HMGCR

HMGCR
  • 文章类型: Journal Article
    临床研究表明,炎症性皮肤病与血脂异常有关。调节脂质也是一种潜在的治疗选择。然而,现有证据存在异质性,缺乏大规模临床试验。观察性研究容易出现偏差,这使得很难确定因果关系。本研究旨在评估降脂药物与炎症性皮肤病之间的因果关系。进行药物靶标孟德尔随机化(MR)分析。降脂药物的遗传靶标,包括枯草原蛋白转化酶kexin9(PCSK9)和3-羟基-3-甲基戊二酰辅助酶A还原酶(HMGCR)抑制剂,被筛选。常见的炎症性皮肤病,包括牛皮癣,过敏性荨麻疹,酒渣鼻,特应性皮炎,系统性硬化症和脂溢性皮炎,被视为结果。基因预测的PCSK9抑制与银屑病风险降低有因果关系(ORIVW[95CI]=0.600[0.474-0.761],p=2.48×10-5)和特应性皮炎(ORIVW[95CI]=0.781[0.633-0.964],p=2.17×10-2)。基因预测的HMGCR抑制降低了脂溢性皮炎的风险(ORIVW[95CI]=0.407[0.168-0.984],p=4.61×10-2),但增加了过敏性荨麻疹的风险(ORIVW[95CI]=3.421[1.374-8.520],p=8.24×10-3)和酒渣鼻(ORIVW[95CI]=3.132[1.260-7.786],p=1.40×10-2)。在所有因果关联中,在更严格的Bonferroni检验后,只有PCSK9抑制显示出对牛皮癣的强大因果效应(p<4.17×10-3,为0.05/12)。通过抑制PCSK9调节脂质可能为银屑病和特应性皮炎提供潜在的治疗靶点。鉴于与HMGCR抑制剂相关的潜在皮肤副作用,PCSK9抑制剂可以被认为是降脂药物的可行替代品。
    Clinical research has revealed that inflammatory skin diseases are associated with dyslipidaemia. Modulating lipids is also a rising potential treatment option. However, there is heterogeneity in the existing evidence and a lack of large-scale clinical trials. Observational research is prone to bias, making it difficult to determine causality. This study aimed to evaluate the causal association between lipid-lowering drugs and inflammatory skin diseases. A drug target Mendelian randomisation (MR) analysis was conducted. Genetic targets of lipid-lowering drugs, including proprotein convertase subtilis kexin 9 (PCSK9) and 3-hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitor, were screened. Common inflammatory skin diseases, including psoriasis, allergic urticaria, rosacea, atopic dermatitis, systemic sclerosis and seborrhoeic dermatitis, were considered as outcomes. Gene-predicted inhibition of PCSK9 was causally associated with a decreased risk of psoriasis (ORIVW [95%CI] = 0.600 [0.474-0.761], p = 2.48 × 10-5) and atopic dermatitis (ORIVW [95%CI] = 0.781 [0.633-0.964], p = 2.17 × 10-2). Gene-predicted inhibition of HMGCR decreased the risk of seborrhoeic dermatitis (ORIVW [95%CI] = 0.407 [0.168-0.984], p = 4.61 × 10-2) but increased the risk of allergic urticaria (ORIVW [95%CI] = 3.421 [1.374-8.520], p = 8.24 × 10-3) and rosacea (ORIVW [95%CI] = 3.132 [1.260-7.786], p = 1.40 × 10-2). Among all causal associations, only PCSK9 inhibition demonstrated a robust causal effect on psoriasis after a more rigorous Bonferroni test (p < 4.17 × 10-3, which is 0.05/12). Modulating lipids via PCSK9 inhibition may offer potential therapeutic targets for psoriasis and atopic dermatitis. Given the potential cutaneous side effects associated with HMGCR inhibitors, PCSK9 inhibitors could be considered viable alternatives in lipid-lowering medication.
