxymethylglutaryl CoA Reductases/genetics , Female , PCSK9 Inhibitors , Hypolipidemic Agents/therapeutic use , Male , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
7.
Biochem Biophys Res Commun ; 710: 149841, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38588613

ABSTRACT

Prostate cancer is the most prevalent malignancy in men. While diagnostic and therapeutic interventions have substantially improved in recent years, disease relapse, treatment resistance, and metastasis remain significant contributors to prostate cancer-related mortality. Therefore, novel therapeutic approaches are needed. Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway which plays an essential role in cholesterol homeostasis. Numerous preclinical studies have provided evidence for the pleiotropic antitumor effects of statins. However, results from clinical studies remain controversial and have shown substantial benefits to even no effects on human malignancies including prostate cancer. Potential statin resistance mechanisms of tumor cells may account for such discrepancies. In our study, we treated human prostate cancer cell lines (PC3, C4-2B, DU-145, LNCaP) with simvastatin, atorvastatin, and rosuvastatin. PC3 cells demonstrated high statin sensitivity, resulting in a significant loss of vitality and clonogenic potential (up to - 70%; p < 0.001) along with an activation of caspases (up to 4-fold; p < 0.001). In contrast, C4-2B and DU-145 cells were statin-resistant. Statin treatment induced a restorative feedback in statin-resistant C4-2B and DU-145 cells through upregulation of the HMGCR gene and protein expression (up to 3-folds; p < 0.01) and its transcription factor sterol-regulatory element binding protein 2 (SREBP-2). This feedback was absent in PC3 cells. Blocking the feedback using HMGCR-specific small-interfering (si)RNA, the SREBP-2 activation inhibitor dipyridamole or the HMGCR degrader SR12813 abolished statin resistance in C4-2B and DU-145 and induced significant activation of caspases by statin treatment (up to 10-fold; p < 0.001). Consistently, long-term treatment with sublethal concentrations of simvastatin established a stable statin resistance of a PC3SIM subclone accompanied by a significant upregulation of both baseline as well as post-statin HMGCR protein (gene expression up to 70-fold; p < 0.001). Importantly, the statin-resistant phenotype of PC3SIM cells was reversible by HMGCR-specific siRNA and dipyridamole. Our investigations reveal a key role of a restorative feedback driven by the HMGCR/SREBP-2 axis in statin resistance mechanisms of prostate cancer cells.


Subject(s)
Acyl Coenzyme A , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Prostatic Neoplasms , Male , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl CoA Reductases/genetics , Hydroxymethylglutaryl CoA Reductases/metabolism , Sterol Regulatory Element Binding Protein 1 , Simvastatin/pharmacology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Caspases , Dipyridamole
8.
Nat Commun ; 15(1): 3642, 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38684680

ABSTRACT

Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance.


Subject(s)
Antifungal Agents , Aspergillus fumigatus , Ergosterol , Fungal Proteins , Hydroxymethylglutaryl CoA Reductases , Triazoles , Aspergillus fumigatus/drug effects , Aspergillus fumigatus/metabolism , Aspergillus fumigatus/genetics , Antifungal Agents/pharmacology , Triazoles/pharmacology , Fungal Proteins/metabolism , Fungal Proteins/genetics , Ergosterol/metabolism , Ergosterol/biosynthesis , Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl CoA Reductases/genetics , Aspergillosis/drug therapy , Aspergillosis/microbiology , Drug Resistance, Fungal/genetics , Drug Resistance, Fungal/drug effects , Gene Expression Regulation, Fungal/drug effects , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P-450 Enzyme System/genetics , Microbial Sensitivity Tests , Sterol 14-Demethylase/metabolism , Sterol 14-Demethylase/genetics , Humans , Mutation
9.
Stroke ; 55(6): 1676-1679, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38572634

