更新于：2024-05-01

Hyperlipoproteinemia Type III

III型高脂蛋白血症

更新于：2024-05-01

基本信息

别名

3ｶﾞﾀｺｳｼｹｯｼｮｳ、3ｶﾞﾀｺｳｼｹﾂｼｮｳ、3ｶﾞﾀｺｳﾘﾎﾟﾀﾝﾊﾟｸｹｯｼｮｳ

+ [114]

简介

An autosomal recessively inherited disorder characterized by the accumulation of intermediate-density lipoprotein (IDL or broad-beta-lipoprotein). IDL has a CHOLESTEROL to TRIGLYCERIDES ratio greater than that of VERY-LOW-DENSITY LIPOPROTEINS. This disorder is due to mutation of APOLIPOPROTEINS E, a receptor-binding component of VLDL and CHYLOMICRONS, resulting in their reduced clearance and high plasma levels of both cholesterol and triglycerides.

关联

项与 III型高脂蛋白血症相关的药物

Simvastatin/Sitagliptin Phosphate

辛伐他汀/磷酸西格列汀一水合物

靶点

DPP-4 x HMG-CoA reductase

作用机制

DPP-4抑制剂 [+1]

在研机构

Merck Gesellschaft mbH

原研机构

Merck Sharp & Dohme Corp.

在研适应症

血脂障碍 [+1]

非在研适应症

冠心病 [+7]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2011-10-07

Amlodipine Besylate/Atorvastatin Calcium

苯磺酸氨氯地平/阿托伐他汀钙

靶点

HMG-CoA reductase x VDCCs

作用机制

HMG-CoA reductase抑制剂 [+1]

在研机构

Pharmacia & Upjohn, Inc. [+2]

原研机构

Pfizer Inc.

在研适应症

II型高脂蛋白血症 [+13]

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2004-01-30

Rosuvastatin Calcium

瑞舒伐他汀钙

靶点

HMG-CoA reductase

作用机制

HMG-CoA reductase抑制剂

在研机构

IPR Pharmaceuticals, Inc. [+4]

原研机构

Shionogi & Co., Ltd.

在研适应症

动脉粥样硬化 [+11]

非在研适应症

创伤性脑损伤 [+12]

最高研发阶段批准上市

首次获批国家/地区

荷兰

首次获批日期2002-11-06

项与 III型高脂蛋白血症相关的临床试验

DRKS00031182 / RecruitingN/A

Prospective investigation of clinical, lipidological, vascular and hepatic parameters with regard to cardiovascular risk factors and primary prevention in childhood

开始日期2023-01-01

申办/合作机构-

NCT05218005 / RecruitingN/AIIT

The Advancing Cardiac Care Unit-based Rapid Assessment and Treatment of hypErcholesterolemia (ACCURATE) Study

ACCURATE will test the hypothesis that opportunistic genetic testing for Familial Hypercholesterolemia (FH) in patients admitted to hospital with an acute coronary syndrome will increase the diagnosis of FH and will impact patient care and outcomes. The study will recruit patients admitted to hospital with an acute coronary syndrome, and research-based genetic testing will be conducted for known FH-causing genetic variants. The results will be returned to the patients' treating physicians. The primary endpoint will be the number of patients with a new diagnosis of FH. The secondary endpoints will be the proportion of patients who undergo intensification of lipid-lowering therapy, the lowest LDL cholesterol level achieved, and the proportion of patients reaching guideline recommended lipid targets in the 12 months after the index acute coronary syndrome.

开始日期2022-01-01

申办/合作机构

University of British Columbia

[+2]

TCTR20220917002 / Completed临床1期

Safety-Consumption and Cholesterol-Lowering Effects of Lactobacillus paracasei TISTR 2593 by the Alternating Cholesterol Metabolism and Parameters Associated with Atherosclerosis in Hypercholesterolemic Subjects

开始日期2021-11-05

申办/合作机构-

100 项与 III型高脂蛋白血症相关的临床结果

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100 项与 III型高脂蛋白血症相关的转化医学

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0 项与 III型高脂蛋白血症相关的专利（医药）

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935

项与 III型高脂蛋白血症相关的文献（医药）

2023-11-23·Journal of clinical lipidology

Genetic risk score in patients with the APOE2/E2 genotype as a predictor of familial dysbetalipoproteinemia.