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  • 文章类型: Journal Article
    帕金森病(PD)是一种常见的神经退行性疾病,其特征是运动和非运动症状,包括认知障碍和痴呆。PD的病因,以及其保护和易感因素,仍然难以捉摸。3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)是调节胆固醇合成的酶。最近,编码HMGCR的基因中的单核苷酸多态性(SNP)与阿尔茨海默病的风险相关。HMGCR转录本的外显子13的可变剪接及其强相关的HMGCR单倍型7(H7:rs17244841,rs3846662,rs17238540)可能下调蛋白质活性和胆固醇合成,与PD相关的低密度脂蛋白胆固醇(LDL)水平较低,可能会影响认知能力。我们对306名PD患者的H7HMGCR基因中的三个SNP进行了基因分型,分为三组-没有认知能力下降,轻度认知障碍(MCI),和PD痴呆-以及242名健康参与者。观察到rs17238540基因型与PD易感性之间的相关性,以及rs3846662与PD患者的认知状态之间的次要关联;然而,对这些组的双面分析没有发现任何意义.我们观察到PD患者中rs17238540和rs17244841的次要等位基因携带者的高密度脂蛋白胆固醇(HDL)血浆水平显着升高。这项研究应该在更大的人群中重复。
    Parkinson\'s disease (PD) is a common neurodegenerative disease characterized by motor and non-motor symptoms including cognitive impairment and dementia. The etiopathogenesis of PD, as well as its protective and susceptibility factors, are still elusive. 3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is an enzyme regulating cholesterol synthesis. Single-nucleotide polymorphisms (SNPs) in the gene coding HMGCR have recently been correlated with the risk of Alzheimer\'s disease. Alternative splicing of exon 13 of the HMGCR transcript and its strongly associated HMGCR haplotype 7 (H7: rs17244841, rs3846662, rs17238540) may downregulate protein activity and cholesterol synthesis, with lower low-density lipoprotein cholesterol (LDL) levels associated with PD that may affect cognitive abilities. We genotyped three SNPs in the H7 HMGCR gene in 306 PD patients divided into three groups-without cognitive decline, with mild cognitive impairment (MCI), and with PD dementia-and in 242 healthy participants. A correlation between the rs17238540 genotype and PD susceptibility as well as a minor association between rs3846662 and cognitive status in PD patients was observed; however, the two-sided analysis of these groups did not reveal any significance. We observed a statistically significant elevated high-density lipoprotein cholesterol (HDL) plasma level in the minor allele carriers of rs17238540 and rs17244841 among PD patients. This study should be replicated in a larger population.
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  • 文章类型: Journal Article
    动脉粥样硬化性心血管疾病(ASCVD)与低密度脂蛋白胆固醇(LDL-C)升高密切相关。在喂食状态下,葡萄糖和胰岛素激活磷酸化去泛素酶USP20的mTORC1。然后USP20稳定HMG-CoA还原酶(HMGCR),从而增加脂质生物合成。在这项研究中,我们应用临床批准的脂质纳米颗粒(LNP)来封装靶向Usp20的siRNA。我们证明了通过siRNA沉默肝Usp20可以降低体重,通过提高UCP1改善胰岛素敏感性和增加能量消耗。在LDLR-/-小鼠中,通过siRNA沉默Usp20降低脂质水平并预防动脉粥样硬化。这项研究表明,基于RNAi的靶向肝Usp20的治疗具有治疗代谢疾病的翻译潜力。
    Atherosclerotic cardiovascular disease (ASCVD) is closely correlated with elevated low-density lipoprotein cholesterol (LDL-C). In feeding state, glucose and insulin activate mTORC1 that phosphorylates the deubiquitylase USP20. USP20 then stabilizes HMG-CoA reductase (HMGCR), thereby increasing lipid biosynthesis. In this study, we applied clinically approved lipid nanoparticles (LNPs) to encapsulate the siRNA targeting Usp20. We demonstrated that silencing of hepatic Usp20 by siRNA decreased body weight, improved insulin sensitivity and increased energy expenditure through elevating UCP1. In Ldlr-/- mice, silencing Usp20 by siRNA decreased lipid levels and prevented atherosclerosis. This study suggests that the RNAi-based therapy targeting hepatic Usp20 has a translational potential to treat metabolic disease.