ABSTRACT

BACKGROUND: The effects of lipid-lowering drug targets on different ischemic stroke subtypes are not fully understood. We aimed to explore the mechanisms by which lipid-lowering drug targets differentially affect the risk of ischemic stroke subtypes and their underlying pathophysiology. METHODS: Using a 2-sample Mendelian randomization approach, we assessed the effects of genetically proxied low-density lipoprotein cholesterol (LDL-c) and 3 clinically approved LDL-lowering drugs (HMGCR [3-hydroxy-3-methylglutaryl-CoA reductase], PCSK9 [proprotein convertase subtilisin/kexin type 9], and NPC1L1 [Niemann-Pick C1-Like 1]) on stroke subtypes and brain imaging biomarkers associated with small vessel stroke (SVS), including white matter hyperintensity volume and perivascular spaces. RESULTS: In genome-wide Mendelian randomization analyses, lower genetically predicted LDL-c was significantly associated with a reduced risk of any stroke, ischemic stroke, and large artery stroke, supporting previous findings. Significant associations between genetically predicted LDL-c and cardioembolic stroke, SVS, and biomarkers, perivascular space and white matter hyperintensity volume, were not identified in this study. In drug-target Mendelian randomization analysis, genetically proxied reduced LDL-c through NPC1L1 inhibition was associated with lower odds of perivascular space (odds ratio per 1-mg/dL decrease, 0.79 [95% CI, 0.67-0.93]) and with lower odds of SVS (odds ratio, 0.29 [95% CI, 0.10-0.85]). CONCLUSIONS: This study provides supporting evidence of a potentially protective effect of LDL-c lowering through NPC1L1 inhibition on perivascular space and SVS risk, highlighting novel therapeutic targets for SVS.


Subject(s)
Cerebral Small Vessel Diseases , Cholesterol, LDL , Ischemic Stroke , Mendelian Randomization Analysis , Proprotein Convertase 9 , Humans , Ischemic Stroke/genetics , Ischemic Stroke/diagnostic imaging , Cholesterol, LDL/blood , Cerebral Small Vessel Diseases/genetics , Cerebral Small Vessel Diseases/diagnostic imaging , Proprotein Convertase 9/genetics , Biomarkers/blood , Membrane Transport Proteins/genetics , Hydroxymethylglutaryl CoA Reductases/genetics , Brain/diagnostic imaging , Membrane Proteins/genetics , Genome-Wide Association Study , Female
10.
Int Immunol ; 36(6): 291-302, 2024 Apr 27.
Article in English | MEDLINE | ID: mdl-38451254

ABSTRACT

Previous observational and experimental studies have suggested a relationship between statin treatments and the augmentation of immunotherapy effects; however, the causal role of statin usage in promoting antitumor immunity remains largely unexplored. Utilizing large-scale genome-wide association studies, we conducted a Mendelian Randomization (MR) analysis to examine the association between genetically proxied inhibition of the gene for 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a specific target of statins, and 524 immunotherapy-related profiles, encompassing immune cells, inflammatory cytokines, immune checkpoints, and gut microbiota. Our findings indicated a suggestive association between statin therapy and proinflammatory as well as antitumor effects; notably, inhibition of HMGCR demonstrated a robust link with increased susceptibility of various immune cell types, including basophil cells, white blood cells, eosinophil cells, neutrophil cells, activated CD8+ T cells, dendritic cells, and natural killer cells; furthermore, a causal relationship was observed between statin use and a decrease in terminal CD8+ T cells, granulocytes, monocytes, and myeloid-derived suppressor cells; genetically proxied statin usage was also significantly associated with elevated levels of proinflammatory cytokines and immunotherapy-related gut microbiota; importantly, the potential inhibition of HMGCR in influencing the response to immunotherapy was confirmed in the real-world cohorts. This study provides novel insights into the regulatory role of HMGCR inhibition in antitumor immunity, suggesting that strategies targeting HMGCR or lipid regulation may hold therapeutic potential for enhancing the efficacy of immunotherapy.


Subject(s)
Immunotherapy , Lipid Metabolism , Mendelian Randomization Analysis , Humans , Immunotherapy/methods , Lipid Metabolism/genetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Genome-Wide Association Study , Inflammation/immunology , Hydroxymethylglutaryl CoA Reductases/immunology , Hydroxymethylglutaryl CoA Reductases/genetics , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/genetics
11.
J Cancer Res Clin Oncol ; 150(2): 106, 2024 Feb 28.
Article in English | MEDLINE | ID: mdl-38418798

