Low apolipoprotein A-I levels in Friedreich's ataxia and in frataxin-deficient cells: Implications for therapy.
Low apolipoprotein A-I levels in Friedreich's ataxia and in frataxin-deficient cells: Implications for therapy.
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DOI：
10.1371/journal.pone.0192779
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Blair IA
中科院分区：
文献类型：
--
作者：
Wang Q;Guo L;Strawser CJ;Hauser LA;Hwang WT;Snyder NW;Lynch DR;Mesaros C;Blair IA
弗里德赖希共济失调（FA）是一种常染色体隐性遗传性神经退行性疾病，其主要由线粒体蛋白共济失调蛋白（frataxin）表达减少引起。FA在人群中的患病率估计为1/50，000，使其成为最常见的遗传性共济失调。奇怪的是，死亡率最常由心肌病和心力衰竭引起，而不是神经系统影响。一般人群中高密度脂蛋白（HDL）和载脂蛋白A-I（ApoA-I）水平降低与心肌病和心力衰竭死亡风险增加相关。然而，FA中心脏病的病理生理学是非血管性的，并且FA中HDL-胆固醇的数据相互矛盾。两项研究表明，与对照组相比，HDL-胆固醇降低，两项研究表明FA与对照组之间没有差异。一项研究还表明，与对照组相比，FA中血清Apo-A-I水平无差异。使用基于高度特异性稳定同位素稀释质谱的测定，我们证明FA患者（134.8 mg/dL，n = 95）的血清ApoA-I与未受影响的对照组（172.1 mg/dL，n = 95）相比降低了21.6%。这与非吸烟者和吸烟者之间血清ApoA-I水平的差异相似。在人肝癌HepG 2细胞中敲减Frataxin> 70%导致分泌的ApoA-I减少20%。辛伐他汀，一种3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，在对照HepG 2细胞中引起HMG-CoA增加200%，在frataxin敲低的HepG 2细胞中类似地增加，回到在对照细胞中发现的水平。与辛伐他汀处理的对照细胞中发现的水平相比，分泌的ApoA-I伴随增加20%。这项研究提供了令人信服的证据表明，与对照组相比，FA患者的ApoA-I水平降低，并表明他汀类药物治疗将使ApoA-I水平正常化。
Friedreich’s ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure. However, the pathophysiology of heart disease in FA is non-vascular and there are conflicting data on HDL-cholesterol in FA. Two studies have shown a decrease in HDL-cholesterol compared with controls and two have shown there was no difference between FA and controls. One also showed that there was no difference in serum Apo-A-I levels in FA when compared with controls. Using a highly specific stable isotope dilution mass spectrometry-based assay, we demonstrated a 21.6% decrease in serum ApoA-I in FA patients (134.8 mg/dL, n = 95) compared with non-affected controls (172.1 mg/dL, n = 95). This is similar to the difference in serum ApoA-I levels between non-smokers and tobacco smokers. Knockdown of frataxin by > 70% in human hepatoma HepG2 cells caused a 20% reduction in secreted ApoA-I. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor caused a 200% increase in HMG-CoA in the control HepG2 cells with a similar increase in the frataxin knockdown HepG2 cells, back to levels found in the control cells. There was a concomitant 20% increase in secreted ApoA-I to levels found in the control cells that were treated with simvastatin. This study provides compelling evidence that ApoA-I levels are reduced in FA patients compared with controls and suggest that statin treatment would normalize the ApoA-I levels.
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