Article

作者: Martin Satny ; Veronika Todorovova ; Tereza Altschmiedova ; Jaroslav A Hubacek ; Lucie Dlouha ; Vera Lanska ; Vladimir Soska ; Ondrej Kyselak ; Tomas Freiberger ; Martin Bobak ; Michal Vrablik

BACKGROUND:

Familial dysbetalipoproteinemia (FD) is an autosomal recessive (rarely dominant) inherited disorder that is almost exclusively associated with the apolipoprotein E gene (APOE) variability. Nonetheless, only a small proportion of APOE2/E2 subjects develop the phenotype for mixed dyslipidemia; the context of other trigger metabolic or genetic factors remains unknown.

METHODS:

One hundred and one patients with FD and eighty controls (all APOE2/E2 homozygotes; rs429358) were screened for 18 single-nucleotide polymorphisms (SNPs) within the genes involved in triglyceride metabolism.

RESULTS:

Two SNPs were significantly associated with the FD phenotype (rs439401 within APOE; P < 0.0005 and rs964184 within ZPR1/APOA5/A4/C3/A1 gene cluster; P < 0.0001). Unweighted genetic risk scores - from these two SNPs (GRS2), and, also, additional 13 SNPs with P-value below 0.9 (GRS15) - were created as an additional tool to improve the risk estimation of FD development in subjects with the APOE2/E2 genotype. Both GRS2 and GRS15 were significantly (P < 0.0001) increased in patients and both GRSs discriminated almost identically between the groups (P = 0.86). Subjects with an unweighted GRS2 of three or more had an almost four-fold higher risk of FD development than other individuals (OR 3.58, CI: 1.78-7.18, P < 0.0005).

CONCLUSIONS:

We identified several SNPs that are individual additive factors influencing FD development. The use of unweighted GRS2 is a simple and clinically relevant tool that further improves the prediction of FD in APOE2/E2 homozygotes with corresponding biochemical characteristics.

2023-09-22·Diseases (Basel, Switzerland)

Studies on the Effects of Hypercholesterolemia on Mouse Ophthalmic Artery Reactivity.

Article

作者: Francesco Buonfiglio ; Ning Xia ; Can Yüksel ; Caroline Manicam ; Subao Jiang ; Jenia Kouchek Zadeh ; Aytan Musayeva ; Eva Elksne ; Norbert Pfeiffer ; Andreas Patzak ; Huige Li ; Adrian Gericke

Atherogenic lipoproteins may impair vascular reactivity, leading to tissue damage in various organs, including the eye. This study aimed to investigate whether ophthalmic artery reactivity is affected in mice lacking the apolipoprotein E gene (ApoE-/-), a model for hypercholesterolemia and atherosclerosis. Twelve-month-old male ApoE-/- mice and age-matched wild-type controls were used to assess vascular reactivity using videomicroscopy. Moreover, the vascular mechanics, lipid content, levels of reactive oxygen species (ROS), and expression of pro-oxidant redox enzymes and the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) were determined in vascular tissue. Unlike the aorta, the ophthalmic artery of ApoE-/- mice developed no signs of endothelial dysfunction and no signs of excessive lipid deposition. Remarkably, the levels of ROS, nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1), NOX2, NOX4, and LOX-1 were increased in the aorta but not in the ophthalmic artery of ApoE-/- mice. Our findings suggest that ApoE-/- mice develop endothelial dysfunction in the aorta by increased oxidative stress via the involvement of LOX-1, NOX1, and NOX2, whereas NOX4 may participate in media remodeling. In contrast, the ophthalmic artery appears to be resistant to chronic apolipoprotein E deficiency. A lack of LOX-1 expression/overexpression in response to increased oxidized low-density lipoprotein levels may be a possible mechanism of action.

2023-09-11·International journal of molecular sciences

Postprandial Hyperlipidemia: Its Pathophysiology, Diagnosis, Atherogenesis, and Treatments.