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  • 文章类型: Journal Article
    目的:我们描述了不同的临床表现,在一个大型国家队列中,抗HMGCR肌病的诊断和结局障碍。
    方法:本研究包括通过线印迹或酶免疫测定,然后进行免疫沉淀发现血清抗HMGCR自身抗体阳性的成年人。
    结果:在确定的75名患者中,72例(96%)的记录将虚弱描述为表现症状。65的记录给出了近端无力的可靠描述。在22/65(33.8%)中,无力被描述为主要或仅下肢无力。75人中有45人(60%)出现亚急性发作(症状持续时间>4周-≤6个月),而22/75(29.3%)则表现为更缓慢的慢性发作(症状持续时间>6个月)。75人中有18人(24%)下跌,2/75人(2.7%)“普遍下跌”。在三名患者中,没有描述任何弱点:两名表现为肌痛,一名表现为Jessner淋巴细胞性皮疹。出现时的肌酸激酶中位数为7337U/L(范围1050-25,500)。38例(50.7%)进行肌肉活检。相关的恶性肿瘤很少见。4例患者恢复无免疫抑制。5年和10年生存率为92.7%(95%CI80.6-97.4%),和82.5%(95%CI61.2-92.8%)。
    结论:反复下跌,在该抗HMGCR肌病队列中,常见的是长前驱症状和显性下肢近端无力。这些特征与虚弱综合征和散发性包涵体肌炎重叠,强调在该临床背景下考虑抗HMGCR肌病的重要性。少数患者在单独停用他汀类药物后康复。
    OBJECTIVE: We describe the varied clinical presentations, barriers in diagnosis and outcomes of anti-HMGCR myopathy in a large national cohort.
    METHODS: Adults found positive for serum anti-HMGCR autoantibodies via line blot or enzyme-immunoassay followed by immunoprecipitation were included in the study.
    RESULTS: Of 75 patients identified, the records of 72 (96 %) described weakness as the presenting symptom. The records of 65 gave a reliable description of proximal weakness. In 22/65 (33.8 %) the weakness was described as predominantly or solely lower limb weakness. Forty-five of 75 (60 %) presented with a subacute onset (duration of symptoms >4 weeks -≤6 months), whilst 22/75 (29.3 %) presented with a more indolent chronic onset (duration of symptoms >6 months). Eighteen of 75 (24 %) suffered falls and 2/75 (2.7 %) had \"general decline\". In three patients no weakness was described: two presented with myalgia and one with a skin rash characterized as Jessner lymphocytic skin rash. Median creatine kinase at presentation was 7337 U/L (range 1050-25,500). Muscle biopsy was performed in 38 (50.7 %). Associated malignancy was infrequent. Four patients recovered without immunosuppression. Five-year and 10-year survival was 92.7 % (95 % CI 80.6-97.4 %), and 82.5 % (95 % CI 61.2-92.8 %) respectively.
    CONCLUSIONS: Recurrent falls, a long prodrome and dominant lower limb proximal weakness were common in this anti-HMGCR myopathy cohort. These features overlap with frailty syndrome and sporadic inclusion body myositis emphasizing the importance of considering anti-HMGCR myopathy in that clinical context. A minority of patients recover after statin withdrawal alone.
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  • 文章类型: Journal Article
    没有可靠的因果证据证明他汀类药物对糖尿病肾病(DN)和糖尿病视网膜病变(DR)的影响,和以前的观察研究结果是矛盾的。来自英国生物银行全基因组关联研究并位于HMGCR周围100kb窗口内的与低密度脂蛋白胆固醇(LDL-C)相关的遗传变异用于替代他汀类药物。与PCSK9抑制剂(对照)比较。DN和DR全基因组关联研究汇总统计来自FinnGen研究。二次MR分析和NHANES横截面数据用于验证。药物靶向孟德尔随机化(MR)用于研究HMGCR和PCSK9基因抑制与DN和DR之间的关系。在Bonferroni校正后,p<0.0125被认为是有意义的。为了对发现进行三角测量,使用全血来源靶基因表达(cis-eQTL)和血浆来源蛋白(cis-pQTL)水平的遗传变异进行二次MR分析,并使用国家健康和营养检查调查的数据进行横断面分析.遗传代理抑制HMGCR与DN和DR的高风险相关(DN:OR=1.79,p=0.01;DR:OR=1.41,p=0.004),而PCSK9没有发现这种关联。二次MR分析证实了这些关联。横断面分析显示,他汀类药物的使用与DR发生率之间存在正相关(OR=1.26,p=0.03),而与肾小球滤过率之间存在显着的负相关(Beta=-1.9,p=0.03)。这项研究提供了遗传证据,表明遗传代理抑制HMGCR与DN/DR的风险增加有关。并且这种作用可能不归因于它们降低LDL-C的特性。对于糖尿病血脂异常患者,PCSK9抑制剂可能是优选的替代方案。
    There is no reliable causal evidence for the effect of statins on diabetic nephropathy (DN) and diabetic retinopathy (DR), and the results of previous observational studies are contradictory. Genetic variants linked to low-density lipoprotein cholesterol (LDL-C) from a UK biobank genome-wide association study and located within a 100kb window around HMGCR were used to proxy statins, comparing with PCSK9 inhibitors (control). DN and DR genome-wide association study summary statistics were obtained from the FinnGen study. Secondary MR analyses and NHANES cross-sectional data were used for validation. Drug-target Mendelian randomization (MR) was applied to investigate the association between the genetically proxied inhibition of HMGCR and PCSK9 with DN and DR, p < 0.0125 was considered significant after Bonferroni Correction. To triangulate the findings, genetic variants of whole blood-derived targets gene expression (cis-eQTL) and plasma-derived protein (cis-pQTL) levels were used to perform secondary MR analyses and data from the National Health and Nutrition Examination Survey were used for cross-sectional analysis. Genetically proxied inhibition of HMGCR was associated with higher risks of DN and DR (DN: OR = 1.79, p = 0.01; DR: OR = 1.41, p = 0.004), while no such association was found for PCSK9. Secondary MR analyses confirmed these associations. Cross-sectional analysis revealed a positive link between statin use and DR incidence (OR = 1.26, p = 0.03) and a significant negative association with glomerular filtration rate (Beta = - 1.9, p = 0.03). This study provides genetic evidence that genetically proxied inhibition of HMGCR is associated with increased risks of DN/DR, and this effect may not be attributed to their LDL-C-lowering properties. For patients with diabetic dyslipidemia, PCSK9 inhibitors may be a preferable alternative.