ABSTRACT

PURPOSE: De novo synthesis of cholesterol and its rate-limiting enzyme, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMGCR), is deregulated in tumors and critical for tumor cell survival and proliferation. However, the role of HMGCR in the induction and maintenance of stem-like states in tumors remains unclear. METHODS: A compiled public database from breast cancer (BC) patients was analyzed with the web application SurvExpress. Cell Miner was used for the analysis of HMGCR expression and statin sensitivity of the NCI-60 cell lines panel. A CRISPRon system was used to induce HMGCR overexpression in the luminal BC cell line MCF-7 and a lentiviral pLM-OSKM system for the reprogramming of MCF-7 cells. Comparisons were performed by two-tailed unpaired t-test for two groups and one- or two-way ANOVA. RESULTS: Data from BC patients showed that high expression of several members of the cholesterol synthesis pathway were associated with lower recurrence-free survival, particularly in hormone-receptor-positive BC. In silico and in vitro analysis showed that HMGCR is expressed in several BC cancer cell lines, which exhibit a subtype-dependent response to statins in silico and in vitro. A stem-like phenotype was demonstrated upon HMGCR expression in MCF-7 cells, characterized by expression of the pluripotency markers NANOG, SOX2, increased CD44 +/CD24low/ -, CD133 + populations, and increased mammosphere formation ability. Pluripotent and cancer stem cell lines showed high expression of HMGCR, whereas cell reprogramming of MCF-7 cells did not increase HMGCR expression. CONCLUSION: HMGCR induces a stem-like phenotype in BC cells of epithelial nature, thus affecting tumor initiation, progression and statin sensitivity.


Subject(s)
Breast Neoplasms , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Female , Breast Neoplasms/pathology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl CoA Reductases/genetics , Hydroxymethylglutaryl CoA Reductases/metabolism , Oxidoreductases , Cholesterol
13.
BMC Med Genomics ; 17(1): 22, 2024 Jan 17.
Article in English | MEDLINE | ID: mdl-38233830

ABSTRACT

BACKGROUND: Coronary artery calcification (CAC) is a highly specific marker of atherosclerosis. Niemann-Pick C1-like 1 (NPC1L1) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are the therapeutic targets of ezetimibe and statins, respectively, which are important for the progression of atherosclerosis. However, CAC's genetic susceptibility with above targets is still unknown. We aimed to investigate the association of NPC1L1 and HMGCR gene polymorphisms with CAC in patients with premature triple-vessel disease (PTVD). METHODS: Four single nucleotide polymorphisms (SNPs) (rs11763759, rs4720470, rs2072183, rs2073547) of NPC1L1, and three SNPs (rs12916, rs2303151, rs4629571) of HMGCR were genotyped in 872 PTVD patients. According to the coronary angiography results, patients were divided into low-degree CAC group and high-degree CAC group. RESULTS: A total of 872 PTVD patients (mean age, 47.71 ± 6.12; male, 72.8%) were finally included for analysis. Multivariate logistic regression analysis showed no significant association between the SNPs of NPC1L1 and HMGCR genes and high-degree CAC in the total population (P > 0.05). Subgroup analysis by gender revealed that the variant genotype (TT/CT) of rs4720470 on NPC1L1 gene was associated with increased risk for high-degree CAC in male patients only (OR = 1.505, 95% CI: 1.008-2.249, P = 0.046) in dominant model, but no significant association was found in female population, other SNPs of NPC1L1 and HMGCR genes (all P > 0.05). CONCLUSIONS: We reported for the first time that the rs4720470 on NPC1L1 gene was associated with high-degree CAC in male patients with PTVD. In the future, whether therapies related to this target could reduce CAC and cardiovascular events deserves further investigation.


Subject(s)
Atherosclerosis , Coronary Artery Disease , Humans , Male , Female , Adult , Middle Aged , Membrane Transport Proteins/genetics , Oxidoreductases/genetics , Coronary Artery Disease/genetics , Polymorphism, Single Nucleotide , Hydroxymethylglutaryl CoA Reductases/genetics
14.
Cell Mol Gastroenterol Hepatol ; 17(1): 29-40, 2024.
Article in English | MEDLINE | ID: mdl-37703945