Review

作者: Hidekatsu Yanai ; Hiroki Adachi ; Mariko Hakoshima ; Hisayuki Katsuyama

Postprandial hyperlipidemia showing postprandial increases in serum triglyceride (TG) is associated with the development of atherosclerotic cardiovascular disease (ASCVD). To diagnose postprandial hyperlipidemia, the oral fat loading test (OFLT) should be performed; however, this test is very time-consuming and is difficult to perform. Elevated serum TG levels reflect an increase in TG-rich lipoproteins (TRLs), such as chylomicrons (CM), very low-density lipoproteins (VLDL), and their remnants (CM remnants [CMRs] and VLDL remnants [VLDLRs]). Understanding of elevation in CMR and/or VLDLR can lead us to understand the existence of postprandial hyperlipidemia. The measurement of apo B48, which is a constituent of CM and CMR; non-fasting TG, which includes TG content in all lipoproteins including CM and CMR; non-high-density lipoprotein cholesterol (non-HDL-C), which includes TRLs and low-density lipoprotein; and remnant cholesterol are useful to reveal the existence of postprandial hyperlipidemia. Postprandial hyperlipidemia is observed in patients with familial type III hyperlipoproteinemia, familial combined hyperlipidemia, chronic kidney disease, metabolic syndrome and type 2 diabetes. Postprandial hyperlipidemia is closely related to postprandial hyperglycemia, and insulin resistance may be an inducing and enhancing factor for both postprandial hyperlipidemia and postprandial hyperglycemia. Remnant lipoproteins and metabolic disorders associated with postprandial hyperlipidemia have various atherogenic properties such as induction of inflammation and endothelial dysfunction. A healthy diet, calorie restriction, weight loss, and exercise positively impact postprandial hyperlipidemia. Anti-hyperlipidemic drugs such pemafibrate, fenofibrate, bezafibrate, ezetimibe, and eicosapentaenoic acid have been shown to improve postprandial hyperlipidemia. Anti-diabetic drugs including metformin, alpha-glucosidase inhibitors, pioglitazone, dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide 1 analogues have been shown to ameliorate postprandial hyperlipidemia. Although sodium glucose cotransporter-2 inhibitors have not been proven to reduce postprandial hyperlipidemia, they reduced fasting apo B48 and remnant lipoprotein cholesterol. In conclusion, it is important to appropriately understand the existence of postprandial hyperlipidemia and to connect it to optimal treatments. However, there are some problems with the diagnosis for postprandial hyperlipidemia. Postprandial hyperlipidemia cannot be specifically defined by measures such as TG levels 2 h after a meal. To study interventions for postprandial hyperlipidemia with the outcome of preventing the onset of ASCVD, it is necessary to define postprandial hyperlipidemia using reference values such as IGT.

