From the Department of Genome Research and Clinical Application, Graduate School of Medicine (M.K., S.A., Y.A., H.B.) and Center for Advanced Medicine, Chiba University Hospital (M.K.), Chiba University, Chiba, Japan; Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.G.H., E.S.G.S.); Department of Nephrology in Internal Medicine, Kitasato University Hospital, Sagamihara, Japan (K.K.); Department of Internal Medicine and Molecular Science, Osaka University Graduate School of Medicine, Suita, Japan (S.Y.); Division of Endocrinology and Metabolism, Department of Medicine, Diabetes Center, Jichi Medical University, Shimotsuke, Japan (S.I.); Chiba University, Chiba, Japan (Y.S.); and Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Sakura, Japan (H.B.).
Arterioscler Thromb Vasc Biol. 2014 Aug;34(8):1756-62. doi: 10.1161/ATVBAHA.114.303420. Epub 2014 May 29.
In familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD), deposition of abnormal lipoproteins in the renal stroma ultimately leads to renal failure. However, fish-eye disease (FED) does not lead to renal damage although the causative mutations for both FLD and FED lie within the same LCAT gene. This study was performed to identify the lipoproteins important for the development of renal failure in genetically diagnosed FLD in comparison with FED, using high-performance liquid chromatography with a gel filtration column.
Lipoprotein profiles of 9 patients with LCAT deficiency were examined. Four lipoprotein fractions specific to both FLD and FED were identified: (1) large lipoproteins (>80 nm), (2) lipoproteins corresponding to large low-density lipoprotein (LDL), (3) lipoproteins corresponding to small LDL to large high-density lipoprotein, and (4) to small high-density lipoprotein. Contents of cholesteryl ester and triglyceride of the large LDL in FLD (below detection limit and 45.8±3.8%) and FED (20.7±6.4% and 28.0±6.5%) were significantly different, respectively. On in vitro incubation with recombinant LCAT, content of cholesteryl ester in the large LDL in FLD, but not in FED, was significantly increased (to 4.2±1.4%), whereas dysfunctional high-density lipoprotein was diminished in both FLD and FED.
Our novel analytic approach using high-performance liquid chromatography with a gel filtration column identified large LDL and high-density lipoprotein with a composition specific to FLD, but not to FED. The abnormal lipoproteins were sensitive to treatment with recombinant LCAT and thus may play a causal role in the renal pathology of FLD.
在家族性卵磷脂胆固醇酰基转移酶（LCAT）缺乏症（FLD）中，异常脂蛋白在肾间质中的沉积最终导致肾衰竭。然而，尽管导致 FLD 和 FED 的突变都位于相同的 LCAT 基因内，但鱼眼病（FED）并不会导致肾脏损伤。本研究旨在使用带有凝胶过滤柱的高效液相色谱法，比较遗传性诊断为 FLD 的患者和 FED 患者，确定导致肾衰竭的重要脂蛋白。
检查了 9 例 LCAT 缺乏症患者的脂蛋白谱。鉴定出与 FLD 和 FED 都相关的 4 种脂蛋白亚类：（1）大脂蛋白（>80nm），（2）与大 LDL 对应的脂蛋白，（3）与小 LDL 到大 HDL 的脂蛋白，以及（4）与小 HDL 对应的脂蛋白。FLD（低于检测限和 45.8±3.8%）和 FED（20.7±6.4%和 28.0±6.5%）中的大 LDL 中的胆固醇酯和甘油三酯含量有显著差异。在体外与重组 LCAT 孵育后，FLD 中的大 LDL 中的胆固醇酯含量显著增加（增加至 4.2±1.4%），但 FED 中的含量没有增加，而功能失调的高密度脂蛋白在 FLD 和 FED 中都减少了。
我们使用带有凝胶过滤柱的高效液相色谱法的新分析方法鉴定了 FLD 特异性而非 FED 特异性的大 LDL 和高密度脂蛋白。异常脂蛋白对重组 LCAT 的治疗敏感，因此可能在 FLD 的肾脏病理中起因果作用。