ABSTRACT

BACKGROUND & AIMS: Observational studies have linked lipid-lowering drug targets pro-protein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA reductase (HMGCR) with adverse liver outcomes; however, liver disease incidence varies across diverse populations, and the long-term hepatic impact of these lipid-lowering drugs among non-white Europeans remains largely unknown. METHODS: We use single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR loci from genome-wide association study data of low-density lipoprotein cholesterol in 4 populations (East Asian [EAS], South Asian [SAS], African [AFR], and European [EUR]) to perform drug-target Mendelian randomization investigating relationships between PCSK9 and HMGCR inhibition and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and bilirubin. RESULTS: Analyses of PCSK9 instruments, including functional variants R46L and E670G, failed to find evidence for relationships of low-density lipoprotein cholesterol lowering via PCSK9 variants and adverse effects on ALT, AST, GGT, or ALP among the cohorts. PCSK9 inhibition was associated with increased direct bilirubin levels in EUR (ß = 0.089; P value = 5.69 × 10-6) and, nominally, in AFR (ß = 0.181; P value = .044). HMGCR inhibition was associated with reduced AST in SAS (ß = -0.705; P value = .005) and, nominally, reduced AST in EAS (ß = -0.096; P value = .03), reduced ALP in EUR (ß = -2.078; P value = .014), and increased direct bilirubin in EUR (ß = 0.071; P value = .032). Sensitivity analyses using genetic instruments derived from circulating PCSK9 protein levels, tissue-specific PCSK9 expression, and HMGCR expression were in alignment, strengthening causal inference. CONCLUSIONS: We did not find ALT, AST, GGT, or ALP associated with genetically proxied PCSK9 and HMGCR inhibition across ancestries. We identified possible relationships in several ancestries between PCSK9 and increased direct and total bilirubin and between HMGCR and reduced AST. These findings support long-term safety profiles and low hepatotoxic risk of PCSK9 and HMGCR inhibition in diverse populations.


Subject(s)
Proprotein Convertase 9 , Subtilisin , Humans , Proprotein Convertase 9/genetics , Genome-Wide Association Study , Mendelian Randomization Analysis , Liver , Bilirubin , Lipoproteins, LDL , Cholesterol , Lipids , Hydroxymethylglutaryl CoA Reductases/genetics
15.
Front Endocrinol (Lausanne) ; 14: 1272167, 2023.
Article in English | MEDLINE | ID: mdl-38047111

ABSTRACT

Objective: The objective of this study was to investigate the association between hydroxymethylglutaryl coenzyme A reductase (HMGCR) inhibition and rheumatoid arthritis (RA) using drug-target Mendelian randomization (MR) and genetic colocalization analyses. Methods: Two sets of genetic instruments were employed to proxy HMGCR inhibitors: expression quantitative trait loci (eQTLs) of target genes from the eQTLGen Consortium and genetic variants associated with low-density lipoprotein cholesterol (LDL-C) levels with HMGCR locus from open genome-wide association studies (GWAS). Positive control analyses were conducted on type 2 diabetes and coronary heart disease, and multiple sensitivity analyses were performed. Results: Genetically proxied expression of eQTL was associated with a lower risk of RA (OR=0.996, 95% CI =0.992-0.999, p= 0.032). Similarly, hydroxymethylglutaryl coenzyme A reductase (HMGCR)-mediated low-density lipoprotein cholesterol was negatively associated with risk of RA (OR=0.995, 95% CI =0.991-0.998, p= 0.007) in the inverse variance weighted (IVW) method. Colocalization analysis suggested a 74.6% posterior probability of sharing a causal variant within the SNPs locus (PH4 = 74.6%). A causal relationship also existed between HMGCR-mediated LDL and RA risk factors. The results were also confirmed by multiple sensitivity analyses. The results in positive control were consistent with the previous study. Conclusion: Our study suggested that HMGCR inhibition was associated with an increased risk of RA while also highlighting an increased risk of current smoking and obesity. These findings contribute to a growing body of evidence regarding the adverse effects of HMGCR inhibition on RA risk, calling for further research on alternative approaches using HMGCR inhibitors in RA management.


Subject(s)
Arthritis, Rheumatoid , Diabetes Mellitus, Type 2 , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Arthritis, Rheumatoid/chemically induced , Arthritis, Rheumatoid/epidemiology , Arthritis, Rheumatoid/genetics , Cholesterol, LDL/genetics , Coenzyme A , Genome-Wide Association Study , Hydroxymethylglutaryl CoA Reductases/genetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Mendelian Randomization Analysis , Risk Factors
16.
Biosci Biotechnol Biochem ; 88(1): 97-106, 2023 Dec 19.
Article in English | MEDLINE | ID: mdl-37952102