项与 III型高脂蛋白血症相关的新闻（医药）

2023-05-03

·生物探索

那些打破家族遗传阿尔茨海默病“魔咒”的人，基因做对了什么？

家族性阿尔茨海默病中的豁免者 Doug Whitney遗传了与母亲、兄长和其他几代亲属相同的基因突变，这种突变让他们在50岁时就患上了阿尔茨海默病，这个年龄相对于阿尔茨海默病平均65岁的起病年龄而言，显得格外年轻。Doug祖父母的14个孩子中，有10个患有早发性阿尔茨海默病。Doug的母亲第一次出现征兆是在1971年的感恩节，她忘记了如何制作一直以来烂熟于心的南瓜派。五年后，她离世了。Doug的兄长则在48岁时开始出现症状。图1 14个兄弟姐妹中，Doug Whitney的母亲Mildred Reiswig Whitney位于后排左起第四。（图源：[1]）这使得Doug的妻儿在他50岁生日过后，对他的健康状况尤为担忧。然而，Doug今年已经73岁了，他的头脑依然清晰，不知为何，因遗传的突变基因而注定的命运似乎被打破了。哥伦比亚一名叫Aliria Piedrahita de Villegas的妇女也是如此，她遗传了家族的PSEN1E280A突变，这是一种常染色体显性突变，只需携带一个基因拷贝即可引起疾病。Aliria本该在40多岁时患上阿尔茨海默病，并在60多岁时死于该病。然而，直到70多岁时，Aliria才开始出现阿尔茨海默病的迹象，最终也并未死于该病，而是在77岁时死于转移性黑色素瘤。目前，全球阿尔茨海默病患者约5000多万，我国患病人数约1000万，是世界上患者人数最多的国家。其中，不到1%的阿尔茨海默病由特定基因突变的单个拷贝引起，一旦子女遗传了与父母相同的突变，几乎就可以肯定会在相同的年纪发病。这些家庭可以帮助科学家了解阿尔茨海默病是如何形成的。现在已经知道，在出现第一个症状之前至少二十年，大脑就发生了悄然的变化，β-淀粉样蛋白开始沉积，然后tau蛋白开始缠结——这段时间被视为潜在的干预窗口。而这些罕见的“幸运儿”，在科学家看来，是大自然提供的一个难能可贵的机会，帮助人们了解自然界中抵抗阿尔茨海默病的机制——如果发现乃至进一步模拟这些机制，将有望开发出治疗甚至是预防性的方法，并且不仅适用于受遗传性阿尔茨海默病威胁的家庭，还将适用于每一个人。互相对抗的基因，抵消疾病后果马萨诸塞州综合医院的神经心理学家Yakeel Quiroz率领团队对Aliria展开了研究。他确实发现了Aliria身上的一些特殊之处：除了PSEN1 E280A突变外，Aliria还携带了APOE3 Christchurch突变的两个拷贝，这可能是抵消了她家族阿尔茨海默病损害的原因。APOE基因编码载脂蛋白E，该蛋白在血液循环中负责运输脂质和胆固醇。APOE基因有三种常见的等位基因，即APOE2、APOE3和APOE4，其中APOE3在人群中分布最广，64%的人口为APOE3纯合。相较于APOE3，携带APOE2可以预防阿尔茨海默病，携带APOE4有增加发病的风险。Aliria携带的这个Christchurch突变，首次是在1987年在新西兰城市Christchurch的一名43岁男子身上被发现，这名男子患有III型高脂蛋白血症（hyperlipoproteinemia type III，HLPP3）。但在Aliria身上，它带来了不同寻常的影响。正如 Quiroz 及其同事现在在神经病理学杂志Acta Neuropathologica上“Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia”一文中报道的那样，Aliria的大脑确实呈现出阿尔茨海默病的病理特征，塞满了淀粉样斑块，但是tau蛋白非常少，而且分布的位置也不是在大脑的记忆中心海马体，而是在控制视觉感知的枕叶皮层。图2 研究成果（图源：[4]）研究的共同第一作者、麻省总医院神经内科的研究院Justin Sanchez表示：“这名患者让我们了解到，在阿尔茨海默病的进展中，存在着许多相互对抗的力量，比如异常蛋白质的积累、炎症、脂质代谢、稳态机制。这些机制或者推动了疾病的发展，或者阻碍进展，这给了我们能够解释为什么某些脑区可以幸免而某些脑区不行的可能。”Quiroz团队进一步使用Aliria和另一位哥伦比亚患者的细胞在实验室培养皿中培养成为脑组织。结果发现，具有Christchurch突变的细胞产生较少的tau蛋白。“因此，Christchurch突变可能会影响tau蛋白病理学的分布，调节常染色体显性阿尔茨海默病的发病年龄、严重程度、进展和临床表现，从而提出可能的治疗策略。”研究人员写道。长期以来，对抗淀粉样蛋白一直被认为是治疗阿尔茨海默病的关键，但这一发现动摇了这一观点。“也许，我们只需要阻止它的下游。”国家老龄化研究所所长Richard Hodes博士说。逃生通道不止一条，探秘道路仍然漫长目光回到Doug Whitney身上，但是他并没有Christchurch突变。因此，圣路易斯华盛顿大学的研究人员正在追踪另一条线索：也许Doug的免疫系统有某种特殊之处，能够保护他的大脑。“逃生通道不止一条。”Hodes补充说。目前，华盛顿大学的研究人员追踪了多个受阿尔茨海默病影响的家庭的约600名成员，最近，另一名与Doug无亲属关系的“逃脱者”也进入了华盛顿大学团队的视线。在哥伦比亚，Quiroz团队也在调查潜在的更多“逃脱者”。寻找答案不仅仅是科学家的追求。Doug的儿子Brian Whitney也继承了致病的家族基因，而且他已经到了关键的50岁，虽然还没有出现任何症状，但谁也无法保证将来会怎样。Brian也是华盛顿大学研究的志愿者，他大约每年需要抽出25天时间，前往远离住址的地方接受不同的健康检查和实验程序，包括每两周一次的实验性抗淀粉样蛋白药物的注射和定期的脑部扫描。尽管这些研究有时令他苦恼甚至想要中止，但当他想起12岁的女儿Emily时，这些念头就消失了。Emily还没有检查过是否继承了家族的致病基因。Brian希望，到Emily成年时，会有一些答案已浮出水面。责编|风立宵校对|风立宵End参考资料：[1]https://medicalxpress.com/news/2023-03-alzheimer-clues-genetic-fate.html[2]https://news.harvard.edu/gazette/story/2022/08/alzheimers-defying-brain-offers-clues-to-treatment-prevention/[3]https://www.alzforum.org/mutations/apoe-r154s-christchurc [4]Sepulveda-Falla, D., Sanchez, J.S., Almeida, M.C. et al. Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer’s dementia. Acta Neuropathol 144, 589–601 (2022). https://doi.org/10.1007/s00401-022-02467-8 本文系生物探索原创，欢迎个人转发分享。其他任何媒体、网站如需转载，须在正文前注明来源生物探索。往期精选围观 ‍全世界只有2个男孩患有这种罕见病，两家人成立了基金会想要攻克它！热文肌动蛋白是卵子质量下降的关键！女性生育力“断崖式下跌”又一机制探明！热文Science Advances：黏连蛋白新功能发现，影响基因的选择性剪接，突变则将导致癌症！热文发现引起T细胞耗竭的关键复合物，有望提高T细胞疗法持久抗癌能力！热文世界DNA日，致敬双螺旋结构发现70周年点击“阅读原文”，了解更多~