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  • 文章类型: Journal Article
    背景:前蛋白转化酶枯草杆菌蛋白酶/kexin9型(PCSK9)抑制剂代表了降低心血管疾病风险的有效策略。然而,PCSK9对骨质疏松的影响尚不清楚。因此,我们采用孟德尔随机化(MR)分析检查PCSK9抑制剂对骨质疏松的影响.
    方法:3-羟基-3-甲基戊二酰辅因子A还原酶(HMGCR)和PCSK9的单核苷酸多态性(SNP)从可用的欧洲家系在线数据库中收集。四项与骨质疏松症相关的全基因组关联研究(GWAS)数据作为主要结果,和冠状动脉疾病(CAD)作为药物靶向MR分析的阳性对照。通过敏感性分析检查的MR分析结果纳入meta分析,以检查PCSK9和HMGCR抑制剂与骨质疏松症之间的因果关系。
    结果:荟萃分析共涉及1,263,102名受试者,表明PCSK9抑制剂可增加骨质疏松风险(P<0.05,I2,39%)。然而,HMGCR抑制剂与骨质疏松症风险无关。此外,使用另一个与暴露相关的GWAS数据集进行了分析的复制,这导致了类似的结论。
    结论:PCSK9抑制剂增加骨质疏松风险。然而,HMGCR抑制剂与骨质疏松症无显著关联。
    BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an effective strategy for reducing cardiovascular disease risk. Yet, PCSK9\'s impact on osteoporosis remains unclear. Hence, we employed Mendelian randomization (MR) analysis for examining PCSK9 inhibitor effects on osteoporosis.
    METHODS: Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for European pedigrees. Four osteoporosis-related genome-wide association studies (GWAS) data served as the main outcomes, and coronary artery disease (CAD) as a positive control for drug-targeted MR analyses. The results of MR analyses examined by sensitivity analyses were incorporated into a meta-analysis for examining causality between PCSK9 and HMGCR inhibitors and osteoporosis.
    RESULTS: The meta-analysis involving a total of 1,263,102 subjects, showed that PCSK9 inhibitors can increase osteoporosis risk (P < 0.05, I2, 39%). However, HMGCR inhibitors are not associated with osteoporosis risk. Additionally, a replication of the analysis was conducted with another exposure-related GWAS dataset, which led to similar conclusions.
    CONCLUSIONS: PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.