ABSTRACT

Considering the absence of prior studies on the cholesterol metabolism-improving effects of eugeniin, the present investigation aimed to explore the potential impact of eugeniin on cholesterol metabolism. This study sought to elucidate the molecular mechanisms involved in this process using HepG2 and Caco-2 cells treated with 5 µm eugeniin. The intracellular cholesterol levels in HepG2 and Caco-2 cells were significantly decreased in the 24-h eugeniin-treated group. The protein and messenger ribonucleic acid (mRNA) levels of the low-density lipoprotein receptor (LDLR) were increased, while 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase protein and mRNA levels were decreased in HepG2 cells 6 h of the eugeniin-treated group. Additionally, LDLR protein and mRNA levels were increased in HepG2 cells after 24 h of eugeniin treatment. In Caco-2, the protein and mRNA levels of ATP-binding cassette transporter 1 were increased after 24 h eugeniin treatment. This novel finding indicates that eugeniin improves cholesterol metabolism in human cell cultures.


Subject(s)
Cholesterol , Hydroxymethylglutaryl CoA Reductases , Humans , Caco-2 Cells , Cholesterol/metabolism , Hep G2 Cells , Hydroxymethylglutaryl CoA Reductases/genetics , Hydroxymethylglutaryl CoA Reductases/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism
17.
J Transl Med ; 21(1): 718, 2023 10 13.
Article in English | MEDLINE | ID: mdl-37833739

ABSTRACT

BACKGROUND: The complex interplay between health, lifestyle and genetics represents a critical area of research for understanding and promoting human well-being. Importantly, genetics plays a key role in determining individual susceptibility to disease and response to lifestyle. The aim of the present study was to identify genetic factors related to the metabolic/inflammatory profile of adolescents providing new insights into the individual predisposition to the different effects of the substances from the environment. METHODS: Association analysis of genetic variants and biochemical parameters was performed in a total of 77 healthy adolescents recruited in the context of the DIMENU study. RESULTS: Polymorphisms of 3-hydroxy-3-methylglutaril coenzyme A reductase (HMGCR; rs142563098), C-reactive protein gene (CRP; rs1417938, rs1130864), cholesteryl ester transfer protein (CETP; rs5030708), interleukin (IL)-10 (IL-10; rs3024509) genes were significantly associated (p < 0.05) with various serum metabolic parameters. Of particular interest were also the correlations between the HMGCRpolymorphism (rs3846663) and tumor necrosis factor (TNF)-α levels, as well Fatty-acid desaturase (FADS) polymorphism (rs7481842) and IL-10 level opening a new link between lipidic metabolism genes and inflammation. CONCLUSION: In this study, we highlighted associations between single nucleotide polymorphisms (SNPs) and serum levels of metabolic and inflammatory parameters in healthy young individuals, suggesting the importance of genetic profiling in the prevention and management of chronic disease.


Subject(s)
Interleukin-10 , Polymorphism, Single Nucleotide , Adolescent , Humans , Alleles , Cholesterol Ester Transfer Proteins/genetics , Genetic Predisposition to Disease , Genotype , Hydroxymethylglutaryl CoA Reductases/genetics , Inflammation/genetics , Polymorphism, Single Nucleotide/genetics , Tumor Necrosis Factor-alpha
18.
J Pharmacol Sci ; 153(3): 104-112, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37770151

ABSTRACT

Statins, which are cholesterol synthesis inhibitors, are well-known therapeutics for dyslipidemia; however, some studies have anticipated their use as anticancer agents. However, epithelial cancer cells show strong resistance to statins through an increased expression of HMG-CoA reductase (HMGCR), an inhibitory target of statins. Castration-resistant prostate cancer (CRPC) cells synthesize androgens from cholesterol on their own. We performed suppression of CYP11A1, a rate-limiting enzyme in androgen synthesis from cholesterol, using siRNA or inhibitors, to examine the effect of steroidogenesis inhibition on statin sensitivity in CRPC cells. Here, we suggested that CYP11A1 silencing sensitized the statin-resistant CRPC cell line DU-145 to atorvastatin via HMGCR downregulation by an increase in intracellular free cholesterol. We further demonstrated that CYP11A1 silencing induced epithelial-mesenchymal transition, which converted DU-145 cells into a statin-sensitive phenotype. This suggests that concomitant use of CYP11A1 inhibitors could be an effective approach for overcoming statin resistance in CRPC. Moreover, we showed that ketoconazole, a CYP11A1 inhibitor, sensitized DU-145 cells to atorvastatin, although not all the molecular events observed in CYP11A1 silencing were reproducible. Although further studies are necessary to clarify the detailed mechanisms, ketoconazole may be effective as a concomitant drug that potentiates the anticancer effect of atorvastatin.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Atorvastatin/pharmacology , Cholesterol Side-Chain Cleavage Enzyme , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/genetics , Ketoconazole , Cholesterol , Cell Line, Tumor , Hydroxymethylglutaryl CoA Reductases/genetics
19.
Medicine (Baltimore) ; 102(39): e34690, 2023 Sep 29.
Article in English | MEDLINE | ID: mdl-37773823