临床研究临床结果

2023-02-09

·生物谷

载脂蛋白E基因产物载脂蛋白E在脂代谢、免疫调节和神经学中起着关键作用。载脂蛋白E基因产物载脂蛋白E在脂代谢、免疫调节和神经学中起着关键作用。三个最常见的载脂蛋白E等位基因ε2、ε3和ε4对应于三种蛋白质亚型：载脂蛋白2、载脂蛋白3和载脂蛋白4，它们只在第112和158位氨基酸上存在差异。作为主要的脂质载体之一，APOE将脂质转运到细胞和组织中，并调节血脂水平。与其在脂质代谢中的功能一致，APOE与许多细胞表面受体具有高亲和力，包括低密度脂蛋白受体和HSPG受体。与APOE3(Cys112/Arg158)或APOE4(Arg112/Arg158)相比，APOE2(Cys112/Cys158)与低密度脂蛋白受体的结合较弱，与III型高脂蛋白血症的隐性形式有关。图片来源: https://doi.org/10.1038/s41422-022-00759-y 近日，来自西湖大学的研究者们在Cell Research杂志上发表了题为“LilrB3 is a putative cell surface receptor of APOE4”的文章，该研究揭示了LilrB3可能是载脂蛋白4的细胞表面受体。载脂蛋白E的三种异构体(APOE2、APOE3和APOE4)只在两个氨基酸位置上有所不同，但发挥着截然不同的免疫调节作用。这种载脂蛋白E异构体依赖的潜在机制仍然是个谜。在本研究中，研究者证明了APOE4，而不是APOE2，与白细胞免疫球蛋白样受体B3(LilrB3)特异性地相互作用。LilrB3胞外区(ECD)的两个离散的免疫球蛋白样结构域识别APOE4的N-末端结构域(NTD)上的正电荷表面补丁。原子结构揭示了两个APOE4分子是如何与两个LilrB3分子特异性结合的，通过形成异四聚体复合体使它们的细胞内信号基序接近。与本研究的生化和结构分析一致，APOE4，而不是APOE2，以LilrB3依赖的方式激活人小胶质细胞(HMC3)进入促炎状态。总之，本研究确认LilrB3可能是APOE4的免疫细胞表面受体，而不是APOE2，这可能对理解APOE亚型的生物学功能以及与疾病的相关性有一定的意义。 LilrB3消融的HMC3细胞对APOE4不再有反应图片来源: https://doi.org/10.1038/s41422-022-00759-y 总之，LilrB3已被确定为APOE4的特异性细胞表面受体，但不是APOE2。这种特定的配体-受体识别的结构基础已经被阐明。LilrB3与APOE4结合，而不是APOE2结合，触发以激活干扰素反应为特征的小胶质细胞HMC3的激活。这些实验结果揭示了载脂蛋白E亚型依赖的功能和疾病的线索。（生物谷 Bioon.com）参考文献 Jiayao Zhou et al. LilrB3 is a putative cell surface receptor of APOE4. Cell Res. 2023 Feb;33(2):116-130. doi: 10.1038/s41422-022-00759-y.