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  • 文章类型: Journal Article
    结直肠癌(CRC)呈现出复杂的景观,以肿瘤间和肿瘤内异质性为特征。RUNX1,一种与调节肿瘤细胞生长有关的基因,生存,和差异化,关于其对CRC预后的影响尚不完全了解。在我们的调查中,我们发现RUNX1表达升高与各种CRC亚型的侵袭性表型之间存在正相关.值得注意的是,敲低RUNX1在体外和体内均显示出抑制CRC增殖的功效,主要通过诱导细胞凋亡和阻碍细胞增殖。机械上,我们揭示了RUNX1和胆固醇合成之间的直接监管联系,通过其对HMGCR表达的控制来介导。在CRC细胞中敲除RUNX1触发HMGCR转录激活,最终导致胆固醇水平升高,随后阻碍癌症进展。临床上,升高的RUNX1表达成为CRC患者不良结局的预后标志物.我们的发现强调了RUNX1在CRC进展中的关键参与及其作为治疗靶标的潜力。RUNX1对胆固醇合成和HMGCR转录调节的独特影响揭示了一个有助于CRC进展的新通路。
    Colorectal cancer (CRC) presents a complex landscape, characterized by both inter-tumor and intra-tumor heterogeneity. RUNX1, a gene implicated in modulating tumor cell growth, survival, and differentiation, remains incompletely understood regarding its impact on CRC prognosis. In our investigation, we discerned a positive correlation between elevated RUNX1 expression and aggressive phenotypes across various CRC subtypes. Notably, knockdown of RUNX1 demonstrated efficacy in restraining CRC proliferation both in vitro and in vivo, primarily through inducing apoptosis and impeding cell proliferation. Mechanistically, we unveiled a direct regulatory link between RUNX1 and cholesterol synthesis, mediated by its control over HMGCR expression. Knockdown of RUNX1 in CRC cells triggered HMGCR transcriptional activation, culminating in elevated cholesterol levels that subsequently hindered cancer progression. Clinically, heightened RUNX1 expression emerged as a prognostic marker for adverse outcomes in CRC patients. Our findings underscore the pivotal involvement of RUNX1 in CRC advancement and its potential as a therapeutic target. The unique influence of RUNX1 on cholesterol synthesis and HMGCR transcriptional regulation uncovers a novel pathway contributing to CRC progression.
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  • 文章类型: Journal Article
    背景:降脂药在老年人中广泛使用,一些研究表明与肌肉相关的症状有关。然而,因果关系仍然不确定。
    方法:使用孟德尔随机化(MR)方法,我们通过抑制羟甲基戊二酰辅酶A还原酶(HMGCR)评估了遗传代理降低的低密度脂蛋白胆固醇(LDL-C)的因果效应,前蛋白转化酶枯草杆菌蛋白酶/kexin9型(PCSK9),和Niemann-PickC1样1(NPC1L1)在肌肉减少症相关性状上,包括低握力,阑尾瘦体重,通常的步行速度。进行了荟萃分析,以结合来自不同联盟的因果估计。
    结果:使用主要来自英国生物银行的LDL-C汇总数据,遗传代理抑制HMGCR与较高的阑尾瘦体重(β=0.087,P=7.56×10-5)和较慢的步行速度(OR=0.918,P=6.06×10-9)有关。相比之下,抑制PCSK9可降低阑尾瘦体重(β=-0.050,P=1.40×10-3),而NPC1L1的抑制对肌肉减少症相关性状没有因果关系。这些结果使用全球血脂遗传学联盟的LDL-C数据进行了验证,表明抑制HMGCR可能会增加四肢瘦体重(β=0.066,P=2.17×10-3)并减慢步行速度(OR=0.932,P=1.43×10-6),而抑制PCSK9可以降低阑尾瘦体重(β=-0.048,P=1.69×10-6)。荟萃分析进一步支持了这些因果关联的稳健性。
    结论:基因代理抑制HMGCR可能会增加肌肉质量,但损害肌肉功能,PCSK9抑制可导致肌肉质量减少,而NPC1L1抑制与肌肉减少症相关性状无关,这类药物可作为肌肉减少症个体或高危人群的可行替代药物.
    BACKGROUND: Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain.
    METHODS: Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums.
    RESULTS: Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10- 5) and slower walking pace (OR = 0.918, P = 6.06 × 10- 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10- 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10- 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10- 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10- 6). Meta-analysis further supported the robustness of these causal associations.
    CONCLUSIONS: Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.