ABSTRACT

BACKGROUND: The causal associations between statin use and male sex hormone levels and related disorders have not been fully understood. In this study, we employed Mendelian randomization for the first time to investigate these associations. METHODS: In two-sample Mendelian randomization framework, genetic proxies for hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition were identified as variants in the HMGCR gene that were associated with both levels of gene expression and low density lipoprotein cholesterol (LDL-C). We assessed the causal relationship between HMGCR inhibitor and 5 sex hormone levels/2 male-related diseases. Additionally, we investigated the association between 4 circulating lipid traits and outcomes. The "inverse variance weighting" method was used as the primary approach, and we assessed for potential heterogeneity and pleiotropy. In a secondary analysis, we revalidated the impact of HMGCR on 7 major outcomes using the summary-data-based Mendelian randomization method. RESULTS: Our study found a significant causal association between genetic proxies for HMGCR inhibitor and decreased levels of total testosterone (TT) (LDL-C per standard deviation = 38.7mg/dL, effect = -0.20, 95% confidence interval [CI] = -0.25 to -0.15) and bioavailable testosterone (BT) (effect = -0.15, 95% CI = -0.21 to -0.10). Obesity-related factors were found to mediate this association. Furthermore, the inhibitor were found to mediate a reduced risk of prostate cancer (odds ratio = 0.81, 95%CI = 0.7-0.93) by lowering bioavailable testosterone levels, without increasing the risk of erectile dysfunction (P = .17). On the other hand, there was a causal association between increased levels of LDL-C, total cholesterol, triglycerides (TG) and decreased levels of TT, sex hormone-binding globulin, and estradiol. CONCLUSIONS: The use of HMGCR inhibitor will reduce testosterone levels and the risk of prostate cancer without the side effect of erectile dysfunction. LDL-C, total cholesterol, and TG levels were protective factors for TT, sex hormone-binding globulin, and estradiol.


Subject(s)
Erectile Dysfunction , Prostatic Neoplasms , Humans , Male , Cholesterol, LDL , Sex Hormone-Binding Globulin , Oxidoreductases , Mendelian Randomization Analysis , Reproductive Health , Testosterone , Estradiol , Genome-Wide Association Study , Risk Factors , Polymorphism, Single Nucleotide , Hydroxymethylglutaryl CoA Reductases/genetics
20.
Biochem Biophys Res Commun ; 677: 13-19, 2023 10 15.
Article in English | MEDLINE | ID: mdl-37541087

ABSTRACT

Statins are cholesterol-lowering drugs that have exhibited potential as cancer therapeutic agents. However, as some cancer cells are resistant to statins, broadening an anticancer spectrum of statins is desirable. The upregulated expression of the statin target enzyme, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR), in statin-treated cancer cells is a well-known mechanism of statin resistance, which can be counteracted by the downregulation of HMGCR gene expression, or degradation of the HMGCR protein. However, the mechanism by which HMGCR degradation influences the anticancer effects of statins remain unreported. We tested the effect of the HMGCR degrader compound SR-12813 at a concentration that did not affect the growth of eight diverse tumor cell lines. Combined treatment with atorvastatin and a low concentration of SR-12813 led to lowering of increased HMGCR expression, and augmented the cytostatic effect of atorvastatin in both statin-resistant and -sensitive cancer cells compared with that of atorvastatin treatment alone. Dual-targeting of HMGCR using statins and SR-12813 (or similar compounds) could provide an improved anticancer therapeutic approach.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Atorvastatin/pharmacology , Up-Regulation , Hydroxymethylglutaryl CoA Reductases/genetics , Hydroxymethylglutaryl CoA Reductases/metabolism
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