Cell Research:最新发现 LilrB3在脂代谢、免疫调节和神经学作用的新机制

免疫疗法临床结果

2022-08-17

·PRNewswire

Boston Heart Diagnostics Launches LipidSeq™-- An NGS Test for Common Genetic Disorders of Lipid Metabolism

FRAMINGHAM, Mass. , Aug. 17, 2022 /PRNewswire/ -- Boston Heart Diagnostics, part of the Eurofins network of companies, announces the launch of LipidSeq™, a revolutionary genetic test for cardiovascular disease. This saliva-based NGS test identifies the most common genetic causes of lipid and lipoprotein disorders. These disorders are associated with premature cardiovascular, pancreatic, kidney, and neurological diseases. Continue Reading When patients have very high levels of low-density lipoprotein cholesterol, triglycerides, or plasma sterols and/or very low levels of high-density lipoprotein cholesterol, there is a likelihood of a genetic mutation. Conditions detected by this 23-gene test include familial forms of hypercholesterolemia, lysosomal acid lipase deficiency, sitosterolemia, cerebrotendinous xanthomatosis, dysbetalipoproteinemia, hypertriglyceridemia, and HDL deficiency states including ApoA-I deficiency, Tangier disease, and LCAT deficiency, as well as other disorders. If there is a genetic basis for the patient's condition, understanding the specific mutation and associated disease can help guide treatment considerations, educate the patient about health risks, and encourage relatives to seek testing to determine if they, too, may be at risk. Boston Heart is the only commercial laboratory able to test biochemical and genetic contributors when diagnosing inherited disorders of lipid metabolism (Reference: Schaefer EJ, Geller AS, Endress G. The biochemical and genetic diagnosis of lipid disorders. Current Opinion in Lipidology 2019; 30:56-62.) Boston Heart Diagnostics announces the launch of LipidSeq™, a revolutionary genetic test for cardiovascular disease. Tweet this Testing of appropriate patients can be done at any age, which favors early identification and treatment of genetically influenced lipid and lipoprotein disorders. Early diagnosis and precision treatment can save lives, and have a significant clinical impact for practitioners, patients, and their families. LipidSeq was developed in collaboration with Eurofins laboratory partner Clinical Enterprise, which performs the genetic sequencing, and in consultation with Dr. Robert A. Hegele of Robarts Research Institute in London, Ontario. Healthcare providers may access this testing for their patients by signing up for an account with Boston Heart. The Boston Heart Customer Care department is available at 877.425.1252 or [email protected]. About Boston Heart Diagnostics Corporation Boston Heart Diagnostics, a subsidiary of Eurofins Scientific (EUFI.PA), is transforming the treatment of cardiovascular disease and related conditions by providing healthcare providers and their patients with novel, personalized diagnostics and integrated customized lifestyle programs that have the power to change the way clinicians and patients communicate about disease and improve health. For more information on Boston Heart Diagnostics, please visit SOURCE Boston Heart Diagnostics