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  • 文章类型: Case Reports
    特发性炎性肌病(IIM)代表一组罕见的自身免疫性疾病,导致肌肉无力,包括多发性肌炎,皮肌炎,免疫介导性坏死性肌病(IMNM),重叠肌炎,和包涵体肌炎。抗3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)抗体IMNM代表了一种罕见但日益被认可的IIM亚型。在这里,我们报告一例65岁女性服用瑞舒伐他汀,出现两个月的进行性近端肌无力,显著的躯干无力,肌酸激酶升高与横纹肌溶解和炎性肌病有关。在延迟测试该特定肌病之后,患者最终在她住院的第8天被诊断为抗HMGCR抗体IMNM。增加了对这种IIM亚型的认识,以及其风险因素和呈现特征,如果在急诊科或住院早期考虑诊断,可能会提高检测速度并缩短住院时间。
    Idiopathic inflammatory myopathy (IIM) represents a rare group of autoimmune conditions resulting in muscle weakness and includes polymyositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), overlap myositis, and inclusion body myositis. Anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibody IMNM represents a rare but increasingly recognized subtype of IIM. Here we report a case of a 65-year-old woman on rosuvastatin who presented with two months of progressive proximal muscle weakness, significant truncal weakness, and elevated creatine kinase concerning for rhabdomyolysis and inflammatory myopathy. The patient was eventually diagnosed on day 8 of her hospital stay with anti-HMGCR antibody IMNM after delayed testing for this specific myopathy. Increased awareness of this IIM subtype, as well as its risk factors and presenting features, might improve rapidity of testing and shorten hospital stays if the diagnosis is considered in the emergency department or early in the hospital course.
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  • 文章类型: Journal Article
    目的:胆固醇代谢异常是动脉粥样硬化性心血管疾病的标志,然而,我们对内源性胆固醇合成如何影响动脉粥样硬化的理解尚不清楚。能量传感器AMP激活的蛋白激酶(AMPK)磷酸化并抑制甲羟戊酸途径HMG-CoA还原酶(HMGCR)中的限速酶。最近的工作表明,当AMPK-HMGCR信号在Apo-/-高胆固醇血症模型中受损时,由于造血干细胞和祖细胞动员和骨髓生成升高,动脉粥样硬化加剧。我们试图使用具有功能性ApoE的非种系高胆固醇血症模型验证AMPK-HMGCR信号轴在动脉粥样硬化中的重要性。
    方法:雄性和雌性HMGCRS871A敲入(KI)小鼠和野生型(WT)同窝动物通过静脉注射功能获得的Pcsk9D374Y-腺相关病毒,然后进行高脂肪和高胆固醇的动脉粥样硬化饮食喂养16周。
    结果:AMPK激活抑制了来自WT的原代骨髓源性巨噬细胞的内源性胆固醇合成,但不抑制HMGCRKI小鼠,不改变胆固醇调节的其他参数。WT和HMGCRKI小鼠之间的动脉粥样硬化斑块面积不变,与性无关。相应地,在骨髓中的造血祖细胞或分化的免疫细胞中没有观察到表型差异,血,或者脾脏,全身炎症标志物无明显变化。当致命照射的雌性小鼠移植KI骨髓时,相对于WT有相似的斑块含量。
    结论:鉴于先前的工作,我们的研究证明了临床前动脉粥样硬化模型比较的重要性,并质疑AMPK介导的控制胆固醇合成在动脉粥样硬化中的重要性.
    OBJECTIVE: Dysregulated cholesterol metabolism is a hallmark of atherosclerotic cardiovascular diseases, yet our understanding of how endogenous cholesterol synthesis affects atherosclerosis is not clear. The energy sensor AMP-activated protein kinase (AMPK) phosphorylates and inhibits the rate-limiting enzyme in the mevalonate pathway HMG-CoA reductase (HMGCR). Recent work demonstrated that when AMPK-HMGCR signaling was compromised in an Apoe-/- model of hypercholesterolemia, atherosclerosis was exacerbated due to elevated hematopoietic stem and progenitor cell mobilization and myelopoiesis. We sought to validate the significance of the AMPK-HMGCR signaling axis in atherosclerosis using a non-germline hypercholesterolemia model with functional ApoE.
    METHODS: Male and female HMGCR S871A knock-in (KI) mice and wild-type (WT) littermate controls were made atherosclerotic by intravenous injection of a gain-of-function Pcsk9D374Y-adeno-associated virus followed by high-fat and high-cholesterol atherogenic western diet feeding for 16 weeks.
    RESULTS: AMPK activation suppressed endogenous cholesterol synthesis in primary bone marrow-derived macrophages from WT but not HMGCR KI mice, without changing other parameters of cholesterol regulation. Atherosclerotic plaque area was unchanged between WT and HMGCR KI mice, independent of sex. Correspondingly, there were no phenotypic differences observed in hematopoietic progenitors or differentiated immune cells in the bone marrow, blood, or spleen, and no significant changes in systemic markers of inflammation. When lethally irradiated female mice were transplanted with KI bone marrow, there was similar plaque content relative to WT.
    CONCLUSIONS: Given previous work, our study demonstrates the importance of preclinical atherosclerosis model comparison and brings into question the importance of AMPK-mediated control of cholesterol synthesis in atherosclerosis.
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